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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter, dose-range, proof-of-concept, 24-week treatment study of IVA337 in adult subjects with nonalcoholic steatohepatitis (NASH)

    Summary
    EudraCT number
    		 2016-001979-70
    Trial protocol
    		 BE   GB   CZ   AT   PT   ES   NL   PL   FR   BG   SI   IT  
    Global end of trial date
    16 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2021
    First version publication date
    01 Apr 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IVA_01_337_HNAS_16_002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03008070
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inventiva S.A.
    Sponsor organisation address
    50 rue de Dijon, Daix, France, 21121
    Public contact
    Mathilde Merot, Regulatory Affairs Manager, INVENTIVA S.A., +33 380447616, native.public@inventivapharma.com
    Scientific contact
    Michael Cooreman, Chief Medical Officer , INVENTIVA S.A., +33 380447616, native.scientists@inventivapharma.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
    16 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study main objective was to assess the safety and the efficacy (based on the activity part of the Steatosis Activity Fibrosis [SAF-A] histological score [inflammation and ballooning]) of a 24-week treatment with 2 doses of lanifibranor (800 mg/day and 1200 mg/day) in NASH adult patients.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jan 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
    Slovenia: 1
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 32
    Country: Number of subjects enrolled
    Bulgaria: 55
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Mauritius: 7
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Switzerland: 4
    Worldwide total number of subjects
    247
    EEA total number of subjects
    179
    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)
    199
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment of patients started in January 2017, and last patient was recruited on March 2019. A total of 868 patients were screened for the study.

    Pre-assignment
    Screening details
    		 Patients were invited to participate into the study by their referent doctor according to the patient’s medical records. Patients had to fulfil all the inclusion and none of the exclusion criteria to be eligible. A total of 247 patients were randomised. Main reason for non randomization was inclusion/exclusion criteria not met (470 - 76%).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LAN800
    Arm description
    		 Patients who received lanifibranor 800mg daily: 2 tablets of lanifibranor and 1 tablet of placebo.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanifibranor
    Investigational medicinal product code
    IVA337
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    White to off-white, bi-convex tablet of 400mg to be taken orally. Each tablet contained 400 mg of the active ingredient in an immediate release formulation.

    Arm title
    		 LAN1200
    Arm description
    		 Patients who received lanifibranor 1200mg daily: 3 tablets of lanifibranor
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanifibranor
    Investigational medicinal product code
    IVA337
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    White to off-white, bi-convex tablet of 400mg to be taken orally. Each tablet contained 400 mg of the active ingredient in an immediate release formulation.

    Arm title
    		 Placebo
    Arm description
    		 Patients who received placebo: 3 tablets of placebo daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match lanifibranor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated tablets containing a mixture of lactose monohydrate, microcrystalline cellulose, sodium starch and magnesium stearate served as placebo. 3 tablets to be taken orally.

    Number of subjects in period 1
    		LAN800 LAN1200 Placebo
    Started
    83
    83
    81
    Completed
    77
    77
    74
    Not completed
    6
    6
    7
         Consent withdrawn by subject
    -
    2
    1
         Adverse event, non-fatal
    3
    3
    3
         Non compliance
    -
    -
    1
         Non-compliance
    1
    -
    -
         Withdrawal by patient + Adverse event non fatal
    1
    -
    -
         Lost to follow-up
    1
    1
    -
         Use of prohibited drug
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LAN800
    Reporting group description
    		 Patients who received lanifibranor 800mg daily: 2 tablets of lanifibranor and 1 tablet of placebo.

    Reporting group title
    LAN1200
    Reporting group description
    		 Patients who received lanifibranor 1200mg daily: 3 tablets of lanifibranor

    Reporting group title
    Placebo
    Reporting group description
    		 Patients who received placebo: 3 tablets of placebo daily

    Reporting group values
    		 LAN800 LAN1200 Placebo Total
    Number of subjects
    		 83 83 81 247
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 69 67 63 199
        From 65-84 years
    		 14 16 18 48
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.0 ( 10.4 ) 52.2 ( 13.8 ) 53.4 ( 13.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 54 49 41 144
        Male
    		 29 34 40 103

    End points

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    End points reporting groups
    Reporting group title
    LAN800
    Reporting group description
    		 Patients who received lanifibranor 800mg daily: 2 tablets of lanifibranor and 1 tablet of placebo.

