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    Clinical Trial Results:
    A Phase 2, Double-Blind, Randomized Study Evaluating the Safety, Tolerability, and Efficacy of GS-4997 in Combination with Prednisolone versus Prednisolone Alone in Subjects with Severe Alcoholic Hepatitis (AH)

    Summary
    EudraCT number
    		 2016-000821-37
    Trial protocol
    		 AT   BE   GB  
    Global end of trial date
    31 May 2018

    Results information
    Results version number
    		 v3(current)
    This version publication date
    18 May 2019
    First version publication date
    06 Jan 2019
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Adding text to “Limitations and Caveats” section

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-416-2124
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02854631
    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 Sciences, Gilead Clinical Study Information Center, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Sciences, Gilead Clinical Study Information Center, 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
    31 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and tolerability of selonsertib (GS-4997) in combination with prednisolone versus prednisolone alone in participants with severe alcoholic hepatitis (AH).
    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
    01 Sep 2016
    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: 33
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United Kingdom: 28
    Worldwide total number of subjects
    104
    EEA total number of subjects
    66
    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)
    100
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Europe and North America. The first participant was screened on 01 September 2016. The last study visit occurred on 31 May 2018. Two participants were randomized in the Selonsertib + Prednisolone arm but were never treated.

    Pre-assignment
    Screening details
    		 166 participants were screened.

    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
    		 Selonsertib + Prednisolone
    Arm description
    		 Participants received selonsertib + prednisolone for 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered for 28 days, without regard to food.

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg (4 X 10 mg tablets) administered once daily for 28 days, without regard to food.

    Arm title
    		 Placebo + Prednisolone
    Arm description
    		 Participants received placebo-to-match selonsertib + prednisolone for 28 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg (4 X 10 mg tablets) administered orally once daily for 28 days, without regard to food.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo-to-match selonsertib tablets administered once daily for 28 days, without regard to food.

    Number of subjects in period 1 [1]
    		Selonsertib + Prednisolone Placebo + Prednisolone
    Started
    50
    52
    Completed
    26
    37
    Not completed
    24
    15
         Adverse event, non-fatal
    1
    2
         Protocol violation
    -
    1
         Death
    12
    8
         Liver biopsy inconsistent with diagnosis
    2
    -
         Withdrew consent
    3
    2
         Investigator's discretion
    2
    -
         Lost to follow-up
    4
    2
    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: Two participants were randomized in Selonsertib + Prednisolone arm but were never treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selonsertib + Prednisolone
    Reporting group description
    		 Participants received selonsertib + prednisolone for 28 days.

    Reporting group title
    Placebo + Prednisolone
    Reporting group description
    		 Participants received placebo-to-match selonsertib + prednisolone for 28 days.

