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    Clinical Trial Results:
    A Study of INT-747 (6-ECDCA) Monotherapy in Patients with Primary Biliary Cirrhosis

    Summary
    EudraCT number
    		 2007-001424-12
    Trial protocol
    		 GB   FR   ES   AT   DE  
    Global end of trial date
    25 Sep 2017

    Results information
    Results version number
    		 v3(current)
    This version publication date
    25 Apr 2021
    First version publication date
    21 May 2016
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    correcting the errors in the section of non-serious AE
    Summary report(s)
    		 Intercept Study 747-201 Results

    Trial information

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    Trial identification
    Sponsor protocol code
    747-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00570765
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Intercept Pharmaceuticals, Inc.
    Sponsor organisation address
    9520 Towne Centre Drive, Suite 200, San Diego, CA, United States, 92121
    Public contact
    Medical Information, Intercept Pharmaceuticals, Inc., +1 844-782-4278, medinfo@interceptpharma.com
    Scientific contact
    Medical Information, Intercept Pharmaceuticals, Inc., +1 844-782-4278, medinfo@interceptpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of obeticholic acid (OCA) in participants with primary biliary cirrhosis (PBC) on alkaline phosphatase (AP) levels and safety.
    Protection of trial subjects
    This study was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 8 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Spain: 2
    Worldwide total number of subjects
    60
    EEA total number of subjects
    34
    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)
    50
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started 12/2007 and completed in 6/2010. Due to positive Phase 2 data in another study (2007-001425-10), power calculations were revised and recruitment ended early. Eligible participants who received treatment in the double-blind (DB) phase could continue receiving obeticholic acid (OCA) in the long-term safety extension (LTSE) phase.

    Pre-assignment
    Screening details
    		 Screening interim allowed for pre-randomization eligibility assessment of 1 to 4 weeks. Other than a 3-month (pre-Screening) washout for ursodeoxycholic acid (UDCA) and other medications, no washout or run-in period was defined between Screening and randomization. During LTSE, OCA dosing (milligrams [mg]) remained oral once daily.

    Period 1
    Period 1 title
    Double-Blind
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DB OCA 10 mg
    Arm description
    		 OCA 10 mg for 3 months during the DB phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Obeticholic Acid
    Investigational medicinal product code
    Other name
    INT-747, 6α-ethyl-chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    OCA 10 mg was administered orally once daily.

    Arm title
    		 DB OCA 50 mg
    Arm description
    		 OCA 50 mg for 3 months during the DB phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Obeticholic Acid
    Investigational medicinal product code
    Other name
    INT-747, 6α-ethyl-chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    OCA 50 mg was administered orally once daily.

    Arm title
    		 DB OCA Placebo
    Arm description
    		 Matching placebo for 3 months during the DB phase.
    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
    Placebo capsule was administered orally once daily.

    Number of subjects in period 1
    		DB OCA 10 mg DB OCA 50 mg DB OCA Placebo
    Started
    20
    16
    24
    Received at Least 1 Dose of Study Drug
    20
    16
    23
    Safety Population
    20
    16
    23
    Completed
    16
    9
    23
    Not completed
    4
    7
    1
         Consent withdrawn by subject
    1
    -
    -
         Did Not Receive Study Drug
    -
    -
    1
         Adverse event, non-fatal
    3
    6
    -
         Protocol deviation
    -
    1
    -
    Period 2
    Period 2 title
    Long-Term Safety Extension (LTSE) Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 LTSE OCA Total
    Arm description
    		 After completion of the 3-month DB phase, all eligible participants were offered the opportunity to enter an open-label LTSE for up to 96 months beginning at 10 mg OCA. Doses up to 50 mg daily were evaluated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Obeticholic Acid
    Investigational medicinal product code
    Other name
    INT-747, 6α-ethyl-chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OCA was administered orally once daily and provided either in capsule or tablet forms. Capsules for the LTSE phase were provided at OCA dose strengths of 10, 25, and 50 mg while tablets were provided at OCA dose strengths of 10 and 25 mg.

