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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib in Subjects with Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis.

    Summary
    EudraCT number
    		 2016-004374-18
    Trial protocol
    		 AT   BE   GB   DE   PT   PL   NL   ES   IT  
    Global end of trial date
    19 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2020
    First version publication date
    26 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-384-1943
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03053050
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    19 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce progression to cirrhosis and associated complications in adults with nonalcoholic steatohepatitis (NASH) and bridging (F3) fibrosis.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 417
    Country: Number of subjects enrolled
    Japan: 80
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Hong Kong: 24
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Taiwan: 21
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    India: 15
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Singapore: 11
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Puerto Rico: 3
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Switzerland: 3
    Worldwide total number of subjects
    808
    EEA total number of subjects
    110
    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)
    616
    From 65 to 84 years
    192
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America, Asia, Europe, Australia, South America, Puerto Rico, and New Zealand. The first participant was screened on 13 February 2017. The last study visit occurred on 19 June 2019.

    Pre-assignment
    Screening details
    		 2250 participants were screened. No participants completed the study. In the Subject Disposition, the number of participants reported in the Randomised Phase arms for "Completed" is the number of participants with a confirmed clinical event who discontinued the randomized phase per protocol.

    Period 1
    Period 1 title
    Randomized Phase
    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
    		 SEL 18 mg
    Arm description
    		 Randomized Phase: SEL 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered once daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets administered once daily

    Arm title
    		 SEL 6 mg
    Arm description
    		 Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6 mg administered once daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets administered once daily

    Arm title
    		 Placebo
    Arm description
    		 Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets administered once daily

    Number of subjects in period 1 [1]
    		SEL 18 mg SEL 6 mg Placebo
    Started
    322
    321
    159
    Completed
    36
    45
    18
    Not completed
    286
    276
    141
         Withdrew Consent
    16
    8
    9
         Adverse Event
    -
    1
    -
         Investigator's Discretion
    6
    6
    3
         Study Terminated by Sponsor
    259
    260
    128
         Lost to follow-up
    5
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 6 participants (2 in SEL 18 mg arm, 2 in SEL 6 mg arm, and 2 in Placebo arm) were randomized but did not receive study treatment.
    Period 2
    Period 2 title
    Open-Label Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-Label SEL 18 mg
    Arm description
    		 Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered once daily

    Number of subjects in period 2
    		Open-Label SEL 18 mg
    Started
    99
    Completed
    0
    Not completed
    99
         Withdrew Consent
    6
         Investigator's Discretion
    4
         Study Terminated by Sponsor
    89

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    SEL 18 mg
    Reporting group description
    		 Randomized Phase: SEL 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks.

    Reporting group title
    SEL 6 mg
    Reporting group description
    		 Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.

    Reporting group values
    		 SEL 18 mg SEL 6 mg Placebo Total
    Number of subjects
    		 322 321 159 802
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57 ( 9.1 ) 57 ( 9.2 ) 57 ( 9.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 181 196 76 453
        Male
    		 141 125 83 349
    Race
    Not Permitted = Local regulators did not allow collection of race or ethnicity information.
    Units: Subjects
        American Indian or Alaska Native
    		 5 1 2 8
        Asian
    		 88 84 41 213
        Black
    		 8 5 2 15
        White
    		 219 227 113 559
        Other
    		 2 3 1 6
        Not Permitted
    		 0 1 0 1
    Ethnicity
    Not Permitted = Local regulators did not allow collection of race or ethnicity information.
    Units: Subjects
        Not Hispanic or Latino
    		 269 269 137 675
        Hispanic or Latino
    		 52 48 22 122
        Not Permitted
    		 1 4 0 5

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    SEL 18 mg
    Reporting group description
    		 Randomized Phase: SEL 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks.

    Reporting group title
    SEL 6 mg
    Reporting group description
    		 Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.
    Reporting group title
    Open-Label SEL 18 mg
    Reporting group description
    		 Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.

    Primary: Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH at Week 48

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    End point title
    		 Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH at Week 48
    End point description
    Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. The Full Analysis Set included all participants who were randomized into the study and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    322
    321
    159
    Units: percentage of participants
        number (confidence interval 95%)
    9.6 (6.6 to 13.4)
    12.1 (8.8 to 16.2)
    13.2 (8.4 to 19.5)
    Statistical analysis title
    		 SEL 18 mg vs Placebo
    Comparison groups
    SEL 18 mg v Placebo
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4941 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 4
    Notes
    [1] - Difference between SEL 18 mg and Placebo, 95% confidence interval (CI) and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and Enhanced Liver Fibrosis (ELF) test score as stratification factors.
    Statistical analysis title
    		 SEL 6 mg vs Placebo
    Comparison groups
    SEL 6 mg v Placebo
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9321 [2]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 6
    Notes
    [2] - Difference between SEL 6 mg and Placebo, 95% CI and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and ELF test score as stratification factors.