    Reporting group values
    		 Selonsertib + Prednisolone Placebo + Prednisolone Total
    Number of subjects
    		 50 52 102
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (standard deviation)
    		 49 ( 10.0 ) 49 ( 9.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 16 37
        Male
    		 29 36 65
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 46 49 95
        Unknown or Not Reported
    		 3 2 5
    Race
    Units: Subjects
        Asian
    		 2 4 6
        Black or African American
    		 0 2 2
        White
    		 44 44 88
        Unknown or Not Reported
    		 4 2 6
    Hospitalized at Time of Screening
    Units: Subjects
        Yes
    		 46 48 94
        No
    		 4 4 8
    Baseline Infection
    Units: Subjects
        Yes
    		 6 11 17
        No
    		 44 41 85
    Days Hospitalized Prior to First Dose Date
    Only participants who were hospitalized were analyzed (Selonsertib + Prednisolone = 46; Placebo + Prednisolone = 48).
    Units: Days
        arithmetic mean (standard deviation)
    		 10 ( 4.6 ) 10 ( 5.2 ) -
    Alanine Aminotransferase (ALT)
    # of Participants Analyzed: Selonsertib + Prednisolone = 49; Placebo + Prednisolone = 52
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    		 45 ( 33.5 ) 48 ( 23.2 ) -
    Aspartate Aminotransferase (AST)
    # of Participants Analyzed: Selonsertib + Prednisolone = 49; Placebo + Prednisolone = 52
    Units: U/L
        arithmetic mean (standard deviation)
    		 122 ( 60.9 ) 129 ( 59.9 ) -
    Gamma Glutamyl Transferase (GGT)
    # of Participants Analyzed: Selonsertib + Prednisolone = 30; Placebo + Prednisolone = 33
    Units: U/L
        arithmetic mean (standard deviation)
    		 238 ( 175.5 ) 278 ( 358.7 ) -
    Alkaline Phosphatase
    # of Participants Analyzed: Selonsertib + Prednisolone = 49; Placebo + Prednisolone = 52
    Units: U/L
        arithmetic mean (standard deviation)
    		 162 ( 62.2 ) 189 ( 111.3 ) -
    Bilirubin
    # of Participants Analyzed: Selonsertib + Prednisolone = 49; Placebo + Prednisolone = 52
    Units: Milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    		 14.3 ( 8.35 ) 14.5 ( 7.78 ) -
    Albumin
    # of Participants Analyzed: Selonsertib + Prednisolone = 49; Placebo + Prednisolone = 52
    Units: Grams per deciltre (g/dL)
        arithmetic mean (standard deviation)
    		 3.1 ( 0.62 ) 3.0 ( 0.53 ) -
    International Normalized Ratio (INR)
    # of Participants Analyzed: Selonsertib + Prednisolone = 47; Placebo + Prednisolone = 52
    Units: Ratio
        arithmetic mean (standard deviation)
    		 1.7 ( 0.31 ) 1.6 ( 0.22 ) -
    Model for End- Stage Liver Disease (MELD) Score
    MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 22 ( 4.2 ) 22 ( 4.4 ) -
    Child-Pugh-Turcotte (CPT) Score
    CPT scores are used to assess the severity of cirrhosis. Scores can range from 5 to 15, with higher scores indicating a greater severity of disease. # of Participants Analyzed: Selonsertib + Prednisolone = 47; Placebo + Prednisolone = 52
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 10 ( 1.2 ) 10 ( 1.3 ) -
    Maddrey DF Score
    Baseline Maddrey Discriminant Function (DF) score is a prognostic tool used to determine the next step of treatment based on the severity of AH. Maddrey DF score of < 32 indicates mild to moderate AH and a lower chance of death in the next few months. Maddrey DF score of ≥ 32 indicates severe AH and a higher chance of death in the next few months. The score has no bounds. # of Participants Analyzed: Selonsertib + Prednisolone = 44; Placebo + Prednisolone = 52
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 42 ( 16.9 ) 38 ( 11.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Selonsertib + Prednisolone
    Reporting group description
    		 Participants received selonsertib + prednisolone for 28 days.

    Reporting group title
    Placebo + Prednisolone
    Reporting group description
    		 Participants received placebo-to-match selonsertib + prednisolone for 28 days.

    Primary: Percentage of Participants with Treatment-Emergent Adverse Events (AE), Serious AEs, AEs Leading to Premature Study Drug Discontinuation, and Grade 3 or 4 Laboratory Abnormalities

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    End point title
    		 Percentage of Participants with Treatment-Emergent Adverse Events (AE), Serious AEs, AEs Leading to Premature Study Drug Discontinuation, and Grade 3 or 4 Laboratory Abnormalities [1]
    End point description
    An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. Safety Analysis Set included participants who were randomized and took at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Day 28 plus 30 days
    Notes
    [1] - 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 statistical analyses was planned for the safety outcome.
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    50
    52
    Units: Percentage of participants
    number (not applicable)
        TEAEs
    94.0
    94.2
        TE SAEs
    50.0
    40.4
        TEAEs (discontinuation of Selonsertib/Placebo)
    18.0
    7.7
        TEAEs (discontinuation of Prednisolone)
    14.0
    11.5
        TEAEs (discontinuation of both drugs in regimen)
    14.0
    7.7
        Laboratory abnormalities (Grade 3 or 4)
    72.0
    72.0
        Laboratory abnormalities (Grade 3)
    42.0
    52.0
        Laboratory abnormalities (Grade 4)
    30.0
    20.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died by Day 28

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    End point title
    		 Percentage of Participants Who Died by Day 28
    End point description
    The percentage of participants who died by Day 28 was calculated. Participants in the Full Analysis Set (participants who took at least 1 dose of study drug, and had histologically-confirmed severe alcoholic hepatitis (AH)) with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    50
    Units: Percentage of participants
        number (not applicable)
    4.3
    4.0
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Selonsertib + Prednisolone v Placebo + Prednisolone
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - P-value from 2-sided Fisher's exact test was used to explore differences between treatment groups in the percentage of participants with an event.

    Secondary: Percentage of Participants Who Died by Week 8

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    End point title
    		 Percentage of Participants Who Died by Week 8
    End point description
    The percentage of participants who died by Week 8 was calculated. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    44
    49
    Units: Percentage of participants
        number (not applicable)
    20.5
    6.1
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Selonsertib + Prednisolone v Placebo + Prednisolone
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.061 [3]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - P-value from 2-sided Fisher's exact test was used to explore differences between treatment groups in the percentage of participants with an event.