    Number of subjects in period 2 [1]
    		LTSE OCA Total
    Started
    28
    Safety Population
    28
    Completed
    16
    Not completed
    12
         Consent withdrawn by subject
    1
         Physician decision
    4
         Adverse event, non-fatal
    7
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Eligible participants who completed the DB phase could choose to enroll in the LTSE phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DB OCA 10 mg
    Reporting group description
    		 OCA 10 mg for 3 months during the DB phase.

    Reporting group title
    DB OCA 50 mg
    Reporting group description
    		 OCA 50 mg for 3 months during the DB phase.

    Reporting group title
    DB OCA Placebo
    Reporting group description
    		 Matching placebo for 3 months during the DB phase.

    Reporting group values
    		 DB OCA 10 mg DB OCA 50 mg DB OCA Placebo Total
    Number of subjects
    		 20 16 24 60
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 16 15 19 50
        >=65 years
    		 4 1 5 10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.8 ( 10.9 ) 54.1 ( 7.3 ) 55.3 ( 10.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 16 21 51
        Male
    		 6 0 3 9
    Region of Enrollment
    Units: Subjects
        France
    		 2 1 1 4
        United States
    		 4 5 8 17
        Canada
    		 3 2 4 9
        Spain
    		 0 1 1 2
        Germany
    		 4 1 3 8
        United Kingdom
    		 7 6 7 20

    End points

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    End points reporting groups
    Reporting group title
    DB OCA 10 mg
    Reporting group description
    		 OCA 10 mg for 3 months during the DB phase.

    Reporting group title
    DB OCA 50 mg
    Reporting group description
    		 OCA 50 mg for 3 months during the DB phase.

    Reporting group title
    DB OCA Placebo
    Reporting group description
    		 Matching placebo for 3 months during the DB phase.
    Reporting group title
    LTSE OCA Total
    Reporting group description
    		 After completion of the 3-month DB phase, all eligible participants were offered the opportunity to enter an open-label LTSE for up to 96 months beginning at 10 mg OCA. Doses up to 50 mg daily were evaluated.

    Primary: DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85

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    End point title
    		 DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85
    End point description
    The percent change in serum ALP from baseline to Day 85 is reported. The baseline value used was the mean of the pretreatment Screening and Day 0 evaluations.
    End point type
    Primary
    End point timeframe
    Baseline, Day 85
    End point values
    		 DB OCA 10 mg DB OCA 50 mg DB OCA Placebo
    Number of subjects analysed
    20
    16
    23
    Units: Percent change
        arithmetic mean (standard deviation)
    -44.5 ( 24.4 )
    -37.6 ( 21.0 )
    0.4 ( 15.3 )
    Statistical analysis title
    		 Percent Change From Baseline to Day 85: Serum ALP
    Comparison groups
    DB OCA 10 mg v DB OCA 50 mg v DB OCA Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Hierarchical testing strategy was proposed to account for multiple comparisons. Statistical significance was evaluated as follows: if statistical significance at alpha=0.05 is shown for the 10 mg OCA versus placebo, then the statistical significance at alpha=0.05 for the 50 mg OCA versus placebo was evaluated. If no statistical significance was shown at alpha=0.05 at the first step, then the subsequent comparison was not considered statistically significant.