    Reporting group title
    LAN1200
    Reporting group description
    		 Patients who received lanifibranor 1200mg daily: 3 tablets of lanifibranor

    Reporting group title
    Placebo
    Reporting group description
    		 Patients who received placebo: 3 tablets of placebo daily

    Primary: SAF Activity score (SAF-A) decrease of at least 2 points with no worsening of the CRN Fibrosis score (CRN-F)

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    End point title
    		 SAF Activity score (SAF-A) decrease of at least 2 points with no worsening of the CRN Fibrosis score (CRN-F)
    End point description
    SAF-A is the activity part of the Steatosis Activity Fibrosis [SAF] histological score, calculated as the sum of lobular inflamation score and balloning score. No worsening of fibrosis means that the CRN fibrosis score (CRN-F) remains stable or decreases.
    End point type
    Primary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number of patients
        Yes
    34
    41
    22
        No
    49
    42
    59
    Statistical analysis title
    		 Comparison of LAN800 vs Placebo
    Statistical analysis description
    The primary endpoint was a binary outcome (Yes/No). Responders rates were compared between the placebo and lanifibranor 800 mg at the end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on diabetic status at baseline (that was the stratified factors in the randomisation). The CMH risk ratio is used to estimate the effect size. Patients with missing data are considered as non-responders.
    Comparison groups
    Placebo v LAN800
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.061
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 2.12
    Statistical analysis title
    		 Comparison of LAN1200 vs Placebo
    Statistical analysis description
    The primary endpoint was a binary outcome (Yes/No). Responders rates were compared between the placebo and lanifibranor 1200 mg at the end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on diabetic status at baseline (that was the stratified factors in the randomisation). The CMH risk ratio is used to estimate the effect size. Patients with missing data are considered as non-responders.
    Comparison groups
    LAN1200 v Placebo
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 2.4

    Secondary: NASH improvement

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    End point title
    		 NASH improvement
    End point description
    NASH improvement is defined as a decrease of at least 2 points in NAS score (sum of CRN Steatosis, Inflammation and Ballooning scores) without worsening of CRN Fibrosis score.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    43
    53
    26
        No
    40
    30
    55
    No statistical analyses for this end point

    Secondary: NASH resolution and no worsening of fibrosis

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    End point title
    		 NASH resolution and no worsening of fibrosis
    End point description
    Resolution of NASH is defined as a CRN Inflammation score equal to 0 or 1, and a CRN Ballooning score equal to 0. No worsening of fibrosis means that the CRN fibrosis score remains stable or decreases.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    27
    37
    15
        No
    56
    46
    66
    No statistical analyses for this end point

    Secondary: Improvement of fibrosis by at least 1 stage and no worsening of NASH

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    End point title
    		 Improvement of fibrosis by at least 1 stage and no worsening of NASH
    End point description
    Improvement of fibrosis is defined as a decrease of at least one stage in CRN Fibrosis score. No worsening of NASH is defined as no increase of CRN Steatosis score, no increase of CRN Inflammation score ans no increase of CRN Ballooning score.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    23
    35
    19
        No
    60
    48
    62
    No statistical analyses for this end point

    Secondary: Activity (SAF-A) improvement

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    End point title
    		 Activity (SAF-A) improvement
    End point description
    SAF-A is the activity part of the Steatosis Activity Fibrosis [SAF] histological score, calculated as the sum of lobular inflamation score and balloning score. Improvement of SAF-A is defined as a decrease of at least 1 point
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    54
    62
    40
        No
    29
    21
    41
    No statistical analyses for this end point

    Secondary: Steatosis (CRN-S) improvement

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    End point title
    		 Steatosis (CRN-S) improvement
    End point description
    Improvement of CRN Steatosis score (CRN-S) is defined as a decrease of at least 1 point.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    46
    54
    21
        No
    37
    29
    60
    No statistical analyses for this end point

    Secondary: Lobular inflammation (CRN-I) improvement

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    End point title
    		 Lobular inflammation (CRN-I) improvement
    End point description
    Improvement of CRN Lobular inflammation score (CRN-I) is defined as a decrease of at least 1 point.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    34
    43
    30
        No
    49
    40
    51
    No statistical analyses for this end point

    Secondary: Hepatocyte balooning (CRN-B) improvement

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    End point title
    		 Hepatocyte balooning (CRN-B) improvement
    End point description
    Improvement of CRN Ballooning (CRN-B) is defined as a decrease of at least 1 point.
    End point type
    Secondary
    End point timeframe
    From basline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    54
    60
    37
        No
    29
    23
    44
    No statistical analyses for this end point