    Secondary: Percentage of Participants Who Died by Week 12

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    End point title
    		 Percentage of Participants Who Died by Week 12
    End point description
    The percentage of participants who died by Week 12 was calculated. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    43
    49
    Units: Percentage of participants
        number (not applicable)
    25.6
    10.2
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Selonsertib + Prednisolone v Placebo + Prednisolone
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06 [4]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [4] - P-value from 2-sided Fisher's exact test was used to explore differences between treatment groups in the percentage of participants with an event.

    Secondary: Percentage of Participants Who Died by Week 24

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    End point title
    		 Percentage of Participants Who Died by Week 24
    End point description
    The percentage of participants who died by Week 24 was calculated. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    41
    48
    Units: Percentage of participants
        number (not applicable)
    31.7
    18.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Selonsertib + Prednisolone v Placebo + Prednisolone
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22 [5]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [5] - P-value from 2-sided Fisher's exact test was used to explore differences between treatment groups in the percentage of participants with an event.

    Secondary: Percentage of Participants Who Received a Liver Transplant

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    End point title
    		 Percentage of Participants Who Received a Liver Transplant
    End point description
    The percentage of participants who received a liver transplant by week 24 was calculcated. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 28, Week 8, Week 12, and Week 24
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    45
    48
    Units: Percentage of participants
    number (not applicable)
        Day 28 (n= 45, 48)
    2.2
    0
        Week 8 (n= 36, 46)
    2.8
    0
        Week 12 (n= 33, 44)
    3.0
    0
        Week 24 (n=29, 39)
    6.9
    2.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Hepatorenal Syndrome (HRS)

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    End point title
    		 Percentage of Participants With Hepatorenal Syndrome (HRS)
    End point description
    The occurrence of HRS was confirmed based on the following diagnostic criteria from the International Ascites Club (IAC): 1) Cirrhosis with ascites, 2) Diagnosis of acute kidney injury (AKI) according to the ICA-AKI criteria, 3) Absence of shock, 4) No current or recent treatment with nephrotoxic drugs, and 5) Absence of parenchymal renal disease as indicated by proteinuria >500 mg/day, microhematuria (> 50 red blood cells per high power field) and/or abnormal renal ultrasonography. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (not applicable)
    4.2
    2.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Infection

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    End point title
    		 Percentage of Participants With Infection
    End point description
    The occurrence of bacterial, fungal, or viral infections was recorded. An infection was considered definite in participants with clinical evidence of infection and a positive culture from a normally sterile source (with the exception of spontaneous bacterial peritonitis). Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (not applicable)
    37.5
    29.4
    No statistical analyses for this end point

    Secondary: Length of Hospital Stay

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    End point title
    		 Length of Hospital Stay
    End point description
    Length of initial hospital stay from first dose date of study drug was calculated for participants who were released from initial hospitalization separately from those who died during their initial hospitalization. Participants in the Full Analysis Set with available data were analyzed. Participants released from initial hospitalization and those who died during initial hospitalization were analyzed separately, so a total of 41 participants and 45 participants were analyzed for the Selonsertib + Prednisolone and Placebo + Prednisolone arms, respectively.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    41
    45
    Units: Days
    arithmetic mean (standard deviation)
        Released from initial hospitalization (n= 38, 43)
    11.0 ( 11.53 )
    11.0 ( 11.25 )
        Died during initial hospitalization (n=3, 2)
    36.0 ( 18.52 )
    6.0 ( 1.41 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Liver Biochemistry Tests: Alanine Aminotransferase (ALT)

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    End point title
    		 Change From Baseline in Liver Biochemistry Tests: Alanine Aminotransferase (ALT)
    End point description
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    49
    Units: U/L
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 45, 47)
    26 ( 40.7 )
    29 ( 28.2 )
        Change at Week 2 (n= 42, 46)
    31 ( 35.0 )
    36 ( 33.6 )
        Change at Week 3 (n= 39, 46)
    24 ( 32.6 )
    24 ( 28.8 )
        Change at Week 4 (n= 35, 46)
    15 ( 28.7 )
    12 ( 32.6 )
        Change at Week 6 (n= 32, 40)
    -10 ( 19.9 )
    -18 ( 21.8 )
        Change at Week 8 (n= 30, 42)
    -13 ( 18.1 )
    -20 ( 24.6 )
        Change at Week 12 (n= 27, 39)
    -15 ( 19.3 )
    -17 ( 42.9 )
        Change at Week 16 (n= 28, 36)
    -14 ( 21.0 )
    -21 ( 28.6 )
        Change at Week 20 (n= 24, 35)
    -12 ( 18.6 )
    -24 ( 21.7 )
        Change at Week 24 (n= 25, 35)
    -12 ( 19.4 )
    -22 ( 21.8 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Liver Biochemistry Tests: Aspartate Aminotransferase (AST)