    Secondary: DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85

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    End point title
    		 DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to Day 85 is reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    End point values
    		 DB OCA 10 mg DB OCA 50 mg DB OCA Placebo
    Number of subjects analysed
    19
    15
    22
    Units: Percent change
        arithmetic mean (standard deviation)
    -73 ( 18 )
    -65 ( 25 )
    -3 ( 22 )
    Statistical analysis title
    		 Percent Change in GGT From Baseline to Day 85
    Comparison groups
    DB OCA 10 mg v DB OCA 50 mg v DB OCA Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85

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    End point title
    		 DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to Day 85 is reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    End point values
    		 DB OCA 10 mg DB OCA 50 mg DB OCA Placebo
    Number of subjects analysed
    19
    15
    22
    Units: Percent change
        arithmetic mean (standard deviation)
    -37 ( 35 )
    -35 ( 25 )
    -4 ( 40 )
    Statistical analysis title
    		 Percent Change in ALT From Baseline to Day 85
    Comparison groups
    DB OCA 10 mg v DB OCA 50 mg v DB OCA Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85

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    End point title
    		 DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to Day 85 is reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    End point values
    		 DB OCA 10 mg DB OCA 50 mg DB OCA Placebo
    Number of subjects analysed
    18
    15
    22
    Units: Percent change
        arithmetic mean (standard deviation)
    0.7 ( 67.3 )
    -1.7 ( 39.9 )
    30.3 ( 69.8 )
    No statistical analyses for this end point

    Secondary: LTSE Phase: Median Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit

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    End point title
    		 LTSE Phase: Median Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit
    End point description
    The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28 [2]
    Units: Percent change
    median (inter-quartile range (Q1-Q3))
        Month 24
    -43.1 (-61.3 to -20.2)
        Month 48
    -44.4 (-65.5 to -18.6)
        Month 72
    -33.4 (-64.5 to -17.9)
        Last Available Visit
    -31.8 (-57.5 to -14.0)
    Notes
    [2] - Month 24 (N=23); Month 48 (N=19); Month 72 (N=17); Last Available Visit (N=28)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Mean Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit

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    End point title
    		 LTSE Phase: Mean Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit
    End point description
    The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months).
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28 [3]
    Units: Percent change
    arithmetic mean (standard deviation)
        Month 24
    -38.8 ( 29.7 )
        Month 48
    -39.3 ( 36.6 )
        Month 72
    -31.7 ( 57.3 )
        Last Available Visit
    -30.4 ( 36.6 )
    Notes
    [3] - Month 24 (N=23); Month 48 (N=19); Month 72 (N=17); Last Available Visit (N=28)
    No statistical analyses for this end point

    Secondary: LTSE: Median Percent Change In GGT From Baseline To Last Available Visit

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    End point title
    		 LTSE: Median Percent Change In GGT From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    -71.1 (-84.3 to -33.8)
    No statistical analyses for this end point

    Secondary: LTSE: Mean Percent Change In GGT From Baseline To Last Available Visit

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    End point title
    		 LTSE: Mean Percent Change In GGT From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent change
        arithmetic mean (standard deviation)
    -55.6 ( 41.4 )
    No statistical analyses for this end point

    Secondary: LTSE: Median Percent Change In ALT From Baseline To Last Available Visit

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    End point title
    		 LTSE: Median Percent Change In ALT From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    -52.2 (-68.4 to -11.6)
    No statistical analyses for this end point

    Secondary: LTSE: Mean Percent Change In ALT From Baseline To Last Available Visit

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    End point title
    		 LTSE: Mean Percent Change In ALT From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to the last available visit is reported. The DB baseline value was used as the baseline. Baseline (DB), Last Available Visit (up to 96 months)
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent change
        arithmetic mean (standard deviation)
    -39.6 ( 42.8 )
    No statistical analyses for this end point

    Secondary: LTSE: Median Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit

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    End point title
    		 LTSE: Median Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    33.3 (-11.1 to 100.0)
    No statistical analyses for this end point

    Secondary: LTSE: Mean Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit

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    End point title
    		 LTSE: Mean Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent change
        arithmetic mean (standard deviation)
    57.8 ( 103.0 )
    No statistical analyses for this end point

    Secondary: LTSE: Median Percent Change In Total Bilirubin From Baseline To Last Available Visit