    Secondary: Fibrosis (CRN-F) improvement

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    End point title
    		 Fibrosis (CRN-F) improvement
    End point description
    Improvement of CRN Fibrosis score (CRN-F) is defined as a decrease of at least 1 point.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    28
    36
    22
        No
    55
    47
    59
    No statistical analyses for this end point

    Secondary: Modified ISHAK Fibrosis (ISHAK-F) improvement

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    End point title
    		 Modified ISHAK Fibrosis (ISHAK-F) improvement
    End point description
    Improvement of Modified ISHAK Fibrosis (ISHAK-F) is defined as a decrease of at least 1 point.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    32
    41
    25
        No
    51
    42
    56
    No statistical analyses for this end point

    Secondary: Absolute change in ALT

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    End point title
    		 Absolute change in ALT
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    74
    72
    Units: U/L
        arithmetic mean (standard error)
    -26.08 ( 3.85 )
    -24.54 ( 3.82 )
    -1.4 ( 3.88 )
    No statistical analyses for this end point

    Secondary: Absolute change in AST

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    End point title
    		 Absolute change in AST
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    74
    72
    Units: U/L
        arithmetic mean (standard error)
    -15.11 ( 3.2 )
    -12.04 ( 3.17 )
    -0.08 ( 3.22 )
    No statistical analyses for this end point

    Secondary: Absolute change in GGT

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    End point title
    		 Absolute change in GGT
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    74
    72
    Units: U/L
        arithmetic mean (standard error)
    -43.38 ( 5.61 )
    -27.87 ( 5.57 )
    4.41 ( 5.65 )
    No statistical analyses for this end point

    Secondary: Absolute change in Fibrinogen

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    End point title
    		 Absolute change in Fibrinogen
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    69
    73
    73
    Units: g/L
        arithmetic mean (standard error)
    -0.17 ( 0.08 )
    -0.1 ( 0.07 )
    0.02 ( 0.07 )
    No statistical analyses for this end point

    Secondary: Absolute change in Hs-CRP

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    End point title
    		 Absolute change in Hs-CRP
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    74
    72
    Units: mg/L
        arithmetic mean (standard error)
    -2.05 ( 0.47 )
    -1.37 ( 0.46 )
    0.11 ( 0.47 )
    No statistical analyses for this end point

    Secondary: Absolute change in Alpha2 macroglobulin

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    End point title
    		 Absolute change in Alpha2 macroglobulin
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    68
    72
    71
    Units: gram(s)/litre
        arithmetic mean (standard error)
    0.15 ( 0.40 )
    0.13 ( 0.38 )
    0.05 ( 0.35 )
    No statistical analyses for this end point

    Secondary: Absolute change in Haptoglobulin

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    End point title
    		 Absolute change in Haptoglobulin
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    74
    72
    Units: g/L
        arithmetic mean (standard deviation)
    -0.053 ( 0.256 )
    -0.099 ( 0.378 )
    0.074 ( 0.291 )
    No statistical analyses for this end point

    Secondary: Absolute change of Fasting Plasma Glucose

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    End point title
    		 Absolute change of Fasting Plasma Glucose
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    71
    73
    72
    Units: mmol/L
        arithmetic mean (standard error)
    -0.78 ( 0.12 )
    -0.6 ( 0.12 )
    0.24 ( 0.12 )
    No statistical analyses for this end point

    Secondary: Absolute change in Insulin

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    End point title
    		 Absolute change in Insulin
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    68
    65
    66
    Units: pmol/L
        arithmetic mean (standard error)
    -118.66 ( 11.66 )
    -114.91 ( 11.75 )
    -35.7 ( 11.6 )
    No statistical analyses for this end point

    Secondary: Absolute change in HOMA index

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    End point title
    		 Absolute change in HOMA index
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    64
    63
    65
    Units: NA
        arithmetic mean (standard error)
    -5.79 ( 0.58 )
    -5.46 ( 0.58 )
    -1.47 ( 0.57 )
    No statistical analyses for this end point

    Secondary: Absolute change in HbA1c

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    End point title
    		 Absolute change in HbA1c
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    74
    72
    Units: percentage
        arithmetic mean (standard error)
    -0.38 ( 0.05 )
    -0.41 ( 0.05 )
    0.07 ( 0.05 )
    No statistical analyses for this end point