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    End point title
    		 Change from Baseline in Liver Biochemistry Tests: Aspartate Aminotransferase (AST)
    End point description
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    49
    Units: U/L
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 45, 45)
    -2 ( 66.9 )
    4 ( 52.8 )
        Change at Week 2 (n= 40, 43)
    -17 ( 58.5 )
    -11 ( 52.9 )
        Change at Week 3 (n= 39, 45)
    -34 ( 38.4 )
    -39 ( 54.0 )
        Change at Week 4 (n= 35, 44)
    -45 ( 35.8 )
    -55 ( 60.2 )
        Change at Week 6 (n= 32, 40)
    -54 ( 45.6 )
    -74 ( 60.0 )
        Change at Week 8 (n= 30, 42)
    -48 ( 46.6 )
    -61 ( 63.5 )
        Change at Week 12 (n= 27, 37)
    -59 ( 45.2 )
    -63 ( 86.5 )
        Change at Week 16 (n= 26, 36)
    -59 ( 56.9 )
    -70 ( 76.4 )
        Change at Week 20 (n= 24, 35)
    -57 ( 46.9 )
    -64 ( 72.6 )
        Change at Week 24 (n= 25, 35)
    -59 ( 49.6 )
    -68 ( 59.4 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Liver Biochemistry Tests: Gamma Glutamyl Transferase (GGT)

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    End point title
    		 Change from Baseline in Liver Biochemistry Tests: Gamma Glutamyl Transferase (GGT)
    End point description
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    29
    33
    Units: U/L
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 26, 31)
    3 ( 79.2 )
    -1 ( 192.5 )
        Change at Week 2 (n= 26, 31)
    9 ( 140.8 )
    9 ( 189.0 )
        Change at Week 3 (n= 24, 32)
    -12 ( 170.2 )
    9 ( 197.1 )
        Change at Week 4 (n= 25, 30)
    -7 ( 169.3 )
    -5 ( 284.0 )
        Change at Week 6 (n= 22, 26)
    -61 ( 139.7 )
    -72 ( 173.4 )
        Change at Week 8 (n= 22, 29)
    -96 ( 137.7 )
    -121 ( 314.2 )
        Change at Week 12 (n= 20, 26)
    -105 ( 136.1 )
    -100 ( 274.0 )
        Change at Week 16 (n= 20, 23)
    -87 ( 157.4 )
    -114 ( 251.3 )
        Change at Week 20 (n= 18, 24)
    -134 ( 150.9 )
    -85 ( 342.9 )
        Change at Week 24 (n= 20, 25)
    -131 ( 154.4 )
    -54 ( 277.0 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Liver Biochemistry Tests: Alkaline Phosphatase

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    End point title
    		 Change from Baseline in Liver Biochemistry Tests: Alkaline Phosphatase
    End point description
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    49
    Units: U/L
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 45, 47)
    11 ( 55.3 )
    -3 ( 63.6 )
        Change at Week 2 (n= 42, 46)
    23 ( 70.7 )
    -5 ( 70.6 )
        Change at Week 3 (n= 39, 46)
    10 ( 68.7 )
    -4 ( 89.8 )
        Change at Week 4 (n= 35, 46)
    8 ( 71.7 )
    -16 ( 89.8 )
        Change at Week 6 (n= 34, 40)
    1 ( 65.3 )
    -21 ( 69.8 )
        Change at Week 8 (n= 30, 42)
    -14 ( 52.6 )
    -47 ( 97.8 )
        Change at Week 12 (n= 27, 40)
    -35 ( 65.0 )
    -52 ( 102.8 )
        Change at Week 16 (n= 28, 36)
    -26 ( 83.1 )
    -50 ( 92.8 )
        Change at Week 20 (n= 24, 35)
    -29 ( 83.3 )
    -45 ( 106.8 )
        Change at Week 24 (n= 25, 36)
    -25 ( 87.3 )
    -43 ( 101.0 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Liver Biochemistry Tests: Bilirubin

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    End point title
    		 Change from Baseline in Liver Biochemistry Tests: Bilirubin
    End point description
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    49
    Units: mg/dL
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 44, 47)
    -2.1 ( 3.99 )
    -4.3 ( 3.46 )
        Change at Week 2 (n= 42, 46)
    -2.9 ( 5.34 )
    -6.3 ( 4.99 )
        Change at Week 3 (n= 39, 46)
    -4.8 ( 7.68 )
    -7.2 ( 6.21 )
        Change at Week 4 (n= 35, 46)
    -6.3 ( 6.01 )
    -8.6 ( 6.52 )
        Change at Week 6 (n= 32, 40)
    -8.7 ( 8.22 )
    -9.3 ( 7.40 )
        Change at Week 8 (n= 30, 42)
    -8.4 ( 7.53 )
    -10.3 ( 7.36 )
        Change at Week 12 (n= 27, 40)
    -9.5 ( 7.86 )
    -11.2 ( 7.79 )
        Change at Week 16 (n= 28, 36)
    -9.4 ( 8.35 )
    -11.3 ( 8.37 )
        Change at Week 20 (n= 24, 35)
    -8.1 ( 9.88 )
    -11.3 ( 7.94 )
        Change at Week 24 (n= 25, 36)
    -9.4 ( 7.72 )
    -10.7 ( 8.09 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Liver Biochemistry Tests: Albumin

