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    Clinical Trial Results:
    A Phase 3, Double-Blind, Placebo-Controlled Trial and Long-Term Safety Extension of Obeticholic Acid in Patients with Primary Biliary Cirrhosis

    Summary
    EudraCT number
    2011-004728-36
    Trial protocol
    BE   NL   DE   SE   AT   ES   GB   IT   PL  
    Global end of trial date
    17 Dec 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    25 Apr 2021
    First version publication date
    30 Sep 2020
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    correction of errors in the section of non-serious AE.

    Trial information

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    Trial identification
    Sponsor protocol code
    747-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01473524
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Intercept Pharmaceuticals, Inc.
    Sponsor organisation address
    4760 Eastgate Mall, San Diego/CA, United States, 92121
    Public contact
    Medical Information, Intercept Pharmaceuticals, Inc., medinfo@interceptpharma.com
    Scientific contact
    Medical Information, Intercept Pharmaceuticals, Inc., 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
    28 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the study were to assess the effects of obeticholic acid (OCA) on serum alkaline phosphatase (ALP) and total bilirubin, together as a composite endpoint and on safety in participants with primary biliary cirrhosis (PBC).
    Protection of trial subjects
    The trial was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All the local regulatory requirements pertinent to safety of trial subjects have also been followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Mar 2012
    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
    Spain: 9
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 54
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Italy: 32
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 14
    Worldwide total number of subjects
    217
    EEA total number of subjects
    146
    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)
    177
    From 65 to 84 years
    39
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment into hospitals and physicians’ clinics started January 2012 and completed December 2012.

    Pre-assignment
    Screening details
    Screening interim allowed for pre-randomization eligibility assessment of 1 to 8 weeks. A total of 217 participants were randomized into the double-blind phase of the study, however, 216 received treatment with study drug. One randomized participant discontinued prior to receiving any study drug.

    Period 1
    Period 1 title
    Double-blind (DB) Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Participants were randomized to receive OCA or matching placebo during the 12-month DB phase.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    DB OCA 5-10 mg
    Arm description
    OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for the remaining 6 months of the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    obeticholic acid
    Investigational medicinal product code
    INT-747
    Other name
    6α-ethyl chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.

    Arm title
    DB OCA 10 mg
    Arm description
    OCA 10 mg 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    obeticholic acid
    Investigational medicinal product code
    INT-747
    Other name
    6α-ethyl chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.

    Arm title
    DB Placebo
    Arm description
    Matching placebo for 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets were administered orally once daily.

    Number of subjects in period 1
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo
    Started
    71
    73
    73
    Received at least 1 dose of study drug
    70
    73
    73
    Completed
    64
    64
    70
    Not completed
    7
    9
    3
         Consent withdrawn by subject
    2
    1
    1
         Adverse event, non-fatal
    4
    8
    2
         Death
    1
    -
    -
    Period 2
    Period 2 title
    Long-Term Safety Extension (LTSE) Phase
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    LTSE OCA (DB OCA 5-10 mg)
    Arm description
    Participants previously receiving OCA 5 to 10 mg in the DB phase received OCA in the open-label long-term safety extension (LTSE) phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    obeticholic acid
    Investigational medicinal product code
    INT-747
    Other name
    6α-ethyl chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.

    Arm title
    LTSE OCA (DB OCA 10 mg)
    Arm description
    Participants previously receiving OCA 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    obeticholic acid
    Investigational medicinal product code
    INT-747
    Other name
    6α-ethyl chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.

    Arm title
    LTSE OCA (DB Placebo)
    Arm description
    Participants previously receiving placebo in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    obeticholic acid
    Investigational medicinal product code
    INT-747
    Other name
    6α-ethyl chenodeoxycholic acid (6-ECDCA)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.

    Number of subjects in period 2 [1]
    LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo)
    Started
    63
    64
    66
    Received at least 1 dose of OCA in LTSE
    63
    64
    66
    Completed
    54
    47
    45
    Not completed
    9
    17
    21
         Liver Transplantation
    -
    -
    1
         Consent withdrawn by subject
    3
    3
    6
         Principal Investigator Decision
    1
    1
    3
         Other Clinical/ Laboratory Adverse Event
    2
    4
    6
         Death
    -
    1
    -
         Pregnancy
    1
    -
    -
         Adverse Event of Pruritus
    1
    5
    2
         Protocol Violation
    -
    -
    1
         Lost to follow-up
    1
    3
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One participant in the double-blind OCA 5-10 mg group did not enroll in the LTSE phase. Four participants in the double-blind placebo group did not enroll in the LTSE phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DB OCA 5-10 mg
    Reporting group description
    OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for the remaining 6 months of the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    DB OCA 10 mg
    Reporting group description
    OCA 10 mg 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    DB Placebo
    Reporting group description
    Matching placebo for 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo Total
    Number of subjects
    71 73 73 217
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    61 56 60 177
        From 65-84 years
    10 16 13 39
        85 years and over
    0 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.7 ± 10.46 56.2 ± 11.00 55.5 ± 10.03 -
    Gender categorical
    Units: Subjects
        Female
    66 63 68 197
        Male
    5 10 5 20
    Race/Ethnicity
    Units: Subjects
        Asian
    1 1 1 3
        Black or African American
    1 1 1 3
        Other
    1 1 5 7
        White
    68 70 66 204
    Region of Enrollment
    Units: Subjects
        United States
    18 19 17 54
        United Kingdom
    8 5 9 22
        Spain
    4 2 3 9
        Canada
    2 2 4 8
        Austria
    2 0 1 3
        Netherlands
    3 7 6 16
        Sweden
    3 1 0 4
        Belgium
    2 9 5 16
        Poland
    4 6 4 14
        Italy
    11 10 11 32
        Australia
    5 1 3 9
        France
    0 0 1 1
        Germany
    9 11 9 29
    ALP
    Units: U/L
        arithmetic mean (standard deviation)
    324.78 ± 115.766 316.34 ± 103.881 327.49 ± 115.014 -
    Total Bilirubin
    Units: umol/L
        arithmetic mean (standard deviation)
    10.172 ± 5.512 11.278 ± 6.634 11.757 ± 7.227 -
    Direct Bilirubin
    Units: umol/L
        arithmetic mean (standard deviation)
    4.399 ± 4.495 4.868 ± 4.473 5.469 ± 6.214 -
    ALT
    Units: U/L
        arithmetic mean (standard deviation)
    61.66 ± 38.766 56.31 ± 39.741 55.99 ± 30.312 -
    AST
    Units: U/L
        arithmetic mean (standard deviation)
    52.32 ± 25.114 50.49 ± 31.100 48.79 ± 22.449 -
    Gamma-Glutamyltransferase
    Units: U/L
        arithmetic mean (standard deviation)
    251.11 ± 166.469 261.07 ± 207.396 309.58 ± 449.356 -
    Subject analysis sets

    Subject analysis set title
    DB OCA 5-10 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat Population: All participants who were randomized and received at least 1 dose of study drug.

    Subject analysis set title
    DB OCA 10 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat Population: All participants who were randomized and received at least 1 dose of study drug.

    Subject analysis set title
    DB Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat Population: All participants who were randomized and received at least 1 dose of study drug.