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    End point title
    		 LTSE: Median Percent Change In Total Bilirubin From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in total bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    5.2 (-21.4 to 25.2)
    No statistical analyses for this end point

    Secondary: LTSE: Mean Percent Change In Total Bilirubin From Baseline To Last Available Visit

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    End point title
    		 LTSE: Mean Percent Change In Total Bilirubin From Baseline To Last Available Visit
    End point description
    As a marker of hepatocellular injury and liver function, the percent change in total bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (DB), Last Available Visit (up to 96 months)
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    28
    Units: Percent Change
        arithmetic mean (standard deviation)
    2.2 ( 35.1 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DB: Adverse events were collected starting when the participant took the first dose of study medication (following Day 0) and during study participation, through the follow-up visit at Month 3. LSTE: Baseline (DB Month 3) up to 96 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    DB OCA 10 mg
    Reporting group description
    		 OCA 10 mg for 3 months during the DB phase.

    Reporting group title
    DB OCA Placebo
    Reporting group description
    		 Matching placebo for 3 months during the DB phase.

    Reporting group title
    LTSE OCA Total
    Reporting group description
    		 After completion of the 3-month DB phase, all participants were offered the opportunity to enter an open-label LTSE for up to 96 months beginning at 10 mg OCA. Doses up to 50 mg daily were evaluated.

    Reporting group title
    DB OCA 50 mg
    Reporting group description
    		 OCA 50 mg for 3 months during the DB phase.