    Primary: Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event

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    End point title
    		 Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event [3]
    End point description
    EFS was assessed by the time to the first clinical event, including progression to cirrhosis on liver biopsy, liver decompensation events, liver transplantation, and all-cause mortality.
    End point type
    Primary
    End point timeframe
    Week 240
    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: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    Units: months
        median (inter-quartile range (Q1-Q3))
    ( to )
    ( to )
    ( to )
    Notes
    [4] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    [5] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    [6] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Had Progression to Cirrhosis at Week 48

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    End point title
    		 Percentage of Participants Who Had Progression to Cirrhosis at Week 48
    End point description
    Progression to cirrhosis was defined as a change in NASH CRN fibrosis stage from < 4 at baseline to 4 at Week 48. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    322
    321
    159
    Units: percentage of participants
        number (confidence interval 95%)
    13.0 (9.6 to 17.2)
    15.6 (11.8 to 20.0)
    15.7 (10.4 to 22.3)
    Statistical analysis title
    		 SEL 18 mg vs Placebo
    Comparison groups
    SEL 18 mg v Placebo
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2593 [7]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.8
         upper limit
    		 2.9
    Notes
    [7] - Difference between SEL 18 mg and Placebo, 95% CI and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and ELF test score as stratification factors.
    Statistical analysis title
    		 SEL 6 mg vs Placebo
    Comparison groups
    SEL 6 mg v Placebo
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.808 [8]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.9
         upper limit
    		 6.1
    Notes
    [8] - Difference between SEL 6 mg vs Placebo, 95% CI and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and ELF test score as stratification factors.

    Secondary: Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240

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    End point title
    		 Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240
    End point description
    Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the NAS criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation.
    End point type
    Secondary
    End point timeframe
    Week 240
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    0 [9]
    0 [10]
    0 [11]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [9] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    [10] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    [11] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48

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    End point title
    		 Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48
    End point description
    Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    322
    321
    159
    Units: percentage of participants
        number (confidence interval 95%)
    12.7 (9.3 to 16.9)
    13.7 (10.1 to 18.0)
    16.4 (11.0 to 23.0)
    Statistical analysis title
    		 SEL 18 mg vs Placebo
    Comparison groups
    SEL 18 mg v Placebo
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5636 [12]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 4.8
    Notes
    [12] - Difference between SEL 18 mg and Placebo, 95% CI and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and ELF test score as stratification factors.
    Statistical analysis title
    		 SEL 6 mg vs Placebo
    Comparison groups
    Placebo v SEL 6 mg
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5915 [13]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.6
         upper limit
    		 4.9
    Notes
    [13] - Difference between SEL 6 mg and Placebo, 95% CI and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and ELF test score as stratification factors.

    Secondary: Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240

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    End point title
    		 Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240
    End point description
    Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis).
    End point type
    Secondary
    End point timeframe
    Week 240
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [14] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint
    [15] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint
    [16] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48

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    End point title
    		 Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48
    End point description
    NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    322
    321
    158
    Units: percentage of participants
        number (confidence interval 95%)
    5.0 (2.9 to 7.9)
    4.4 (2.4 to 7.2)
    8.9 (4.9 to 14.4)
    Statistical analysis title
    		 SEL 18 mg vs Placebo
    Comparison groups
    SEL 18 mg v Placebo
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2455 [17]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 2.2
    Notes
    [17] - Difference between SEL 18 mg and Placebo, 95% CI and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and ELF test score as stratification factors.
    Statistical analysis title
    		 SEL 6 mg vs Placebo
    Comparison groups
    SEL 6 mg v Placebo
    Number of subjects included in analysis
    479
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1371 [18]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 1.3
    Notes
    [18] - Difference between SEL 6 mg and Placebo, 95% CI and p-value were obtained by stratum-adjusted Mantel-Haenszel method with baseline diabetes mellitus status and ELF test score as stratification factors.

    Secondary: Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 240

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    End point title
    		 Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 240
    End point description
    NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN.
    End point type
    Secondary
    End point timeframe
    Week 240
    End point values
    		 SEL 18 mg SEL 6 mg Placebo
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [19] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    [20] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    [21] - No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date up to last dose (maximum: 111.4 weeks) plus 30 days
    Adverse event reporting additional description
    The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    SEL 18 mg
    Reporting group description
    		 Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks.

    Reporting group title
    SEL 6 mg
    Reporting group description
    		 Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.

    Reporting group title
    Open-Label SEL 18 mg
    Reporting group description
    		 Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.