    Subject analysis set title
    Overall LTSE OCA
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    After completion of the 12-month DB phase all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Subject analysis sets values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo Overall LTSE OCA
    Number of subjects
    70
    73
    73
    193
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    60
    56
    60
    157
        From 65-84 years
    10
    16
    13
    36
        85 years and over
    0
    1
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.8 ± 10.53
    56.2 ± 11.00
    55.5 ± 10.03
    55.4 ± (10.01)
    Gender categorical
    Units: Subjects
        Female
    65
    63
    68
    177
        Male
    5
    10
    5
    16
    Race/Ethnicity
    Units: Subjects
        Asian
    1
    1
    1
    2
        Black or African American
    1
    1
    1
    3
        Other
    1
    1
    5
    7
        White
    67
    70
    66
    181
    Region of Enrollment
    Units: Subjects
        United States
    18
    19
    17
    48
        United Kingdom
    8
    5
    9
    18
        Spain
    4
    2
    3
    9
        Canada
    2
    2
    4
    8
        Austria
    2
    0
    1
    3
        Netherlands
    3
    7
    6
    15
        Sweden
    3
    1
    0
    2
        Belgium
    2
    9
    5
    15
        Poland
    4
    6
    4
    13
        Italy
    11
    10
    11
    29
        Australia
    5
    1
    3
    8
        France
    0
    0
    1
    1
        Germany
    8
    11
    9
    24
    ALP
    Units: U/L
        arithmetic mean (standard deviation)
    325.87 ± 116.238
    316.34 ± 103.881
    327.49 ± 115.014
    317.11 ± 120.153
    Total Bilirubin
    Units: umol/L
        arithmetic mean (standard deviation)
    10.192 ± 5.549
    11.278 ± 6.634
    11.757 ± 7.227
    11.483 ± 6.99
    Direct Bilirubin
    Units: umol/L
        arithmetic mean (standard deviation)
    4.398 ± 4.528
    4.868 ± 4.473
    5.469 ± 6.214
    5.259 ± 5.589
    ALT
    Units: U/L
        arithmetic mean (standard deviation)
    61.56 ± 39.037
    56.31 ± 39.741
    55.99 ± 30.312
    56.70 ± 37.030
    AST
    Units: U/L
        arithmetic mean (standard deviation)
    52.25 ± 25.289
    50.49 ± 31.100
    48.79 ± 22.449
    51.24 ± 33.485
    Gamma-Glutamyltransferase
    Units: U/L
        arithmetic mean (standard deviation)
    252.83 ± 167.038
    261.07 ± 207.396
    309.58 ± 449.356
    275.21 ± 306.020

    End points

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    End points reporting groups
    Reporting group title
    DB OCA 5-10 mg
    Reporting group description
    OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for the remaining 6 months of the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    DB OCA 10 mg
    Reporting group description
    OCA 10 mg 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    DB Placebo
    Reporting group description
    Matching placebo for 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
    Reporting group title
    LTSE OCA (DB OCA 5-10 mg)
    Reporting group description
    Participants previously receiving OCA 5 to 10 mg in the DB phase received OCA in the open-label long-term safety extension (LTSE) phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    LTSE OCA (DB OCA 10 mg)
    Reporting group description
    Participants previously receiving OCA 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    LTSE OCA (DB Placebo)
    Reporting group description
    Participants previously receiving placebo in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Subject analysis set title
    DB OCA 5-10 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat Population: All participants who were randomized and received at least 1 dose of study drug.

    Subject analysis set title
    DB OCA 10 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat Population: All participants who were randomized and received at least 1 dose of study drug.

    Subject analysis set title
    DB Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat Population: All participants who were randomized and received at least 1 dose of study drug.

    Subject analysis set title
    Overall LTSE OCA
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    After completion of the 12-month DB phase all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Primary: DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo

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    End point title
    DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo
    End point description
    Percentage of participants at Month 12 with ALP < 1.67 x upper limit of normal (ULN) and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
    End point type
    Primary
    End point timeframe
    DB Month 12
    End point values
    DB OCA 10 mg DB Placebo
    Number of subjects analysed
    73
    73
    Units: percentage of participants
        number (not applicable)
    47
    10
    Statistical analysis title
    ALP and Total Bilirubin: OCA 10 mg at Month 12
    Statistical analysis description
    Statistical analysis of composite endpoint ALP and total bilirubin.
    Comparison groups
    DB OCA 10 mg v DB Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - H0: The response rates are equal between placebo and 10 mg OCA. H1: The response rates are different between placebo and 10 mg OCA.
    [2] - Cochran–Mantel–Haenszel General Association test stratified by randomization strata factor.

    Primary: LTSE Phase: Composite Endpoint ALP And Total Bilirubin

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    End point title
    LTSE Phase: Composite Endpoint ALP And Total Bilirubin [3]
    End point description
    Percentage of participants at Months 24, 36, 48, and 60 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. DB Month 12 is the baseline for the LTSE phase.
    End point type
    Primary
    End point timeframe
    Baseline (DB Month 12), LTSE Months 24, 36, 48, and 60
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Quantitative statistical analyses were not performed for this end point.
    End point values
    LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
    Number of subjects analysed
    63 [4]
    64 [5]
    66 [6]
    193 [7]
    Units: percentage of participants
    number (not applicable)
        Baseline (Double-blind Month 12)
    51
    56
    9
    38
        LTSE Month 12
    55
    58
    41
    51
        LTSE Month 24
    60
    61
    54
    58
        LTSE Month 36
    48
    51
    49
    49
        LTSE Month 48
    52
    55
    60
    56
        LTSE Month 60
    48
    52
    50
    50
    Notes
    [4] - Baseline (63); Month 12 (60); Month 24 (57); Month 36 (56); Month 48 (50); Month 60 (31)
    [5] - Baseline (63); Month 12 (59); Month 24 (57); Month 36 (55); Month 48 (53); Month 60 (21)
    [6] - Baseline (66); Month 12 (59); Month 24 (52); Month 36 (49); Month 48 (48); Month 60 (24)
    [7] - Baseline (192); Month 12 (178); Month 24 (166); Month 36 (160); Month 48 (151); Month 60 (76)
    No statistical analyses for this end point

    Secondary: DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo

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    End point title
    DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo
    End point description
    Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
    End point type
    Secondary
    End point timeframe
    DB Month 6
    End point values
    DB OCA 10 mg DB Placebo
    Number of subjects analysed
    73
    73
    Units: percentage of participants
        number (not applicable)
    51
    7
    Statistical analysis title
    ALP and Total Bilirubin: OCA 10 mg at Month 6
    Statistical analysis description
    Statistical analysis of composite endpoint ALP and total bilirubin.
    Comparison groups
    DB OCA 10 mg v DB Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    < 0.0001 [9]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [8] - H0: The response rates are equal between placebo and 10 mg OCA. H1: The response rates are different between placebo and 10 mg OCA.
    [9] - Cochran–Mantel–Haenszel General Association test stratified by randomization strata factor.

    Secondary: DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo

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    End point title
    DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo
    End point description
    Percentage of participants at Month 12 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
    End point type
    Secondary
    End point timeframe
    DB Month 12
    End point values
    DB OCA 5-10 mg DB Placebo
    Number of subjects analysed
    70
    73
    Units: percentage of participants
        number (not applicable)
    46
    10
    Statistical analysis title
    ALP and Total Bilirubin: OCA 5-10 mg at Month 12
    Statistical analysis description
    Statistical analysis of composite endpoint ALP and total bilirubin.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    < 0.0001 [11]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [10] - H0: The response rates are equal between placebo and 5-10 mg OCA. H1: The response rates are different between placebo and 5-10 mg OCA.
    [11] - Cochran–Mantel–Haenszel General Association test stratified by randomization strata factor.