    Serious adverse events
    		 DB OCA 10 mg DB OCA Placebo LTSE OCA Total DB OCA 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    9 / 28 (32.14%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed [1]
    0 / 14 (0.00%)
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed [2]
    0 / 14 (0.00%)
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event affected only female participants.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event affected only female participants.
    Frequency threshold for reporting non-serious adverse events: 4.99%
    Non-serious adverse events
    		 DB OCA 10 mg DB OCA Placebo LTSE OCA Total DB OCA 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 20 (90.00%)
    19 / 23 (82.61%)
    28 / 28 (100.00%)
    16 / 16 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Lipoma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Lung neoplasm
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Thyroid neoplasm
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Varicose vein
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Chest discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Chills
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Fatigue
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 23 (13.04%)
    14 / 28 (50.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    3
    16
    1
    Feeling cold
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    3 / 28 (10.71%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    7
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    7 / 28 (25.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    11
    0
    Pyrexia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Sarcoidosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Breast tenderness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gynaecomastia
         subjects affected / exposed [3]
    1 / 14 (7.14%)
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Menorrhagia
         subjects affected / exposed [4]
    1 / 14 (7.14%)
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Ovarian cyst
         subjects affected / exposed [5]
    0 / 14 (0.00%)
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    5 / 28 (17.86%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    5
    1
    Dyspnoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nasal congestion
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sinus congestion
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    5 / 28 (17.86%)
    2 / 16 (12.50%)
         occurrences all number
    2
    1
    6
    2
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Weight decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    3
    1
    White blood cells urine
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Fall
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    5 / 28 (17.86%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Patella fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Post-traumatic pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Procedural pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Palpitations
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 23 (17.39%)
    5 / 28 (17.86%)
    0 / 16 (0.00%)
         occurrences all number
    0
    5
    5
    0
    Facial neuralgia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    4 / 20 (20.00%)
    5 / 23 (21.74%)
    8 / 28 (28.57%)
    2 / 16 (12.50%)
         occurrences all number
    5
    6
    12
    3
    Irregular sleep phase
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Migraine
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    6
    1
    Paraesthesia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Coagulopathy
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lymphoid tissue hyperplasia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dry eye
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    3 / 28 (10.71%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    3
    1
    Iritis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Abdominal distension
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    6 / 28 (21.43%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    8
    2
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    6 / 28 (21.43%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    10
    2
    Abdominal pain lower
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    7 / 28 (25.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    10
    0
    Abdominal tenderness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Coeliac disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Colonic polyp
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    9 / 28 (32.14%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    11
    2
    Diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    8 / 28 (28.57%)
    2 / 16 (12.50%)
         occurrences all number
    0
    1
    12
    2
    Diverticulum
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Dry mouth
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    5
    0
    Dyspepsia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Faecal incontinence
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Faeces pale
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    2
    Flatulence
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    5 / 28 (17.86%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    7
    1
    Glossodynia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    5 / 28 (17.86%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    5
    2
    Hiatus hernia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nausea
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 23 (17.39%)
    11 / 28 (39.29%)
    4 / 16 (25.00%)
         occurrences all number
    0
    5
    19
    4
    Oesophagitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Parotid gland enlargement
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Salivary gland enlargement
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    1 / 28 (3.57%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    3
    1
    Vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    4 / 28 (14.29%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    8
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Hepatic pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Dry skin
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    1 / 28 (3.57%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    1
    1
    Eczema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Lichen planus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    14 / 20 (70.00%)
    7 / 23 (30.43%)
    25 / 28 (89.29%)
    15 / 16 (93.75%)
         occurrences all number
    24
    11
    107
    22
    Rash
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    3 / 28 (10.71%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    3
    1
    Rash macular
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Rash papular
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Spider naevus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Vitiligo
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Renal cyst
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 23 (8.70%)
    13 / 28 (46.43%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    33
    0
    Back pain
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 23 (17.39%)
    7 / 28 (25.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    4
    8
    0
    Fibromyalgia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Muscle spasm
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 23 (4.35%)
    5 / 28 (17.86%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    7
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    5 / 28 (17.86%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    6
    0
    Myalgia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    6 / 28 (21.43%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    12
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Osteoporosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    6 / 28 (21.43%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    8
    1
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Tendonitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Cystitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    4 / 28 (14.29%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    6
    1
    Ear infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Eye infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Herpes zoster
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Laryngitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 23 (8.70%)
    3 / 28 (10.71%)
    1 / 16 (6.25%)
         occurrences all number
    3
    2
    5
    1
    Otitis media
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rhinitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sinusitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    6 / 28 (21.43%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    11
    1
    Tinea pedis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Tooth infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 23 (0.00%)
    9 / 28 (32.14%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    11
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 23 (0.00%)
    5 / 28 (17.86%)
    1 / 16 (6.25%)
         occurrences all number
    3
    0
    9
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Fluid overload
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 23 (0.00%)
    6 / 28 (21.43%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Notes
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event affected only female participants.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event affected only female participants.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event affected only female participants.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2007
    Added additional Day 8 visit of the DB phase.
    13 Nov 2008
    Added an LTSE, open-label phase.
    17 Feb 2009
    Added additional study assessments and mandated study discontinuation criteria.
    16 Jun 2009
    Added specified LTSE duration and a 2-week visit for Placebo arm in the DB phase.
    12 Feb 2010
    Correction to Schedule of Procedures.
    16 Dec 2010
    Requested an extension to previously requested 18-month LTSE phase duration.
    12 Feb 2011
    Requested an extension of duration of open-label treatment from 18 months to 36 months.
    26 Apr 2012
    Added tablet information and also included a request for an extension in duration to the LTSE phase to 54 months.
    04 Mar 2014
    Requested to further extend the study duration for an additional 18 months (to 72 months).
    30 Sep 2015
    Increased the study duration for a further 18 months (to 90 months).
    14 Feb 2017
    Revised and consolidated 2 prior amendments by removing language regarding OCA doses above 50 mg and for the United Kingdom only, extending the study duration to 108 months.

    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.
    Limitations of the study include the use of ursodeoxycholic acid that disallowed meeting key inclusion/exclusion criteria, a short double-blind phase, and the reason participants were not receiving ursodeoxycholic acid at baseline was not captured.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29023915
    For support, Contact us.
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