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    End point title
    		 Change from Baseline in Liver Biochemistry Tests: Albumin
    End point description
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    49
    Units: g/dL
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 45, 47)
    0.2 ( 0.45 )
    0.2 ( 0.31 )
        Change at Week 2 (n= 42, 46)
    0.3 ( 0.47 )
    0.4 ( 0.45 )
        Change at Week 3 (n= 39, 46)
    0.3 ( 0.58 )
    0.4 ( 0.54 )
        Change at Week 4 (n= 35, 46)
    0.4 ( 0.63 )
    0.5 ( 0.57 )
        Change at Week 6 (n= 34, 40)
    0.2 ( 0.82 )
    0.4 ( 0.67 )
        Change at Week 8 (n= 30, 42)
    0.3 ( 0.80 )
    0.6 ( 0.66 )
        Change at Week 12 (n= 27, 40)
    0.5 ( 0.82 )
    0.6 ( 0.68 )
        Change at Week 16 (n= 28, 36)
    0.5 ( 0.95 )
    0.7 ( 0.64 )
        Change at Week 20 (n= 24, 35)
    0.8 ( 0.92 )
    0.8 ( 0.68 )
        Change at Week 24 (n= 25, 36)
    0.8 ( 0.76 )
    0.8 ( 0.68 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Liver Biochemistry Tests: International Normalized Ratio (INR)

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    End point title
    		 Change from Baseline in Liver Biochemistry Tests: International Normalized Ratio (INR)
    End point description
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    45
    49
    Units: Ratio
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 42, 47)
    -0.1 ( 0.28 )
    -0.1 ( 0.16 )
        Change at Week 2 (n= 39, 45)
    -0.2 ( 0.32 )
    -0.2 ( 0.23 )
        Change at Week 3 (n= 34, 43)
    -0.3 ( 0.38 )
    -0.2 ( 0.25 )
        Change at Week 4 (n= 33, 46)
    -0.3 ( 0.36 )
    -0.2 ( 0.18 )
        Change at Week 6 (n= 31, 40)
    -0.2 ( 0.40 )
    -0.2 ( 0.33 )
        Change at Week 8 (n= 26, 42)
    -0.3 ( 0.43 )
    -0.3 ( 0.19 )
        Change at Week 12 (n= 23, 40)
    -0.3 ( 0.41 )
    -0.3 ( 0.19 )
        Change at Week 16 (n= 26, 35)
    -0.3 ( 0.40 )
    -0.3 ( 0.22 )
        Change at Week 20 (n= 22, 34)
    -0.3 ( 0.42 )
    -0.3 ( 0.27 )
        Change at Week 24 (n= 25, 34)
    -0.4 ( 0.36 )
    -0.3 ( 0.32 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Lille Response (score < 0.45) at Day 7

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    End point title
    		 Percentage of Participants with Lille Response (score < 0.45) at Day 7
    End point description
    The Lille score is a tool used to predict which participants with severe alcoholic hepatitis (AH) were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). The Lille score was calculated using baseline factors: age, albumin, total bilirubin, serum creatinine, prothrombin time; and the change in total bilirubin between baseline (Day 1) and Day 7. Lille response was defined as having a Lille score < 0.45. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 7
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (not applicable)
    77.1
    86.3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Selonsertib + Prednisolone v Placebo + Prednisolone
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3 [6]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [6] - P-value was calculated using the 2-sided Fisher's exact test and was used to explore differences between groups in the percentage of participants with response/non-response.