    Secondary: DB Phase: Composite Endpoint ALP and Total Bilirubin, 5-10 mg Versus Placebo

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    End point title
    DB Phase: Composite Endpoint ALP and Total Bilirubin, 5-10 mg Versus Placebo
    End point description
    Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
    End point type
    Secondary
    End point timeframe
    DB Month 6
    End point values
    DB OCA 5-10 mg DB Placebo
    Number of subjects analysed
    70
    73
    Units: percentage of participants
        number (not applicable)
    34
    7
    Statistical analysis title
    ALP and Total Bilirubin: OCA 5-10 mg at Month 6
    Statistical analysis description
    Statistical analysis of composite endpoint ALP and total bilirubin.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    < 0.0001 [13]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [12] - H0: The response rates are equal between placebo and 5-10 mg OCA. H1: The response rates are different between placebo and 5-10 mg OCA.
    [13] - Cochran–Mantel–Haenszel General Association test stratified by randomization strata factor.

    Secondary: DB Phase: ALP Absolute Change From Baseline To Month 12

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    End point title
    DB Phase: ALP Absolute Change From Baseline To Month 12
    End point description
    Blood samples were evaluated for ALP levels. ALP Absolute Change From Baseline (ALP at Month 12 - ALP at Baseline) is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Month 12
    End point values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo
    Number of subjects analysed
    64 [14]
    62 [15]
    70 [16]
    Units: U/L
        least squares mean (standard error)
    -112.51 ± 14.36
    -129.90 ± 14.60
    -14.42 ± 14.74
    Notes
    [14] - Participants who had analyzable data at the specified timepoint.
    [15] - Participants who had analyzable data at the specified timepoint.
    [16] - Participants who had analyzable data at the specified timepoint.
    Statistical analysis title
    ALP Change From Baseline To Month 12
    Statistical analysis description
    Statistical analysis of the ALP change from baseline to Month 12.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    ANCOVA
    Confidence interval
    Notes
    [17] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
    Statistical analysis title
    ALP Change From Baseline To Month 12
    Statistical analysis description
    Statistical analysis of the ALP change from baseline to Month 12.
    Comparison groups
    DB Placebo v DB OCA 10 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    ANCOVA
    Confidence interval
    Notes
    [18] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

    Secondary: DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12

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    End point title
    DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12
    End point description
    Blood samples were evaluated for bilirubin levels. Total bilirubin absolute change from baseline (total bilirubin at Month 12 - total bilirubin at Baseline) is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Month 12
    End point values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo
    Number of subjects analysed
    64 [19]
    62 [20]
    70 [21]
    Units: umol/L
        least squares mean (standard error)
    -0.33 ± 0.68
    -0.90 ± 0.71
    1.98 ± 0.70
    Notes
    [19] - Had analyzable data at the specified timepoint.
    [20] - Had analyzable data at the specified timepoint.
    [21] - Had analyzable data at the specified timepoint.
    Statistical analysis title
    Total Bilirubin Change From Baseline to Month 12
    Statistical analysis description
    Statistical analysis of the total bilirubin change from baseline to Month 12.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [22]
    Method
    ANCOVA
    Confidence interval
    Notes
    [22] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
    Statistical analysis title
    Total Bilirubin Change From Baseline to Month 12
    Statistical analysis description
    Statistical analysis of the total bilirubin change from baseline to Month 12.
    Comparison groups
    DB Placebo v DB OCA 10 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    ANCOVA
    Confidence interval
    Notes
    [23] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

    Secondary: DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12

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    End point title
    DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12
    End point description
    Blood samples were evaluated for bilirubin levels. Direct bilirubin absolute change from baseline (direct bilirubin at Month 12 - direct bilirubin at Baseline) is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Month 12
    End point values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo
    Number of subjects analysed
    64 [24]
    62 [25]
    70 [26]
    Units: umol/L
        least squares mean (standard error)
    -0.13 ± 0.52
    -0.49 ± 0.54
    1.89 ± 0.53
    Notes
    [24] - Had analyzable data at specified timepoint.
    [25] - Had analyzable data at specified timepoint.
    [26] - Had analyzable data at specified timepoint.
    Statistical analysis title
    Direct Bilirubin Change from Baseline to Month 12
    Statistical analysis description
    Statistical analysis of direct bilirubin change from baseline.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [27]
    Method
    ANCOVA
    Confidence interval
    Notes
    [27] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
    Statistical analysis title
    Direct Bilirubin Change from Baseline to Month 12
    Statistical analysis description
    Statistical analysis of direct bilirubin change from baseline.
    Comparison groups
    DB OCA 10 mg v DB Placebo
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    ANCOVA
    Confidence interval
    Notes
    [28] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

    Secondary: DB Phase: ALT Absolute Change From Baseline To Month 12

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    End point title
    DB Phase: ALT Absolute Change From Baseline To Month 12
    End point description
    Blood samples were evaluated for ALT levels. ALT absolute change from baseline (ALT at Month 12 - ALT at Baseline) is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Month 12
    End point values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo
    Number of subjects analysed
    64 [29]
    62 [30]
    70 [31]
    Units: U/L
        least squares mean (standard error)
    -21.26 ± 3.27
    -25.31 ± 3.35
    -4.95 ± 3.32
    Notes
    [29] - Had analyzable data at specified timepoints.
    [30] - Had analyzable data at specified timepoints.
    [31] - Had analyzable data at specified timepoints.
    Statistical analysis title
    ALT Change From Baseline to Month 12
    Statistical analysis description
    Statistical analysis of ALT change from baseline.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    ANCOVA
    Confidence interval
    Notes
    [32] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
    Statistical analysis title
    ALT Change From Baseline to Month 12
    Statistical analysis description
    Statistical analysis of ALT change from baseline.
    Comparison groups
    DB Placebo v DB OCA 10 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [33]
    Method
    ANCOVA
    Confidence interval
    Notes
    [33] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

    Secondary: DB Phase: AST Absolute Change From Baseline To Month 12

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    End point title
    DB Phase: AST Absolute Change From Baseline To Month 12
    End point description
    Blood samples were evaluated for AST levels. AST absolute change from baseline (AST at Month 12 - AST at Baseline) is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Month 12
    End point values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo
    Number of subjects analysed
    64 [34]
    62 [35]
    70 [36]
    Units: U/L
        least squares mean (standard error)
    -13.03 ± 4.17
    -15.00 ± 4.28
    1.04 ± 4.22
    Notes
    [34] - Had analyzable data at specified timepoint.
    [35] - Had analyzable data at specified timepoint.
    [36] - Had analyzable data at specified timepoint.
    Statistical analysis title
    AST Change From Baseline to Month 12
    Statistical analysis description
    Statistical Analysis for AST change from baseline.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [37]
    Method
    ANCOVA
    Confidence interval
    Notes
    [37] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
    Statistical analysis title
    AST Change From Baseline to Month 12
    Statistical analysis description
    Statistical Analysis for AST change from baseline.
    Comparison groups
    DB Placebo v DB OCA 10 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [38]
    Method
    ANCOVA
    Confidence interval
    Notes
    [38] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

