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    Clinical Trial Results:
    A multi-centre, double-blind, parallel-group, randomised, placebo-controlled phase IIa study to investigate safety, tolerability, pharmacodynamics, and pharmacokinetics of different doses of orally administered BI 1467335 during a 12-week treatment period compared to placebo in patients with clinical evidence of NASH

    Summary
    EudraCT number
    		 2016-000499-83
    Trial protocol
    		 NL   BE   DE   IE   GB   ES  
    Global end of trial date
    14 Jun 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Dec 2020
    First version publication date
    24 Jun 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of NCT Number in section Trial Information / Additional Trial Identifier.

    Trial information

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    Trial identification
    Sponsor protocol code
    1386-0004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03166735
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany,
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.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
    26 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The key objectives of this trial were the proof of mechanism, support of dose finding, and safety evaluation of different doses of BI 1467335 compared to placebo in patients with clinical evidence of non-alcoholic steato-hepatitis (NASH).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 58
    Worldwide total number of subjects
    113
    EEA total number of subjects
    51
    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)
    96
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study is a multi-centre, double-blind, parallel-group, randomised, placebo-controlled phase IIa study to investigate safety, tolerability, pharmacodynamics, and pharmacokinetics of different doses of orally administered BI 1467335 (for 12-weeks) compared to placebo in patients with clinical evidence of Non-alcoholic steato-hepatitis (NASH).

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily.

    Arm title
    		 BI 1467335 1 milligram (mg)
    Arm description
    		 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1467335
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Arm title
    		 BI 1467335 3 milligram (mg)
    Arm description
    		 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1467335
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Arm title
    		 BI 1467335 6 milligram (mg)
    Arm description
    		 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1467335
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Arm title
    		 BI 1467335 10 milligram (mg)
    Arm description
    		 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1467335
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Number of subjects in period 1
    		Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Started
    32
    16
    16
    17
    32
    Completed
    32
    13
    13
    16
    28
    Not completed
    0
    3
    3
    1
    4
         Consent withdrawn by subject
    -
    -
    1
    1
    2
         follow-up not completed as planned
    -
    1
    1
    -
    1
         Lost to follow-up
    -
    2
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily.

    Reporting group title
    BI 1467335 1 milligram (mg)
    Reporting group description
    		 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 3 milligram (mg)
    Reporting group description
    		 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 6 milligram (mg)
    Reporting group description
    		 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 10 milligram (mg)
    Reporting group description
    		 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg) Total
    Number of subjects
    		 32 16 16 17 32 113
    Age categorical
    Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication.
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 26 12 12 17 29 96
        From 65-84 years
    		 6 4 4 0 3 17
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication.
    Units: years
        arithmetic mean (standard deviation)
    		 51.8 ( 12.3 ) 52.6 ( 13.3 ) 53.9 ( 11.5 ) 48.2 ( 10.1 ) 49.8 ( 14.0 ) -
    Sex: Female, Male
    Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication.
    Units: Participants
        Female
    		 13 10 8 9 18 58
        Male
    		 19 6 8 8 14 55
    Race (NIH/OMB)
    Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 1 1 0 0 0 2
        Native Hawaiian or Other Pacific Islander
    		 1 1 0 0 0 2
        Black or African American
    		 0 0 0 0 0 0
        White
    		 30 14 16 17 32 109
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 11 5 5 4 8 33
        Not Hispanic or Latino
    		 21 11 11 13 24 80
        Unknown or Not Reported
    		 0 0 0 0 0 0
    Plasma amine oxidase copper-containing 3 (AOC3) baseline concentration
    Plasma amine oxidase copper-containing 3 (AOC3) baseline concentration. Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication.
    Units: microgram per liter (µg/l)
        arithmetic mean (standard deviation)
    		 471.4063 ( 165.6802 ) 537.7143 ( 204.4100 ) 498.0000 ( 141.0225 ) 527.2941 ( 142.3722 ) 516.1613 ( 144.0727 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily.