    Secondary: Percentage of Participants with a Lille Null Response (score ≥ 0.56) at Day 7

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    End point title
    		 Percentage of Participants with a Lille Null Response (score ≥ 0.56) at Day 7
    End point description
    The Lille score is a tool used to predict which participants with severe AH were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). The Lille score was calculated using baseline factors: age, albumin, total bilirubin, serum creatinine, prothrombin time; and the change in total bilirubin between baseline (Day 1) and Day 7. Lille null response was defined as having a Lille score ≥ 0.56. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 7
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (not applicable)
    14.6
    7.8
    No statistical analyses for this end point

    Secondary: Lille Score at Day 7 as a Continuous Variable

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    End point title
    		 Lille Score at Day 7 as a Continuous Variable
    End point description
    The Lille score is a tool used to predict which participants with severe AH were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). The Lille score was calculated using baseline factors: age, albumin, total bilirubin, serum creatinine, prothrombin time; and the change in total bilirubin between baseline (Day 1) and Day 7. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 7
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    48
    Units: Lille score
        arithmetic mean (standard deviation)
    0.254 ( 0.2495 )
    0.178 ( 0.1534 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Estimated Mortality at Month 2 and Month 6: Combined Scoring Including Lille Score at Day 7 and Baseline Model for End-Stage Liver Disease (MELD) Score

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    End point title
    		 Percentage of Participants With Estimated Mortality at Month 2 and Month 6: Combined Scoring Including Lille Score at Day 7 and Baseline Model for End-Stage Liver Disease (MELD) Score
    End point description
    The Lille score is a tool used to predict which participants with severe AH were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity. A scoring system combining the Lille score at Day 7 and the baseline MELD score was used to calculate the percentage of participants expected to die by Month 2 and by Month 6. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7 Time Points Used to Calculate Overall Mortality Risk at Months 2 and 6
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    47
    48
    Units: Percentage of participants
    arithmetic mean (standard deviation)
        Mortality Risk at Month 2
    13.0 ( 10.94 )
    9.7 ( 6.57 )
        Mortality Risk at Month 6
    19.8 ( 15.15 )
    15.2 ( 9.28 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Prognostic Index: Model for End-Stage Liver Disease (MELD) Score

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    End point title
    		 Change from Baseline in Prognostic Index: Model for End-Stage Liver Disease (MELD) Score
    End point description
    MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity. Change from Baseline was calculated as the value at endpoint minus the value at Baseline. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    49
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 44, 47)
    -2 ( 2.9 )
    -3 ( 2.6 )
        Change at Week 2 (n= 42, 45)
    -3 ( 4.0 )
    -5 ( 3.5 )
        Change at Week 3 (n= 36, 43)
    -4 ( 4.7 )
    -5 ( 3.9 )
        Change at Week 4 (n= 35, 46)
    -5 ( 5.2 )
    -6 ( 3.9 )
        Change at Week 6 (n= 32, 39)
    -6 ( 6.1 )
    -7 ( 5.2 )
        Change at Week 8 (n= 28, 41)
    -7 ( 5.9 )
    -8 ( 4.7 )
        Change at Week 12 (n= 26, 40)
    -7 ( 6.0 )
    -10 ( 4.8 )
        Change at Week 16 (n= 29, 35)
    -7 ( 6.5 )
    -9 ( 5.5 )
        Change at Week 20 (n= 23, 34)
    -8 ( 7.6 )
    -10 ( 5.4 )
        Change at Week 24 (n= 26, 34)
    -9 ( 6.1 )
    -10 ( 5.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Prognostic Index: Child-Pugh-Turcotte (CPT) Score

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    End point title
    		 Change from Baseline in Prognostic Index: Child-Pugh-Turcotte (CPT) Score
    End point description
    CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation. Scores can range from 5 to 15, with higher scores indicating a greater severity of disease. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    45
    49
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 41, 47)
    0 ( 1.5 )
    -1 ( 0.9 )
        Change at Week 2 (n= 39, 45)
    -1 ( 1.4 )
    -1 ( 1.4 )
        Change at Week 3 (n= 34, 43)
    -1 ( 1.7 )
    -1 ( 1.4 )
        Change at Week 4 (n= 33, 46)
    -1 ( 1.9 )
    -2 ( 1.7 )
        Change at Week 6 (n= 28, 39)
    -1 ( 2.1 )
    -2 ( 1.7 )
        Change at Week 8 (n= 26, 41)
    -2 ( 2.4 )
    -2 ( 1.5 )
        Change at Week 12 (n= 23, 40)
    -2 ( 2.2 )
    -3 ( 1.7 )
        Change at Week 16 (n= 26, 35)
    -2 ( 2.4 )
    -3 ( 1.8 )
        Change at Week 20 (n= 22, 34)
    -3 ( 2.3 )
    -3 ( 1.6 )
        Change at Week 24 (n= 24, 34)
    -3 ( 1.7 )
    -3 ( 1.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Prognostic Index: Maddrey Discriminant Function (DF) Score