    Secondary: DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12

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    End point title
    DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12
    End point description
    Blood samples were evaluated for GGT levels. GGT absolute change from baseline (GGT at Month 12 - GGT at Baseline) is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Month 12
    End point values
    DB OCA 5-10 mg DB OCA 10 mg DB Placebo
    Number of subjects analysed
    64 [39]
    62 [40]
    70 [41]
    Units: U/L
        least squares mean (standard error)
    -140.83 ± 24.70
    -176.66 ± 25.58
    6.70 ± 25.56
    Notes
    [39] - Had analyzable data at specified timepoint.
    [40] - Had analyzable data at specified timepoint.
    [41] - Had analyzable data at specified timepoint.
    Statistical analysis title
    GGT Change From Baseline to Month 12
    Statistical analysis description
    Statistical Analysis for GGT change from baseline.
    Comparison groups
    DB OCA 5-10 mg v DB Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [42]
    Method
    ANCOVA
    Confidence interval
    Notes
    [42] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
    Statistical analysis title
    GGT Change From Baseline to Month 12
    Statistical analysis description
    Statistical Analysis for GGT change from baseline.
    Comparison groups
    DB Placebo v DB OCA 10 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [43]
    Method
    ANCOVA
    Confidence interval
    Notes
    [43] - ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

    Secondary: LTSE Phase: ALP Levels

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    End point title
    LTSE Phase: ALP Levels
    End point description
    Blood samples were evaluated for ALP levels.
    End point type
    Secondary
    End point timeframe
    LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60
    End point values
    LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
    Number of subjects analysed
    63 [44]
    64 [45]
    66 [46]
    193 [47]
    Units: U/L
    arithmetic mean (standard deviation)
        LTSE Day 0
    218.69 ± 100.328
    191.24 ± 61.381
    317.79 ± 139.666
    243.75 ± 118.910
        LTSE Month 12
    209.49 ± 93.157
    198.68 ± 75.799
    226.28 ± 105.404
    211.47 ± 92.439
        LTSE Month 24
    195.14 ± 80.361
    194.57 ± 66.593
    215.99 ± 83.469
    201.47 ± 77.117
        LTSE Month 36
    204.52 ± 68.019
    214.66 ± 158.831
    205.37 ± 65.206
    208.27 ± 107.114
        LTSE Month 48
    189.75 ± 55.929
    192.00 ± 59.761
    198.70 ± 65.551
    193.38 ± 60.170
        LTSE Month 60
    200.90 ± 97.475
    191.37 ± 62.404
    209.38 ± 82.240
    200.94 ± 83.436
    Notes
    [44] - Day 0 (63); Month 12 (60); Month 24 (57); Month 36 (56); Month 48 (50); Month 60 (31)
    [45] - Day 0 (63); Month 12 (59); Month 24 (57); Month 36 (55); Month 48 (53); Month 60 (21)
    [46] - Day 0 (66); Month 12 (59); Month 24 (52); Month 36 (49); Month 48 (48); Month 60 (24)
    [47] - Day 0 (192); Month 12 (178); Month 24 (166); Month 36 (160); Month 48 (151); Month 60 (76)
    No statistical analyses for this end point

    Secondary: LTSE Phase: ALP Change From DB Baseline

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    End point title
    LTSE Phase: ALP Change From DB Baseline
    End point description
    Blood samples were evaluated for ALP levels. ALP Change From Baseline (ALP at LTSE Months 12, 24, 36, 48, and 60 - ALP at Baseline) is presented. DB baseline is the mean of all available evaluations prior to DB treatment.
    End point type
    Secondary
    End point timeframe
    DB Baseline, LTSE Months 12, 24, 36, 48, and 60
    End point values
    LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
    Number of subjects analysed
    63 [48]
    64 [49]
    66 [50]
    193 [51]
    Units: U/L
    arithmetic mean (standard deviation)
        Month 12
    -106.63 ± 98.448
    -104.39 ± 82.496
    -104.36 ± 83.074
    -105.13 ± 87.882
        Month 24
    -120.86 ± 96.614
    -102.52 ± 79.413
    -100.99 ± 87.181
    -108.34 ± 87.980
        Month 36
    -100.98 ± 109.952
    -84.65 ± 137.293
    -112.73 ± 89.661
    -98.96 ± 114.635
        Month 48
    -118.23 ± 101.527
    -101.50 ± 91.335
    -115.51 ± 106.774
    -111.49 ± 99.433
        Month 60
    -118.99 ± 147.126
    -117.49 ± 95.587
    -119.52 ± 108.949
    -118.74 ± 121.391
    Notes
    [48] - Month 12 (60); Month 24 (57); Month 36 (56); Month 48 (50); Month 60 (31)
    [49] - Month 12 (59); Month 24 (57); Month 36 (55); Month 48 (53); Month 60 (21)
    [50] - Month 12 (59); Month 24 (52); Month 36 (49); Month 48 (48); Month 60 (24)
    [51] - Month 12 (178); Month 24 (166); Month 36 (160); Month 48 (151); Month 60 (60)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DB Phase: Baseline up to 12 months (1 year). LSTE phase: Baseline (DB Month 12) up to 60 months (5 years).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    DB 5-10 mg
    Reporting group description
    OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.

    Reporting group title
    DB Placebo
    Reporting group description
    Matching placebo for 12 months during the DB phase.

    Reporting group title
    DB OCA 10 mg
    Reporting group description
    OCA 10 mg for 12 months during the DB phase.

    Reporting group title
    LTSE OCA (DB OCA 5-10 mg)
    Reporting group description
    Participants previously receiving OCA 5 to 10 mg in the DB phase received OCA beginning at 5 mg in the open-label LTSE for up to 5 years, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    LTSE OCA (DB 10 mg)
    Reporting group description
    Participants previously receiving OCA 10 mg in the DB phase received OCA beginning at 5 mg in the open-label LTSE for up to 5 years, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    LTSE OCA (DB Placebo)
    Reporting group description
    Participants previously receiving placebo in the DB phase received OCA beginning at 5 mg in the open-label LTSE for up to 5 years, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Reporting group title
    Overall LTSE OCA
    Reporting group description
    After completion of the 12-month DB phase, all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