    Reporting group title
    BI 1467335 1 milligram (mg)
    Reporting group description
    		 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 3 milligram (mg)
    Reporting group description
    		 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 6 milligram (mg)
    Reporting group description
    		 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 10 milligram (mg)
    Reporting group description
    		 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Primary: Plasma amine oxidase copper-containing 3 (AOC3) activity after 12 weeks of treatment, relative to baseline in percent

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    End point title
    		 Plasma amine oxidase copper-containing 3 (AOC3) activity after 12 weeks of treatment, relative to baseline in percent
    End point description
    The patient-specific plasma AOC3 activity at time t (24 hours after the last dose in week 12) relative to baseline in percentage was calculated as follows: %AOC3at = [(AOC3at - AOC3at,back) ⁄ (AOC3abase - AOC3abase,back)]*100 with AOC3at the AOC3 activity measured at time t, AOC3at,back the background noise at time t, AOC3abase the AOC3 activity measured at baseline and AOC3abase,back the background noise at baseline. A dose-response relationship was analysed using a non-linear regression model to estimate the daily dosage needed to reach 10% of AOC3 activity (i.e. 90% inhibition) 12 weeks after treatment. Per Protocol Set (PPS): patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint.
    End point type
    Primary
    End point timeframe
    Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    30 [1]
    12 [2]
    14 [3]
    11 [4]
    24 [5]
    Units: Percentage relative to baseline
        arithmetic mean (standard deviation)
    102 ( 13.0 )
    24.0 ( 11.9 )
    13.1 ( 10.4 )
    8.27 ( 5.19 )
    2.06 ( 3.62 )
    Notes
    [1] - PPS
    [2] - PPS
    [3] - PPS
    [4] - PPS
    [5] - PPS
    Statistical analysis title
    		 Estimated dose reaching <=10% activity
    Statistical analysis description
    D10: Estimated dose reaching <=10% activity the first time.
    Comparison groups
    Placebo v BI 1467335 1 milligram (mg) v BI 1467335 3 milligram (mg) v BI 1467335 6 milligram (mg) v BI 1467335 10 milligram (mg)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    		 non-linear regression
    Parameter type
    		 Predicted mean daily dose in mg
    Point estimate
    3.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9999
         upper limit
    		 99999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [6] - The model fit used power of mean variance estimates (POM) to account for heterogeneity. 0.9999 & 99999 stand for 'not applicable'.

    Secondary: Percentage of participants with drug-related adverse events (AEs)

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    End point title
    		 Percentage of participants with drug-related adverse events (AEs)
    End point description
    Percentage of participants with drug-related adverse events (AEs). Percentages are calculated using total number of patients per treatment as the denominator. Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication.
    End point type
    Secondary
    End point timeframe
    Start of treatment till end of treatment + 28 days, up to 113 days.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    32 [7]
    16 [8]
    16 [9]
    17 [10]
    32 [11]
    Units: Percentage of participants
        number (not applicable)
    25.0
    31.3
    12.5
    11.8
    25.0
    Notes
    [7] - TS
    [8] - TS
    [9] - TS
    [10] - TS
    [11] - TS
    No statistical analyses for this end point

    Secondary: Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent

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    End point title
    		 Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent
    End point description
    Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    28 [12]
    12 [13]
    13 [14]
    14 [15]
    27 [16]
    Units: Percentage relative to baseline
        arithmetic mean (standard error)
    92.66 ( 106.55 )
    97.32 ( 110.13 )
    87.49 ( 109.79 )
    80.61 ( 109.43 )
    77.57 ( 106.66 )
    Notes
    [12] - PPS
    [13] - PPS
    [14] - PPS
    [15] - PPS
    [16] - PPS
    Statistical analysis title
    		 MCPMod Sigmoidal Emax model fit
    Statistical analysis description
    Model assumptions: 30% of the maximum effect is achieved at 3 mg and 90% of the maximum effect is achieved at 7 mg of BI 1467335. MCPMod = multiple comparison procedures and modelling.
    Comparison groups
    Placebo v BI 1467335 1 milligram (mg) v BI 1467335 3 milligram (mg) v BI 1467335 6 milligram (mg) v BI 1467335 10 milligram (mg)
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 = 0.0212 [18]
    Method
    		 MCPMod Sigmoidal Emax model fit.
    Confidence interval
    Notes
    [17] - The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod.
    [18] - p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose−response curve) with alpha 0.05, one−sided.

    Secondary: Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent

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    End point title
    		 Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent
    End point description
    Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    27 [19]
    12 [20]
    13 [21]
    14 [22]
    23 [23]
    Units: Percentage relative to baseline
        arithmetic mean (standard error)
    93.77 ( 105.91 )
    105.17 ( 108.93 )
    90.09 ( 108.72 )
    84.12 ( 108.34 )
    87.83 ( 106.26 )
    Notes
    [19] - PPS
    [20] - PPS
    [21] - PPS
    [22] - PPS
    [23] - PPS
    Statistical analysis title
    		 MCPMod Sigmoidal Emax model fit
    Statistical analysis description
    Model assumptions: 30% of the maximum effect is achieved at 3 mg and 90% of the maximum effect is achieved at 7 mg of BI 1467335.
    Comparison groups
    Placebo v BI 1467335 1 milligram (mg) v BI 1467335 3 milligram (mg) v BI 1467335 6 milligram (mg) v BI 1467335 10 milligram (mg)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 [24]
    P-value
    		 = 0.127 [25]
    Method
    		 MCPMod Sigmoidal Emax model fit.
    Confidence interval
    Notes
    [24] - The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod.
    [25] - p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose−response curve) with alpha 0.05, one−sided.