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    End point title
    		 Change from Baseline in Prognostic Index: Maddrey Discriminant Function (DF) Score
    End point description
    Baseline Maddrey DF score is a prognostic tool used to determine the next step of treatment based on the severity of AH. Maddrey DF score of < 32 indicates mild to moderate AH and a lower chance of death in the next few months. Maddrey DF score of ≥ 32 indicates severe AH and a higher chance of death in the next few months. The score has no bounds. Participants in the Full Analysis Set with available baseline and any postbaseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 24 weeks
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    42
    49
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 1 (n= 39, 47)
    -8 ( 15.2 )
    -10 ( 7.7 )
        Change at Week 2 (n= 37, 45)
    -13 ( 18.1 )
    -15 ( 11.4 )
        Change at Week 3 (n= 33, 43)
    -17 ( 21.8 )
    -17 ( 13.3 )
        Change at Week 4 (n= 31, 46)
    -19 ( 20.0 )
    -19 ( 10.9 )
        Change at Week 6 (n= 27, 39)
    -20 ( 23.2 )
    -19 ( 17.6 )
        Change at Week 8 (n= 25, 41)
    -19 ( 21.5 )
    -21 ( 12.0 )
        Change at Week 12 (n= 22, 40)
    -23 ( 21.8 )
    -23 ( 12.2 )
        Change at Week 16 (n= 24, 35)
    -23 ( 22.6 )
    -23 ( 13.7 )
        Change at Week 20 (n= 21, 34)
    -25 ( 26.2 )
    -23 ( 15.4 )
        Change at Week 24 (n= 23, 34)
    -27 ( 21.7 )
    -22 ( 16.9 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Survival at Day 28 Using Kaplan-Meier

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    End point title
    		 Percentage of Participants With Survival at Day 28 Using Kaplan-Meier
    End point description
    The percentage of participants with survival at Day 28 using Kaplan-Meier was calculated. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (confidence interval 95%)
    95.7 (84.0 to 98.9)
    96.1 (85.2 to 99.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Survival at Week 8 Using Kaplan-Meier

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    End point title
    		 Percentage of Participants With Survival at Week 8 Using Kaplan-Meier
    End point description
    The percentage of participants with survival at Week 8 using Kaplan-Meier was calculated. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (confidence interval 95%)
    80.0 (65.1 to 89.1)
    94.0 (82.6 to 98.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Survival at Week 12 Using Kaplan-Meier

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    End point title
    		 Percentage of Participants With Survival at Week 12 Using Kaplan-Meier
    End point description
    The percentage of participants with survival at Week 12 using Kaplan-Meier was calculated. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (confidence interval 95%)
    75.3 (59.8 to 85.5)
    89.9 (77.5 to 95.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Survival at Week 24 Using Kaplan-Meier

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    End point title
    		 Percentage of Participants With Survival at Week 24 Using Kaplan-Meier
    End point description
    The percentage of participants with survival at Week 24 using Kaplan-Meier was calculated. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Number of subjects analysed
    48
    51
    Units: Percentage of participants
        number (confidence interval 95%)
    70.3 (54.3 to 81.6)
    81.7 (67.7 to 90.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events: Up to Day 28 plus 30 days; All-Cause Mortality: Up to 24 weeks
    Adverse event reporting additional description
    Safety Analysis Set included all participants who were randomized and took at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Selonsertib + Prednisolone
    Reporting group description
    		 Participants received selonsertib (GS-4997) 18 mg tablet orally once daily + prednisolone 40 mg (4 x 10 mg tablets) orally once daily for 28 days.

    Reporting group title
    Placebo + Prednisolone
    Reporting group description
    		 Participants received placebo-to-match selonsertib 18 mg tablet orally once daily + prednisolone 40 mg (4 x 10 mg tablets) orally once daily for 28 days.