    Serious adverse events
    DB 5-10 mg DB Placebo DB OCA 10 mg LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 70 (15.71%)
    3 / 73 (4.11%)
    8 / 73 (10.96%)
    30 / 63 (47.62%)
    19 / 64 (29.69%)
    20 / 66 (30.30%)
    69 / 193 (35.75%)
         number of deaths (all causes)
    1
    0
    0
    1
    1
    0
    2
         number of deaths resulting from adverse events
    1
    0
    0
    1
    1
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm malignant
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplast malignant recurrent
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip neoplastm malignant stage unspecified
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal oncocytoma
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Polyserositis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Medical observation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic ulcer
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    2 / 64 (3.13%)
    0 / 66 (0.00%)
    4 / 193 (2.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 3
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    2 / 64 (3.13%)
    0 / 66 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    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
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
    4 / 193 (2.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    2 / 66 (3.03%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic artery aneurysm
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperplastic cholecystopathy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Neurodermatitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal atrophy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    2 / 63 (3.17%)
    5 / 64 (7.81%)
    0 / 66 (0.00%)
    7 / 193 (3.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 6
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic sclerosis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    3 / 63 (4.76%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    4 / 193 (2.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4.5%
    Non-serious adverse events
    DB 5-10 mg DB Placebo DB OCA 10 mg LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 70 (91.43%)
    62 / 73 (84.93%)
    64 / 73 (87.67%)
    61 / 63 (96.83%)
    62 / 64 (96.88%)
    64 / 66 (96.97%)
    187 / 193 (96.89%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    5 / 63 (7.94%)
    6 / 64 (9.38%)
    8 / 66 (12.12%)
    19 / 193 (9.84%)
         occurrences all number
    0
    1
    2
    6
    7
    8
    21
    Hypotension
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    2 / 64 (3.13%)
    4 / 66 (6.06%)
    8 / 193 (4.15%)
         occurrences all number
    0
    0
    0
    2
    3
    4
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    6 / 66 (9.09%)
    11 / 193 (5.70%)
         occurrences all number
    2
    1
    1
    2
    7
    6
    15
    Fatigue
         subjects affected / exposed
    11 / 70 (15.71%)
    10 / 73 (13.70%)
    17 / 73 (23.29%)
    24 / 63 (38.10%)
    24 / 64 (37.50%)
    15 / 66 (22.73%)
    63 / 193 (32.64%)
         occurrences all number
    13
    12
    25
    46
    43
    20
    109
    Influenza like illness
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    3 / 73 (4.11%)
    4 / 63 (6.35%)
    6 / 64 (9.38%)
    1 / 66 (1.52%)
    11 / 193 (5.70%)
         occurrences all number
    1
    1
    4
    4
    9
    1
    14
    Oedema peripheral
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 73 (2.74%)
    5 / 73 (6.85%)
    10 / 63 (15.87%)
    8 / 64 (12.50%)
    8 / 66 (12.12%)
    26 / 193 (13.47%)
         occurrences all number
    2
    3
    7
    15
    12
    10
    37
    Pyrexia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    5 / 73 (6.85%)
    5 / 63 (7.94%)
    6 / 64 (9.38%)
    5 / 66 (7.58%)
    16 / 193 (8.29%)
         occurrences all number
    0
    1
    6
    6
    8
    5
    19
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 73 (2.74%)
    1 / 73 (1.37%)
    4 / 63 (6.35%)
    2 / 64 (3.13%)
    1 / 66 (1.52%)
    7 / 193 (3.63%)
         occurrences all number
    2
    2
    1
    4
    2
    1
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 73 (6.85%)
    6 / 73 (8.22%)
    12 / 63 (19.05%)
    11 / 64 (17.19%)
    12 / 66 (18.18%)
    35 / 193 (18.13%)
         occurrences all number
    5
    9
    6
    23
    16
    16
    55
    Dyspnoea
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 73 (4.11%)
    1 / 73 (1.37%)
    1 / 63 (1.59%)
    4 / 64 (6.25%)
    2 / 66 (3.03%)
    7 / 193 (3.63%)
         occurrences all number
    1
    3
    1
    1
    6
    2
    9
    Epistaxis
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 73 (4.11%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    2 / 64 (3.13%)
    3 / 66 (4.55%)
    8 / 193 (4.15%)
         occurrences all number
    3
    4
    0
    4
    3
    5
    12
    Nasal congestion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    3 / 63 (4.76%)
    2 / 64 (3.13%)
    0 / 66 (0.00%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    2
    3
    2
    0
    5
    Oropharyngeal pain
         subjects affected / exposed
    5 / 70 (7.14%)
    1 / 73 (1.37%)
    6 / 73 (8.22%)
    6 / 63 (9.52%)
    8 / 64 (12.50%)
    4 / 66 (6.06%)
    18 / 193 (9.33%)
         occurrences all number
    5
    1
    8
    6
    11
    6
    23
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    1 / 64 (1.56%)
    3 / 66 (4.55%)
    7 / 193 (3.63%)
         occurrences all number
    3
    3
    0
    5
    1
    3
    9
    Depressed mood
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 63 (0.00%)
    4 / 64 (6.25%)
    1 / 66 (1.52%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    2
    0
    5
    2
    7
    Depression
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    5 / 63 (7.94%)
    5 / 64 (7.81%)
    3 / 66 (4.55%)
    13 / 193 (6.74%)
         occurrences all number
    1
    0
    1
    6
    6
    4
    16
    Insomnia
         subjects affected / exposed
    2 / 70 (2.86%)
    7 / 73 (9.59%)
    3 / 73 (4.11%)
    6 / 63 (9.52%)
    7 / 64 (10.94%)
    7 / 66 (10.61%)
    20 / 193 (10.36%)
         occurrences all number
    2
    8
    3
    6
    7
    11
    24
    Sleep disorder
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    1 / 64 (1.56%)
    2 / 66 (3.03%)
    6 / 193 (3.11%)
         occurrences all number
    7
    0
    0
    8
    1
    2
    11
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    3 / 66 (4.55%)
    3 / 193 (1.55%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    3
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    0
    1
    5
    1
    7
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
    3 / 66 (4.55%)
    4 / 193 (2.07%)
         occurrences all number
    0
    0
    1
    0
    1
    4
    5
    Weight decreased
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    2 / 64 (3.13%)
    1 / 66 (1.52%)
    6 / 193 (3.11%)
         occurrences all number
    0
    0
    0
    3
    2
    1
    6
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    4 / 66 (6.06%)
    4 / 193 (2.07%)
         occurrences all number
    1
    1
    0
    0
    0
    4
    4
    Contusion
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 73 (2.74%)
    2 / 73 (2.74%)
    2 / 63 (3.17%)
    5 / 64 (7.81%)
    3 / 66 (4.55%)
    10 / 193 (5.18%)
         occurrences all number
    3
    2
    3
    2
    5
    3
    10
    Excoriation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    0 / 66 (0.00%)
    4 / 193 (2.07%)
         occurrences all number
    0
    0
    1
    1
    3
    0
    4
    Fall
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    4 / 63 (6.35%)
    0 / 64 (0.00%)
    4 / 66 (6.06%)
    8 / 193 (4.15%)
         occurrences all number
    0
    0
    0
    4
    0
    4
    8