    Serious adverse events
    		 SEL 18 mg SEL 6 mg Placebo Open-Label SEL 18 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 322 (14.60%)
    36 / 321 (11.21%)
    17 / 159 (10.69%)
    6 / 99 (6.06%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carcinoid tumour pulmonary
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemangioma of skin
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic lymphoma
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testicular necrosis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic hydrothorax
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ammonia increased
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic leak
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 321 (0.62%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    1 / 159 (0.63%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Internal hernia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis interstitial
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 322 (0.93%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 321 (0.62%)
    2 / 159 (1.26%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 321 (0.62%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 321 (0.00%)
    1 / 159 (0.63%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 321 (0.00%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 321 (0.31%)
    0 / 159 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SEL 18 mg SEL 6 mg Placebo Open-Label SEL 18 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    248 / 322 (77.02%)
    254 / 321 (79.13%)
    130 / 159 (81.76%)
    48 / 99 (48.48%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    10 / 322 (3.11%)
    5 / 321 (1.56%)
    8 / 159 (5.03%)
    0 / 99 (0.00%)
         occurrences all number
    10
    5
    9
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    36 / 322 (11.18%)
    38 / 321 (11.84%)
    18 / 159 (11.32%)
    5 / 99 (5.05%)
         occurrences all number
    50
    47
    19
    6
    Dizziness
         subjects affected / exposed
    16 / 322 (4.97%)
    30 / 321 (9.35%)
    2 / 159 (1.26%)
    2 / 99 (2.02%)
         occurrences all number
    17
    32
    2
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    35 / 322 (10.87%)
    33 / 321 (10.28%)
    12 / 159 (7.55%)
    3 / 99 (3.03%)
         occurrences all number
    39
    35
    12
    4
    Oedema peripheral
         subjects affected / exposed
    18 / 322 (5.59%)
    9 / 321 (2.80%)
    4 / 159 (2.52%)
    3 / 99 (3.03%)
         occurrences all number
    18
    9
    4
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    52 / 322 (16.15%)
    47 / 321 (14.64%)
    30 / 159 (18.87%)
    8 / 99 (8.08%)
         occurrences all number
    64
    59
    43
    8
    Constipation
         subjects affected / exposed
    40 / 322 (12.42%)
    43 / 321 (13.40%)
    19 / 159 (11.95%)
    4 / 99 (4.04%)
         occurrences all number
    43
    49
    19
    6
    Nausea
         subjects affected / exposed
    32 / 322 (9.94%)
    39 / 321 (12.15%)
    14 / 159 (8.81%)
    6 / 99 (6.06%)
         occurrences all number
    37
    46
    20
    6
    Abdominal pain upper
         subjects affected / exposed
    33 / 322 (10.25%)
    26 / 321 (8.10%)
    16 / 159 (10.06%)
    5 / 99 (5.05%)
         occurrences all number
    33
    28
    17
    5
    Abdominal pain
         subjects affected / exposed
    22 / 322 (6.83%)
    27 / 321 (8.41%)
    15 / 159 (9.43%)
    3 / 99 (3.03%)
         occurrences all number
    25
    34
    15
    3
    Vomiting
         subjects affected / exposed
    19 / 322 (5.90%)
    18 / 321 (5.61%)
    8 / 159 (5.03%)
    1 / 99 (1.01%)
         occurrences all number
    24
    22
    12
    1
    Abdominal distension
         subjects affected / exposed
    13 / 322 (4.04%)
    12 / 321 (3.74%)
    8 / 159 (5.03%)
    2 / 99 (2.02%)
         occurrences all number
    14
    12
    9
    2
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    42 / 322 (13.04%)
    50 / 321 (15.58%)
    25 / 159 (15.72%)
    0 / 99 (0.00%)
         occurrences all number
    42
    50
    25
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 322 (8.70%)
    18 / 321 (5.61%)
    14 / 159 (8.81%)
    3 / 99 (3.03%)
         occurrences all number
    31
    21
    14
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    23 / 322 (7.14%)
    20 / 321 (6.23%)
    11 / 159 (6.92%)
    3 / 99 (3.03%)
         occurrences all number
    24
    21
    11
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    33 / 322 (10.25%)
    30 / 321 (9.35%)
    18 / 159 (11.32%)
    3 / 99 (3.03%)
         occurrences all number
    35
    31
    20
    3
    Back pain
         subjects affected / exposed
    33 / 322 (10.25%)
    27 / 321 (8.41%)
    11 / 159 (6.92%)
    3 / 99 (3.03%)
         occurrences all number
    37
    27
    11
    3
    Pain in extremity
         subjects affected / exposed
    20 / 322 (6.21%)
    15 / 321 (4.67%)
    11 / 159 (6.92%)
    5 / 99 (5.05%)
         occurrences all number
    22
    15
    11
    5
    Muscle spasms