    Secondary: Absolute change in Total Cholesterol

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    End point title
    		 Absolute change in Total Cholesterol
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    74
    73
    Units: mmol/L
        arithmetic mean (standard error)
    -0.02 ( 0.08 )
    -0.07 ( 0.07 )
    0.01 ( 0.08 )
    No statistical analyses for this end point

    Secondary: Absolute change of HDL-Cholesterol

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    End point title
    		 Absolute change of HDL-Cholesterol
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    71
    74
    73
    Units: mmol/L
        arithmetic mean (standard error)
    0.16 ( 0.02 )
    0.11 ( 0.02 )
    0.01 ( 0.02 )
    No statistical analyses for this end point

    Secondary: Absolute change of LDL-Cholesterol

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    End point title
    		 Absolute change of LDL-Cholesterol
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    71
    73
    69
    Units: mmol/L
        arithmetic mean (standard error)
    0.03 ( 0.07 )
    0.03 ( 0.07 )
    0.01 ( 0.07 )
    No statistical analyses for this end point

    Secondary: Absolute change in Triglycerides

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    End point title
    		 Absolute change in Triglycerides
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    71
    74
    72
    Units: mmol/L
        arithmetic mean (standard error)
    -0.49 ( 0.09 )
    -0.44 ( 0.09 )
    0.06 ( 0.09 )
    No statistical analyses for this end point

    Secondary: Absolute change in Apo A1

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    End point title
    		 Absolute change in Apo A1
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    72
    73
    72
    Units: mg/dL
        arithmetic mean (standard error)
    -0.29 ( 2.19 )
    -4.39 ( 2.16 )
    0.03 ( 2.18 )
    No statistical analyses for this end point

    Secondary: Absolute change in Adiponectin

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    End point title
    		 Absolute change in Adiponectin
    End point description
    Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    66
    73
    72
    Units: microgram(s)/millilitre
        arithmetic mean (standard error)
    11.95 ( 1.51 )
    17.12 ( 1.44 )
    -0.35 ( 1.44 )
    No statistical analyses for this end point

    Secondary: Resolution of NASH and improvement of fibrosis by at least 1 stage

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    End point title
    		 Resolution of NASH and improvement of fibrosis by at least 1 stage
    End point description
    Resolution of NASH is defined as a CRN Inflammation score equal to 0 or 1, and a CRN Ballooning score equal to 0. Improvement of fibrosis is defined as a decrease of at least one stage in CRN Fibrosis score.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24.
    End point values
    		 LAN800 LAN1200 Placebo
    Number of subjects analysed
    83
    83
    81
    Units: number
        Yes
    17
    26
    6
        No
    66
    57
    75
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On or after the first dose of treatment up to 30 days post last dose.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    LAN800
    Reporting group description
    		 Patients who received lanifibranor 800mg daily: 2 tablets of lanifibranor and 1 tablet of placebo.

    Reporting group title
    LAN1200
    Reporting group description
    		 Patients who received lanifibranor 1200mg daily: 3 tablets of lanifibranor

    Reporting group title
    Placebo
    Reporting group description
    		 Patients who received placebo: 3 tablets of placebo daily