    Ligament rupture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    0 / 64 (0.00%)
    3 / 66 (4.55%)
    3 / 193 (1.55%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    3
    Meniscus lesion
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    5 / 64 (7.81%)
    1 / 66 (1.52%)
    7 / 193 (3.63%)
         occurrences all number
    0
    0
    0
    2
    5
    1
    8
    Procedural pain
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    8 / 63 (12.70%)
    4 / 64 (6.25%)
    4 / 66 (6.06%)
    16 / 193 (8.29%)
         occurrences all number
    4
    3
    1
    9
    5
    7
    21
    Rib fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    2 / 64 (3.13%)
    0 / 66 (0.00%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    0
    3
    2
    0
    5
    Scratch
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    3 / 73 (4.11%)
    1 / 63 (1.59%)
    6 / 64 (9.38%)
    2 / 66 (3.03%)
    9 / 193 (4.66%)
         occurrences all number
    1
    0
    4
    1
    7
    3
    11
    Tendon rupture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    3 / 64 (4.69%)
    0 / 66 (0.00%)
    3 / 193 (1.55%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    2 / 66 (3.03%)
    6 / 193 (3.11%)
         occurrences all number
    0
    0
    0
    1
    7
    2
    10
    Bradycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    4 / 193 (2.07%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    4
    Cardiac murmur
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    3 / 63 (4.76%)
    2 / 64 (3.13%)
    2 / 66 (3.03%)
    7 / 193 (3.63%)
         occurrences all number
    0
    0
    1
    3
    2
    2
    7
    Palpitations
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 73 (1.37%)
    5 / 73 (6.85%)
    4 / 63 (6.35%)
    5 / 64 (7.81%)
    2 / 66 (3.03%)
    11 / 193 (5.70%)
         occurrences all number
    3
    1
    5
    6
    5
    2
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 73 (2.74%)
    2 / 73 (2.74%)
    5 / 63 (7.94%)
    7 / 64 (10.94%)
    2 / 66 (3.03%)
    14 / 193 (7.25%)
         occurrences all number
    5
    2
    2
    9
    7
    2
    18
    Headache
         subjects affected / exposed
    12 / 70 (17.14%)
    13 / 73 (17.81%)
    6 / 73 (8.22%)
    20 / 63 (31.75%)
    15 / 64 (23.44%)
    9 / 66 (13.64%)
    44 / 193 (22.80%)
         occurrences all number
    26
    16
    7
    43
    22
    10
    75
    Hypoaesthesia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    3 / 193 (1.55%)
         occurrences all number
    1
    0
    0
    5
    0
    0
    5
    Paraesthesia
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    2 / 64 (3.13%)
    3 / 66 (4.55%)
    7 / 193 (3.63%)
         occurrences all number
    1
    1
    1
    3
    2
    3
    8
    Sciatica
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    3 / 63 (4.76%)
    3 / 64 (4.69%)
    3 / 66 (4.55%)
    9 / 193 (4.66%)
         occurrences all number
    0
    0
    1
    3
    4
    4
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 73 (5.48%)
    3 / 73 (4.11%)
    8 / 63 (12.70%)
    7 / 64 (10.94%)
    4 / 66 (6.06%)
    19 / 193 (9.84%)
         occurrences all number
    2
    5
    3
    12
    8
    5
    25
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 63 (1.59%)
    1 / 64 (1.56%)
    3 / 66 (4.55%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    1
    4
    1
    4
    9
    Splenomegaly
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    4 / 63 (6.35%)
    2 / 64 (3.13%)
    1 / 66 (1.52%)
    7 / 193 (3.63%)
         occurrences all number
    0
    0
    0
    5
    2
    1
    8
    Thrombocytopenia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    3 / 64 (4.69%)
    2 / 66 (3.03%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    0
    0
    3
    2
    5
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    6 / 193 (3.11%)
         occurrences all number
    2
    1
    0
    3
    3
    1
    7
    Vertigo
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    4 / 63 (6.35%)
    2 / 64 (3.13%)
    2 / 66 (3.03%)
    8 / 193 (4.15%)
         occurrences all number
    1
    0
    0
    7
    2
    2
    11
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    6 / 193 (3.11%)
         occurrences all number
    0
    0
    1
    2
    4
    1
    7
    Conjunctivitis
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 73 (2.74%)
    2 / 73 (2.74%)
    2 / 63 (3.17%)
    5 / 64 (7.81%)
    1 / 66 (1.52%)
    8 / 193 (4.15%)
         occurrences all number
    1
    2
    2
    4
    6
    1
    11
    Dry eye
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 73 (5.48%)
    4 / 73 (5.48%)
    3 / 63 (4.76%)
    10 / 64 (15.63%)
    2 / 66 (3.03%)
    15 / 193 (7.77%)
         occurrences all number
    3
    4
    4
    4
    11
    2
    17
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    5 / 70 (7.14%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    5 / 63 (7.94%)
    0 / 64 (0.00%)
    2 / 66 (3.03%)
    7 / 193 (3.63%)
         occurrences all number
    5
    5
    0
    5
    0
    2
    7
    Abdominal distension
         subjects affected / exposed
    3 / 70 (4.29%)
    7 / 73 (9.59%)
    3 / 73 (4.11%)
    5 / 63 (7.94%)
    7 / 64 (10.94%)
    5 / 66 (7.58%)
    17 / 193 (8.81%)
         occurrences all number
    3
    7
    3
    7
    7
    5
    19
    Abdominal pain
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 73 (8.22%)
    1 / 73 (1.37%)
    11 / 63 (17.46%)
    7 / 64 (10.94%)
    8 / 66 (12.12%)
    26 / 193 (13.47%)
         occurrences all number
    3
    6
    1
    15
    9
    8
    32
    Abdominal pain lower
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    3 / 63 (4.76%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    1
    4
    1
    1
    6
    Abdominal pain upper
         subjects affected / exposed
    5 / 70 (7.14%)
    5 / 73 (6.85%)
    4 / 73 (5.48%)
    9 / 63 (14.29%)
    10 / 64 (15.63%)
    12 / 66 (18.18%)
    31 / 193 (16.06%)
         occurrences all number
    5
    8
    5
    12
    11
    13
    36
    Ascites
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    6 / 63 (9.52%)
    1 / 64 (1.56%)
    3 / 66 (4.55%)
    10 / 193 (5.18%)
         occurrences all number
    1
    0
    1
    9
    1
    4
    14
    Constipation
         subjects affected / exposed
    5 / 70 (7.14%)
    4 / 73 (5.48%)
    5 / 73 (6.85%)
    12 / 63 (19.05%)
    9 / 64 (14.06%)
    7 / 66 (10.61%)
    28 / 193 (14.51%)
         occurrences all number
    5
    7
    5
    12
    9
    8
    29
    Dental caries
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    4 / 63 (6.35%)
    1 / 64 (1.56%)
    4 / 66 (6.06%)
    9 / 193 (4.66%)
         occurrences all number
    2
    0
    0
    5
    1
    6
    12
    Diarrhoea
         subjects affected / exposed
    2 / 70 (2.86%)
    8 / 73 (10.96%)
    8 / 73 (10.96%)
    8 / 63 (12.70%)
    11 / 64 (17.19%)
    14 / 66 (21.21%)
    33 / 193 (17.10%)
         occurrences all number
    3
    13
    10
    15
    17
    26
    58
    Dry mouth
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 73 (2.74%)
    3 / 73 (4.11%)
    3 / 63 (4.76%)
    5 / 64 (7.81%)
    3 / 66 (4.55%)
    11 / 193 (5.70%)
         occurrences all number
    2
    2
    3
    4
    5
    3
    12
    Dyspepsia
         subjects affected / exposed
    4 / 70 (5.71%)
    8 / 73 (10.96%)
    0 / 73 (0.00%)
    7 / 63 (11.11%)
    8 / 64 (12.50%)
    5 / 66 (7.58%)
    20 / 193 (10.36%)
         occurrences all number
    4
    11
    0
    12
    8
    5
    25
    Gastric polyps
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    0 / 66 (0.00%)
    4 / 193 (2.07%)
         occurrences all number
    0
    0
    2
    1
    4
    0
    5
    Gastritis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    6 / 64 (9.38%)
    3 / 66 (4.55%)
    11 / 193 (5.70%)
         occurrences all number
    1
    0