         subjects affected / exposed
    16 / 322 (4.97%)
    17 / 321 (5.30%)
    7 / 159 (4.40%)
    2 / 99 (2.02%)
         occurrences all number
    17
    18
    7
    2
    Musculoskeletal pain
         subjects affected / exposed
    14 / 322 (4.35%)
    18 / 321 (5.61%)
    8 / 159 (5.03%)
    2 / 99 (2.02%)
         occurrences all number
    14
    19
    10
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    41 / 322 (12.73%)
    46 / 321 (14.33%)
    21 / 159 (13.21%)
    6 / 99 (6.06%)
         occurrences all number
    54
    53
    27
    7
    Nasopharyngitis
         subjects affected / exposed
    46 / 322 (14.29%)
    40 / 321 (12.46%)
    21 / 159 (13.21%)
    0 / 99 (0.00%)
         occurrences all number
    71
    64
    23
    0
    Sinusitis
         subjects affected / exposed
    21 / 322 (6.52%)
    21 / 321 (6.54%)
    12 / 159 (7.55%)
    5 / 99 (5.05%)
         occurrences all number
    30
    29
    14
    5
    Influenza
         subjects affected / exposed
    19 / 322 (5.90%)
    20 / 321 (6.23%)
    14 / 159 (8.81%)
    4 / 99 (4.04%)
         occurrences all number
    20
    21
    16
    4
    Urinary tract infection
         subjects affected / exposed
    14 / 322 (4.35%)
    27 / 321 (8.41%)
    13 / 159 (8.18%)
    3 / 99 (3.03%)
         occurrences all number
    20
    32
    21
    3
    Bronchitis
         subjects affected / exposed
    23 / 322 (7.14%)
    21 / 321 (6.54%)
    6 / 159 (3.77%)
    1 / 99 (1.01%)
         occurrences all number
    25
    26
    7
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2017
    1. Clarified that events of hepatic decompensation included portal hypertension-related bleeding that required endoscopy, hospitalization and would be adjudicated by the Hepatic Events/Drug-Induced Liver Injury Adjudication Committee. 2. Hepatocellular carcinoma (HCC) was removed as a component of primary clinical efficacy endpoint. 3. The outcome of “death” was changed to “all-cause mortality” to clarify that all deaths would be included in EFS analysis. 4. References to a HepQuant substudy were removed. Only subjects enrolled at participating US sites could participate. 5. Laboratory parameters and assessments at screening were clarified; INR ≤ 1.4 and platelet count ≥100,000/μL were added as inclusion criteria. 6. Stool frequency assessment was added to the study procedures at all visits, beginning with baseline/Day 1. 7. EFS assessed as time to the first clinical event, including HCC, as well as progression to cirrhosis, liver decompensation events, liver transplantation, and all-cause mortality, was added as an exploratory efficacy endpoint. 8. Clarified that a sensitivity analysis of EFS that included hepatic clinical events and liver-related death would be performed. 9. Clarified that all clinical events except all-cause mortality and liver transplantation required confirmation by the Hepatic Events Adjudication Committee. 10. A stratified log-rank test was added to the exploratory endpoint analysis to compare between-group differences (SEL 18 mg, SEL 6 mg, Placebo) in time to the first clinical events, including HCC. 11. Estimated glomerular filtration rate (eGFR) calculation was included at all visits. 12. Specified that single PK sampling would be performed who entered OL phase and had severe hepatic impairment (Child-Pugh [CP] Class C) and renal impairment (eGFR < 30 mL/min). 13. Clarified that subjects in OL phase who completed study treatment should complete the Week 240/EOT visit. 14. A telephone follow-up visit to occur 12 weeks after Week 240 visit.
    31 May 2018
    1. Added abdominal ultrasound to be performed for HCC surveillance in the OL phase. 2. An early termination (ET) visit that was to be completed within 30 days after the last dose of study drug and the list of assessments to be performed at the visit was clarified for subjects who prematurely discontinued the study. 3. Clarified that hepatic clinical events would be adjudicated and deaths would be reviewed by the Hepatic Events/DILI Adjudication Committee during the randomized phase of the study; DILI events and cardiovascular events, including deaths, were to be adjudicated in the OL phase of the study by the hepatic events/DILI and cardiovascular Adjudication Committees, as appropriate. 4. Clinical trial information was updated, based on updates to the SEL Investigator’s Brochure, including the numbers of SEL studies conducted and subjects dosed, updated safety data, final study data, and completion of studies.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Jun 2019
    Based on the results of the Week 48 analysis, the study was terminated early for lack of efficacy as prespecified in the clinical study protocol.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Based on the results of the Week 48 analysis, the study was terminated early for lack of efficacy as prespecified in the clinical study protocol.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31271665
    http://www.ncbi.nlm.nih.gov/pubmed/30779990
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