    Serious adverse events
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 50 (50.00%)
    21 / 52 (40.38%)
         number of deaths (all causes)
    14
    9
         number of deaths resulting from adverse events
    8
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood lactic acid increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 52 (9.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain lower
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Hepatorenal syndrome
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Alcoholic liver disease
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cirrhosis alcoholic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Peritonitis bacterial
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal abscess central nervous system
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection fungal
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Selonsertib + Prednisolone Placebo + Prednisolone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 50 (86.00%)
    42 / 52 (80.77%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 52 (5.77%)
         occurrences all number
    4
    3
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    12 / 50 (24.00%)
    7 / 52 (13.46%)
         occurrences all number
    13
    9
    Headache
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 52 (3.85%)
         occurrences all number
    4
    2
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    12 / 50 (24.00%)
    11 / 52 (21.15%)
         occurrences all number
    12
    12
    Fatigue
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 52 (11.54%)
         occurrences all number
    4
    6
    Oedema
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 52 (11.54%)
         occurrences all number
    4
    6
    Asthenia
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 52 (3.85%)
         occurrences all number
    4
    2
    Pyrexia
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 52 (7.69%)
         occurrences all number
    1
    5
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    15 / 50 (30.00%)
    14 / 52 (26.92%)
         occurrences all number
    15
    14
    Constipation
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 52 (9.62%)
         occurrences all number
    6
    5
    Diarrhoea
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 52 (7.69%)
         occurrences all number
    4
    4
    Nausea
         subjects affected / exposed
    6 / 50 (12.00%)
    2 / 52 (3.85%)
         occurrences all number
    7
    2
    Varices oesophageal
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 52 (7.69%)
         occurrences all number
    3
    4
    Abdominal pain upper
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 52 (1.92%)
         occurrences all number
    4
    1
    Vomiting
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 52 (1.92%)
         occurrences all number
    5
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 52 (11.54%)
         occurrences all number
    3
    6
    Epistaxis
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 52 (3.85%)
         occurrences all number
    5
    2
    Cough
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 52 (5.77%)
         occurrences all number
    2
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 50 (16.00%)
    4 / 52 (7.69%)
         occurrences all number
    8
    4
    Rash
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 52 (9.62%)
         occurrences all number
    2
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 52 (9.62%)
         occurrences all number
    5
    5
    Agitation
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 52 (1.92%)
         occurrences all number
    7
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 52 (7.69%)
         occurrences all number
    3
    4
    Infections and infestations
    Sepsis
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 52 (0.00%)
         occurrences all number
    5
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    15 / 50 (30.00%)
    1 / 52 (1.92%)
         occurrences all number
    15
    1
    Hypokalaemia
         subjects affected / exposed
    7 / 50 (14.00%)
    4 / 52 (7.69%)
         occurrences all number
    7
    4
    Hyperglycaemia
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 52 (7.69%)
         occurrences all number
    4
    5
    Hypomagnesaemia
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 52 (5.77%)
         occurrences all number
    4
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 52 (7.69%)
         occurrences all number
    1
    6
    Hypophosphataemia
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 52 (1.92%)
         occurrences all number
    4
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2016
    -Added 2 inclusion criteria to further define the clinical diagnosis of severe AH -Updated guidance on subject management during the hospitalization period -Removed the interim analysis for decision-making purposes and clarified when the primary analysis would be conducted -Updated data included for Section 1.2.5. Clinical Trials for GS-4997 -Clarified the fixed dosing of PRED (ie, no tapering of the PRED dose) -Updated subject SEL/placebo and PRED stopping rules and a relevant paragraph in the toxicity management section of the protocol -Added adjudication criteria for the evaluation of potential drug-induced liver injury (DILI) -Added trial stopping criteria and clarified the Data
    11 Jan 2017
    -Removed information in the Introduction that was included in the current version of the Investigators Brochure -Added data from the GS-US-384-1497 study to the Introduction -Clarified that local laboratory testing results could be used to confirm eligibility; made other clarifications to study procedures throughout -Added mortality assessment at Week 8 as a secondary objective -Added assessment of changes in Fibroscan as an exploratory objective -Updated text related to the Lille score calculation at Day 7 and PRED discontinuation for subjects with a null response at Day 7; added Lille null response as a secondary endpoint -Added FibroScan in subjects without ascites, for sites that have instrument capability, to the study procedures -Added exclusion criteria #10 to exclude subjects with clinical suspicion of pneumonia -Updated exclusion criteria #21 to allow subjects to enroll if systemic corticosteroids were started 3 or fewer days before baseline/Day 1 -Updated exclusion criteria #22 to remove the prohibition of CYP3A4 inhibitors. Strong CYP3A4 inducers continued to be disallowed. -Added standardized treatment guidelines for sepsis -Provided guidance for the treatment of pneumonia infections -Added text to allow subjects to be randomized and stratified by MELD score based on local laboratory testing -Included additional biomarkers for future assessments -Clarified reporting periods for nonserious adverse events (AEs) and serious adverse events (SAEs) -Provided guidance on PRED dose reduction or interruption
    04 Aug 2017
    -Inserted updated information on efficacy results from previous clinical trials in Section 1 -HepQuant testing and all references to the HepQuant substudy were removed from the protocol. -Clarified use of chest x-ray, HBV, HCV, HIV serology, and urine drug testing to allow results (including hospital transfers) within 10 days of screening to determine eligibility -Added language regarding re-screening of subjects -Clarified posttreatment visit requirements for subjects prematurely discontinued from both study drugs -Clarified liver biopsy requirement regarding inadequate biopsy samples that do not suggest an alternative diagnosis to AH -Clarified PK language regarding dialysis and subjects on renal replacement therapy -Changed ALT/AST stopping criteria to exclude > 5 x postbaseline nadir for ALT and AST; and allowed for investigator discretion if there is an alternative cause -Clarified Lille score parameters for study drug discontinuation -Updated Appendix 2 to provide further clarification on certain study procedures

    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.
    An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.
    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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