    1
    2
    7
    3
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 73 (5.48%)
    4 / 73 (5.48%)
    7 / 63 (11.11%)
    9 / 64 (14.06%)
    4 / 66 (6.06%)
    20 / 193 (10.36%)
         occurrences all number
    2
    6
    5
    7
    12
    4
    23
    Haemorrhoids
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    5 / 63 (7.94%)
    1 / 64 (1.56%)
    5 / 66 (7.58%)
    11 / 193 (5.70%)
         occurrences all number
    0
    2
    0
    6
    1
    5
    12
    Hiatus hernia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    0
    1
    3
    1
    5
    Nausea
         subjects affected / exposed
    4 / 70 (5.71%)
    9 / 73 (12.33%)
    8 / 73 (10.96%)
    14 / 63 (22.22%)
    13 / 64 (20.31%)
    10 / 66 (15.15%)
    37 / 193 (19.17%)
         occurrences all number
    5
    18
    10
    20
    19
    15
    54
    Portal hypertensive gastropathy
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    0 / 64 (0.00%)
    2 / 66 (3.03%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    0
    3
    0
    2
    5
    Rectal haemorrhage
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    1 / 63 (1.59%)
    2 / 64 (3.13%)
    4 / 66 (6.06%)
    7 / 193 (3.63%)
         occurrences all number
    0
    0
    2
    1
    2
    4
    7
    Toothache
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    5 / 64 (7.81%)
    3 / 66 (4.55%)
    10 / 193 (5.18%)
         occurrences all number
    0
    1
    1
    2
    6
    3
    11
    Varices oesophageal
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    8 / 63 (12.70%)
    2 / 64 (3.13%)
    1 / 66 (1.52%)
    11 / 193 (5.70%)
         occurrences all number
    1
    0
    0
    8
    3
    1
    12
    Vomiting
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 73 (6.85%)
    3 / 73 (4.11%)
    5 / 63 (7.94%)
    7 / 64 (10.94%)
    2 / 66 (3.03%)
    14 / 193 (7.25%)
         occurrences all number
    3
    8
    3
    7
    9
    2
    18
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    5 / 63 (7.94%)
    4 / 64 (6.25%)
    1 / 66 (1.52%)
    10 / 193 (5.18%)
         occurrences all number
    2
    0
    0
    6
    4
    1
    11
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    2 / 64 (3.13%)
    4 / 66 (6.06%)
    7 / 193 (3.63%)
         occurrences all number
    0
    0
    0
    1
    2
    4
    7
    Hepatomegaly
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    4 / 193 (2.07%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    4
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    0 / 64 (0.00%)
    2 / 66 (3.03%)
    5 / 193 (2.59%)
         occurrences all number
    1
    0
    0
    5
    0
    7
    12
    Dry skin
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    5 / 66 (7.58%)
    9 / 193 (4.66%)
         occurrences all number
    1
    1
    2
    1
    3
    5
    9
    Eczema
         subjects affected / exposed
    4 / 70 (5.71%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    5 / 63 (7.94%)
    4 / 64 (6.25%)
    5 / 66 (7.58%)
    14 / 193 (7.25%)
         occurrences all number
    4
    0
    2
    5
    4
    7
    16
    Erythema
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    3 / 73 (4.11%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    3 / 66 (4.55%)
    8 / 193 (4.15%)
         occurrences all number
    1
    0
    3
    4
    4
    4
    12
    Hyperhidrosis
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
    3 / 193 (1.55%)
         occurrences all number
    1
    2
    0
    3
    0
    0
    3
    Night sweats
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
    4 / 193 (2.07%)
         occurrences all number
    3
    0
    0
    3
    0
    1
    4
    Pruritus
         subjects affected / exposed
    39 / 70 (55.71%)
    28 / 73 (38.36%)
    50 / 73 (68.49%)
    49 / 63 (77.78%)
    51 / 64 (79.69%)
    50 / 66 (75.76%)
    150 / 193 (77.72%)
         occurrences all number
    93
    49
    99
    249
    198
    180
    627
    Rash
         subjects affected / exposed
    3 / 70 (4.29%)
    3 / 73 (4.11%)
    4 / 73 (5.48%)
    7 / 63 (11.11%)
    5 / 64 (7.81%)
    2 / 66 (3.03%)
    14 / 193 (7.25%)
         occurrences all number
    3
    3
    4
    9
    5
    2
    16
    Rash pruritic
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    0 / 63 (0.00%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    4 / 193 (2.07%)
         occurrences all number
    0
    0
    2
    0
    3
    1
    4
    Skin lesion
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 73 (4.11%)
    1 / 73 (1.37%)
    3 / 63 (4.76%)
    5 / 64 (7.81%)
    6 / 66 (9.09%)
    14 / 193 (7.25%)
         occurrences all number
    0
    3
    1
    5
    7
    8
    20
    Urticaria
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    5 / 193 (2.59%)
         occurrences all number
    0
    3
    0
    1
    4
    4
    9
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    6 / 193 (3.11%)
         occurrences all number
    0
    0
    0
    2
    3
    1
    6
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    4 / 63 (6.35%)
    3 / 64 (4.69%)
    3 / 66 (4.55%)
    10 / 193 (5.18%)
         occurrences all number
    4
    1
    1
    4
    3
    3
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 70 (5.71%)
    3 / 73 (4.11%)
    7 / 73 (9.59%)
    14 / 63 (22.22%)
    17 / 64 (26.56%)
    15 / 66 (22.73%)
    46 / 193 (23.83%)
         occurrences all number
    5
    3
    7
    17
    23
    18
    58
    Back pain
         subjects affected / exposed
    4 / 70 (5.71%)
    8 / 73 (10.96%)
    4 / 73 (5.48%)
    10 / 63 (15.87%)
    11 / 64 (17.19%)
    10 / 66 (15.15%)
    31 / 193 (16.06%)
         occurrences all number
    4
    8
    5
    13
    15
    10
    38
    Bone pain
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    1
    1
    3
    1
    5
    Joint swelling
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    1 / 64 (1.56%)
    4 / 66 (6.06%)
    8 / 193 (4.15%)
         occurrences all number
    0
    0
    0
    3
    1
    4
    8
    Muscle spasms
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 73 (5.48%)
    2 / 73 (2.74%)
    4 / 63 (6.35%)
    4 / 64 (6.25%)
    3 / 66 (4.55%)
    11 / 193 (5.70%)
         occurrences all number
    2
    5
    2
    4
    7
    3
    14
    Musculoskeletal pain
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    4 / 63 (6.35%)
    5 / 64 (7.81%)
    3 / 66 (4.55%)
    12 / 193 (6.22%)
         occurrences all number
    1
    1
    1
    5
    6
    3
    14
    Myalgia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    3 / 73 (4.11%)
    4 / 63 (6.35%)
    7 / 64 (10.94%)
    2 / 66 (3.03%)
    13 / 193 (6.74%)
         occurrences all number
    1
    0
    3
    5
    9
    2
    16
    Neck pain
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    3 / 63 (4.76%)
    4 / 64 (6.25%)
    5 / 66 (7.58%)
    12 / 193 (6.22%)
         occurrences all number
    1
    2
    2
    3
    4
    5
    12
    Osteoarthritis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    4 / 63 (6.35%)
    6 / 64 (9.38%)
    5 / 66 (7.58%)
    15 / 193 (7.77%)
         occurrences all number
    0
    1
    1
    5
    8
    7
    20
    Osteopenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    9 / 63 (14.29%)
    6 / 64 (9.38%)
    6 / 66 (9.09%)
    21 / 193 (10.88%)
         occurrences all number
    1
    0
    1
    9
    6
    7
    22
    Osteoporosis
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 73 (2.74%)
    1 / 73 (1.37%)
    2 / 63 (3.17%)
    4 / 64 (6.25%)
    5 / 66 (7.58%)
    11 / 193 (5.70%)
         occurrences all number
    1
    2
    1
    2
    5
    6
    13
    Pain in extremity
         subjects affected / exposed
    3 / 70 (4.29%)
    3 / 73 (4.11%)
    1 / 73 (1.37%)
    7 / 63 (11.11%)
    5 / 64 (7.81%)
    8 / 66 (12.12%)
    20 / 193 (10.36%)
         occurrences all number
    3
    3
    1