    Serious adverse events
    		 LAN800 LAN1200 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 83 (3.61%)
    7 / 83 (8.43%)
    3 / 81 (3.70%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 83 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Foot operation
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 83 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Pneumobilia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Undifferentiated connective tissue disease
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 83 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LAN800 LAN1200 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 83 (30.12%)
    23 / 83 (27.71%)
    19 / 81 (23.46%)
    Investigations
    Weight increased
         subjects affected / exposed
    8 / 83 (9.64%)
    7 / 83 (8.43%)
    0 / 81 (0.00%)
         occurrences all number
    8
    7
    0
    Transaminases increased
         subjects affected / exposed
    5 / 83 (6.02%)
    2 / 83 (2.41%)
    0 / 81 (0.00%)
         occurrences all number
    5
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 83 (4.82%)
    7 / 83 (8.43%)
    4 / 81 (4.94%)
         occurrences all number
    6
    7
    5
    Dizziness
         subjects affected / exposed
    2 / 83 (2.41%)
    6 / 83 (7.23%)
    3 / 81 (3.70%)
         occurrences all number
    3
    6
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 83 (2.41%)
    10 / 83 (12.05%)
    6 / 81 (7.41%)
         occurrences all number
    2
    10
    6
    Oedema peripheral
         subjects affected / exposed
    5 / 83 (6.02%)
    7 / 83 (8.43%)
    2 / 81 (2.47%)
         occurrences all number
    5
    7
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 83 (9.64%)
    10 / 83 (12.05%)
    1 / 81 (1.23%)
         occurrences all number
    8
    11
    2
    Nausea
         subjects affected / exposed
    8 / 83 (9.64%)
    7 / 83 (8.43%)
    3 / 81 (3.70%)
         occurrences all number
    8
    7
    3
    Constipation
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 83 (6.02%)
    6 / 81 (7.41%)
         occurrences all number
    3
    5
    6
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 83 (3.61%)
    3 / 83 (3.61%)
    5 / 81 (6.17%)
         occurrences all number
    4
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Mar 2017
    • Inclusion/exclusion criteria were updated: o The contraceptive method was to be followed for at least one menstruation cycle after the end of the study. o Patients with type 2 diabetes on insulin, patients with any clinically significant ECG abnormality reported by central ECG reading, patients with CPK >5xULN and patients with osteopenia or any other well documented bone disease with the exception of patients treated with vitamin D and/or calcium based supplements for preventive reasons, were to be excluded from the study. Also, details of the excipients were added to the criterion excluding patients with hypersensitivity to IMP excipients. • Prohibited and allowed medications update: i) specification of the prohibited anticoagulants medications (warfarin, dabigatran, rivaroxaban and apixaban); ii) addition of some medications allowed during the study (antiplatelet agents, aspirin, ticlopidine, clopidogrel, prasugrel and ticagrelor).
    03 Aug 2017
    • The initial study enrolment period of 6 months was extended to 16 months. Consequently, the expected study completion date was extended to Q1 2019, • Regarding laboratory assays, beta human chorionic gonadotropin (βHCG) was added at screening as biological parameter to collect to assess pregnancy, INR was added to specify the measure used to express the prothrombin time and the laboratory category for plasma iron, transferrin and ferritin was updated to chemistry to be consistent with the Clinical Data Interchange Standards Consortium (CDISC). • Number of kits to be dispensed at each visit was clarified as well as the process for accountability. • Upon request of DSMB members, the frequency of the DSMB meeting was updated: the formal analysis meeting to review data was to be held every 50 patients for the entire duration of the study.
    02 Nov 2017
    • A liver biopsy was added as screening tests procedures when a liver biopsy was not performed within 6 months from screening. For these patients, the screening phase was organised in 3 successive and detailed steps to avoid unnecessary biopsy and the screening period was extended to 8 weeks. • Two (2) exclusion criteria were added for patients undergoing an MRI/LMS in the selected centres: patients suffering from claustrophobia to a degree to not tolerate MRI scanning procedure and patients with metallic implant of any sort preventing MRI examination were to be excluded from the study. • A FibroScan® was to be performed at screening and at the end of the treatment period, if available, to evaluate TE and CAP. FibroScan® at screening was mandatory only if a liver biopsy within the 6 months prior screening was not available. • In selected centres (Bulgaria), a LMS was set for patient’s liver examination at screening, to propose to undergo a liver biopsy only for the patients who would have had a higher probability of fulfilling the histological inclusion criteria.
    09 Jul 2019
    • Minor modifications of anti-diabetic treatments or dosages were allowed if done in a context of stable type 2 diabetes (HbA1c <8.5% in the previous 6 months). • Exclusion criteria were clarified: o Patients with a history of sustained excess alcohol ingestion in the year before the pre-study treatment biopsy were to be excluded. o Details on dosages of drugs known to produce hepatic steatosis were given as exclusion criteria. Similarly, the route of administration (oral) was specified for corticosteroids as prohibited concomitant medication. • The percent of patients with at least one-point improvement of fibrosis score on a 4-point scale (SAF) without worsening of NASH, defined as no increase for ballooning, or inflammation, or steatosis, using the SAF scoring system, from baseline to end of treatment (Week 24) was added as secondary endpoint. • The following exploratory endpoints were added: TE and CAP changes from baseline to the end of treatment and if deemed necessary, the change in the semi-quantitative score of ballooning and stellate cell activation from baseline to end of treatment. • P3NP was added as central laboratory test for efficacy assessment to be performed before and at the end of the treatment period.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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