    Secondary: Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent

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    End point title
    		 Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent
    End point description
    Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    29 [26]
    12 [27]
    13 [28]
    14 [29]
    28 [30]
    Units: Percentage relative to baseline
        arithmetic mean (standard error)
    96.62 ( 102.31 )
    97.58 ( 103.56 )
    100.52 ( 103.45 )
    98.47 ( 103.34 )
    94.71 ( 102.34 )
    Notes
    [26] - PPS
    [27] - PPS
    [28] - PPS
    [29] - PPS
    [30] - PPS
    Statistical analysis title
    		 MCPMod exponential model fit
    Statistical analysis description
    Model assumptions: 90% of the maximum effect is achieved at 7 mg of BI 1467335.
    Comparison groups
    Placebo v BI 1467335 1 milligram (mg) v BI 1467335 3 milligram (mg) v BI 1467335 6 milligram (mg) v BI 1467335 10 milligram (mg)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 [31]
    P-value
    		 = 0.3324 [32]
    Method
    		 MCPMod exponential model fit.
    Confidence interval
    Notes
    [31] - The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod.
    [32] - p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose−response curve) with alpha 0.05, one−sided.

    Secondary: Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent

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    End point title
    		 Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent
    End point description
    Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    29 [33]
    12 [34]
    13 [35]
    14 [36]
    28 [37]
    Units: Percentage relative to baseline
        arithmetic mean (standard error)
    91.37 ( 105.24 )
    99.42 ( 108.25 )
    92.44 ( 108.09 )
    99.51 ( 107.71 )
    83.70 ( 105.40 )
    Notes
    [33] - PPS
    [34] - PPS
    [35] - PPS
    [36] - PPS
    [37] - PPS
    Statistical analysis title
    		 MCPMod exponential model fit
    Statistical analysis description
    Model assumptions: 90% of the maximum effect is achieved at 7 mg of BI 1467335.
    Comparison groups
    Placebo v BI 1467335 1 milligram (mg) v BI 1467335 3 milligram (mg) v BI 1467335 6 milligram (mg) v BI 1467335 10 milligram (mg)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 [38]
    P-value
    		 = 0.129 [39]
    Method
    		 MCPMod exponential model fit.
    Confidence interval
    Notes
    [38] - The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod.
    [39] - p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose−response curve) with alpha 0.05, one−sided.

    Secondary: Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent

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    End point title
    		 Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent
    End point description
    Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A MMRM over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    29 [40]
    12 [41]
    12 [42]
    14 [43]
    26 [44]
    Units: Percentage relative to baseline
        arithmetic mean (standard error)
    101.35 ( 111.15 )
    155.04 ( 117.61 )
    96.87 ( 117.54 )
    80.51 ( 116.32 )
    78.08 ( 111.59 )
    Notes
    [40] - PPS
    [41] - PPS
    [42] - PPS
    [43] - PPS
    [44] - PPS
    Statistical analysis title
    		 MCPMod Sigmoidal Emax model fit
    Statistical analysis description
    Model assumptions: 30% of the maximum effect is achieved at 3 mg and 90% of the maximum effect is achieved at 7 mg of BI 1467335.
    Comparison groups
    Placebo v BI 1467335 1 milligram (mg) v BI 1467335 3 milligram (mg) v BI 1467335 6 milligram (mg) v BI 1467335 10 milligram (mg)
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 [45]
    P-value
    		 = 0.0042 [46]
    Method
    		 MCPMod Sigmoidal Emax model fit.
    Confidence interval
    Notes
    [45] - The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod.
    [46] - p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose−response curve) with alpha 0.05, one−sided.