    11
    5
    9
    25
    Plantar fasciitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    0 / 63 (0.00%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
    4 / 193 (2.07%)
         occurrences all number
    0
    0
    2
    0
    4
    1
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 70 (5.71%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    7 / 63 (11.11%)
    7 / 64 (10.94%)
    6 / 66 (9.09%)
    20 / 193 (10.36%)
         occurrences all number
    4
    0
    1
    7
    7
    10
    24
    Cystitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    5 / 63 (7.94%)
    5 / 64 (7.81%)
    2 / 66 (3.03%)
    12 / 193 (6.22%)
         occurrences all number
    2
    0
    2
    12
    15
    3
    30
    Diverticulum
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    0 / 66 (0.00%)
    5 / 193 (2.59%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    5
    Ear infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    1 / 63 (1.59%)
    1 / 64 (1.56%)
    3 / 66 (4.55%)
    5 / 193 (2.59%)
         occurrences all number
    0
    1
    1
    1
    2
    3
    6
    Gastroenteritis
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    4 / 63 (6.35%)
    1 / 64 (1.56%)
    5 / 66 (7.58%)
    10 / 193 (5.18%)
         occurrences all number
    3
    0
    1
    4
    1
    6
    11
    Herpes zoster
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 63 (1.59%)
    7 / 64 (10.94%)
    4 / 66 (6.06%)
    12 / 193 (6.22%)
         occurrences all number
    0
    0
    1
    1
    8
    4
    13
    Influenza
         subjects affected / exposed
    5 / 70 (7.14%)
    4 / 73 (5.48%)
    4 / 73 (5.48%)
    12 / 63 (19.05%)
    12 / 64 (18.75%)
    10 / 66 (15.15%)
    34 / 193 (17.62%)
         occurrences all number
    5
    5
    4
    17
    17
    17
    51
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    4 / 63 (6.35%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
    6 / 193 (3.11%)
         occurrences all number
    2
    1
    0
    8
    2
    5
    15
    Nasopharyngitis
         subjects affected / exposed
    17 / 70 (24.29%)
    13 / 73 (17.81%)
    13 / 73 (17.81%)
    23 / 63 (36.51%)
    23 / 64 (35.94%)
    11 / 66 (16.67%)
    57 / 193 (29.53%)
         occurrences all number
    27
    19
    15
    66
    39
    22
    127
    Oral herpes
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    3 / 63 (4.76%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
    5 / 193 (2.59%)
         occurrences all number
    1
    1
    1
    4
    1
    1
    6
    Pharyngitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 63 (1.59%)
    3 / 64 (4.69%)
    2 / 66 (3.03%)
    6 / 193 (3.11%)
         occurrences all number
    0
    1
    0
    1
    6
    2
    9
    Pneumonia
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    2 / 73 (2.74%)
    2 / 63 (3.17%)
    5 / 64 (7.81%)
    5 / 66 (7.58%)
    12 / 193 (6.22%)
         occurrences all number
    0
    0
    2
    2
    8
    6
    16
    Respiratory tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 73 (4.11%)
    0 / 73 (0.00%)
    5 / 63 (7.94%)
    4 / 64 (6.25%)
    4 / 66 (6.06%)
    13 / 193 (6.74%)
         occurrences all number
    0
    3
    0
    6
    5
    5
    16
    Sinusitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    4 / 73 (5.48%)
    7 / 63 (11.11%)
    9 / 64 (14.06%)
    8 / 66 (12.12%)
    24 / 193 (12.44%)
         occurrences all number
    1
    0
    5
    7
    11
    11
    29
    Tooth infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    2 / 66 (3.03%)
    7 / 193 (3.63%)
         occurrences all number
    2
    0
    0
    3
    3
    2
    8
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 70 (5.71%)
    8 / 73 (10.96%)
    4 / 73 (5.48%)
    12 / 63 (19.05%)
    11 / 64 (17.19%)
    11 / 66 (16.67%)
    34 / 193 (17.62%)
         occurrences all number
    4
    8
    4
    21
    17
    16
    54
    Urinary tract infection
         subjects affected / exposed
    4 / 70 (5.71%)
    8 / 73 (10.96%)
    4 / 73 (5.48%)
    17 / 63 (26.98%)
    19 / 64 (29.69%)
    15 / 66 (22.73%)
    51 / 193 (26.42%)
         occurrences all number
    6
    15
    6
    31
    27
    23
    81
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 63 (0.00%)
    3 / 64 (4.69%)
    3 / 66 (4.55%)
    6 / 193 (3.11%)
         occurrences all number
    0
    0
    0
    0
    3
    5
    8
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 73 (2.74%)
    0 / 73 (0.00%)
    3 / 63 (4.76%)
    2 / 64 (3.13%)
    3 / 66 (4.55%)
    8 / 193 (4.15%)
         occurrences all number
    0
    2
    0
    4
    2
    3
    9
    Vitamin D deficiency
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    2 / 63 (3.17%)
    3 / 64 (4.69%)
    3 / 66 (4.55%)
    8 / 193 (4.15%)
         occurrences all number
    0
    1
    0
    2
    3
    3
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2012
    • The schedule of transient elastography assessments was altered. • Changes to entry criteria were made to better reflect the intent of the protocol. • Liver biopsy schedule was adjusted.
    24 Sep 2012
    • The requirement for use of contraception was extended to 30 days after the end of treatment visit. • The titration procedure was edited to include 10 mg increments. • Baseline dual-emission x-ray absorptiometry scan was removed as a requirement for participants who had a scan within 6 months prior to enrollment.
    25 Aug 2014
    • Protocol was modified to allow participants who were tolerating 5 mg OCA daily to be titrated to a maximum of 10 mg daily. Participants who were titrated above 10 mg prior to Version 4 were allowed to remain on their current dose or be decreased as clinically indicated. • Requirement for LTSE Follow-up visit was removed.
    21 Mar 2018
    • Introduction was revised to highlight the need for close monitoring specifically in participants with clinical evidence of hepatic decompensation and other complications due to advanced cirrhosis. • Effective with Protocol Version 5: All participants under Protocol Version 3 and prior who were receiving > 10 mg OCA daily had their doses down-titrated to ≤ 10 mg OCA daily. After implementation of Protocol Version 5, no participant was titrated beyond 10 mg OCA at any time during the LTSE. Additionally, dosing regimens were updated for participants with moderate and severe hepatic impairment (Child-Pugh B and Child-Pugh C), not to exceed 10 mg OCA twice weekly, to align with label dosing guidelines. •Updated with discontinuation criteria for decompensation events and biochemical thresholds. A plan for monitoring and a drug-induced liver injury algorithm was included to ensure careful monitoring and drug interruption/discontinuation. Additionally, “Close Observation” per “Food and Drug Administration Guidance for Industry on Drug Induced Liver Injury” was clearly defined in the protocol to ensure that participants who experienced a potential drug-induced liver injury underwent a full evaluation. • Guidance added that participants should be instructed to contact the site promptly upon awareness if they develop signs and symptoms of potential hepatic decompensation. • Guidance added that the investigator should contact the study Medical Monitor upon awareness when any signs and symptoms of hepatic decompensation are observed in any participant. • Guidance added for monitoring amylase and lipase levels in participants experiencing acute pancreatitis or cholecystitis. • List of analytes amended and samples for biomarkers of hepatic fibrosis and/or inflammation, bile acids, PBC autoantibodies, and other cytokines and interleukins were no longer to be collected or analyzed in the LTSE phase.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/19554543
    http://www.ncbi.nlm.nih.gov/pubmed/27532829
    http://www.ncbi.nlm.nih.gov/pubmed/30922873
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