    Secondary: Total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent

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    End point title
    		 Total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent
    End point description
    total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.
    End point values
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg)
    Number of subjects analysed
    28 [47]
    11 [48]
    13 [49]
    14 [50]
    26 [51]
    Units: Percentage relative to baseline
        arithmetic mean (standard error)
    92.44 ( 109.13 )
    128.33 ( 114.64 )
    99.56 ( 113.78 )
    94.74 ( 113.10 )
    81.47 ( 109.35 )
    Notes
    [47] - PPS
    [48] - PPS
    [49] - PPS
    [50] - PPS
    [51] - PPS
    Statistical analysis title
    		 MCPMod exponential model fit
    Statistical analysis description
    Model assumptions: 90% of the maximum effect is achieved at 7 mg of BI 1467335
    Comparison groups
    Placebo v BI 1467335 1 milligram (mg) v BI 1467335 3 milligram (mg) v BI 1467335 6 milligram (mg) v BI 1467335 10 milligram (mg)
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 [52]
    P-value
    		 = 0.0728 [53]
    Method
    		 MCPMod exponential model fit.
    Confidence interval
    Notes
    [52] - The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod.
    [53] - p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose−response curve) with alpha 0.05, one−sided.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    start of treatment till end of treatment + 28 days, up to 113 days.
    Adverse event reporting additional description
    Adverse events are reported based on the Treated Set (all patients who signed the informed consent and were treated with at least one dose of the trial medication).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily.

    Reporting group title
    BI 1467335 1 milligram (mg)
    Reporting group description
    		 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 3 milligram (mg)
    Reporting group description
    		 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 6 milligram (mg)
    Reporting group description
    		 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    BI 1467335 10 milligram (mg)
    Reporting group description
    		 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strenghts. For blinding reasons, all patients took 5 tablets verum or placebo daily.

    Reporting group title
    Total BI 1467335
    Reporting group description
    		 Sum of all BI 1467335 arms

    Serious adverse events
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg) Total BI 1467335
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    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
    Nasal septum deviation
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    H1N1 influenza
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    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
    Sinusitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BI 1467335 1 milligram (mg) BI 1467335 3 milligram (mg) BI 1467335 6 milligram (mg) BI 1467335 10 milligram (mg) Total BI 1467335
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 32 (56.25%)
    12 / 16 (75.00%)
    12 / 16 (75.00%)
    13 / 17 (76.47%)
    17 / 32 (53.13%)
    54 / 81 (66.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Subclavian steal syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Early satiety
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    5 / 32 (15.63%)
    6 / 81 (7.41%)
         occurrences all number
    3
    0
    1
    0
    5
    6
    Influenza like illness
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 32 (6.25%)
    2 / 81 (2.47%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 32 (3.13%)
    3 / 81 (3.70%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    Dry throat
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    Epistaxis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    Paranasal sinus discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Sinus pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    Weight increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    2 / 81 (2.47%)
         occurrences all number
    0
    0
    1
    0
    1
    2
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Vascular procedure complication
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    3 / 32 (9.38%)
    6 / 81 (7.41%)
         occurrences all number
    0
    1
    2
    0
    3
    6
    Headache
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 16 (18.75%)
    0 / 16 (0.00%)
    4 / 17 (23.53%)
    2 / 32 (6.25%)
    9 / 81 (11.11%)
         occurrences all number
    4
    5
    0
    5
    2
    12
    Sciatica
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Tension headache
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    2 / 81 (2.47%)
         occurrences all number
    2
    1
    0
    0
    1
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 32 (3.13%)
    3 / 81 (3.70%)
         occurrences all number
    1
    2
    0
    1
    1
    4
    Abdominal pain lower
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
    3 / 32 (9.38%)
    7 / 81 (8.64%)
         occurrences all number
    3
    1
    1
    2
    3
    7
    Dry mouth
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    1
    1
    0
    1
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 32 (6.25%)
    3 / 81 (3.70%)
         occurrences all number
    1
    0
    0
    1
    2
    3
    Flatulence
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    0
    0
    2
    3
    Nausea
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 16 (25.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    5 / 32 (15.63%)
    10 / 81 (12.35%)
         occurrences all number
    1
    4
    1
    0
    5
    10
    Pouchitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Toothache
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 32 (6.25%)
    2 / 81 (2.47%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Rash erythematous
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Rash papular
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    4 / 81 (4.94%)
         occurrences all number
    2
    2
    1
    0
    1
    4
    Muscular weakness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    3
    0
    1
    0
    0
    1
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    3
    0
    0
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 16 (18.75%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
    5 / 32 (15.63%)
    11 / 81 (13.58%)
         occurrences all number
    4
    3
    2
    1
    5
    11
    Otitis media
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    1
    0
    1
    1
    0
    2
    Tooth abscess
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    2
    0
    1
    1
    0
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    3 / 81 (3.70%)
         occurrences all number
    2
    2
    0
    0
    1
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    2 / 81 (2.47%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Hyperlipidaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2018
    Global Amendment 5 (dated 12 Sep 2018): Sample size reduction from 147 to 108 randomised patients due to a lower expected variability for ALT based on new external and blinded internal data

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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