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    Summary
    EudraCT Number:2016-001979-70
    Sponsor's Protocol Code Number:IVA_01_337_HNAS_16_002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-001979-70
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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)
    A.3.2Name or abbreviated title of the trial where available
    IVA_01_337_HNAS_16_002
    A.4.1Sponsor's protocol code numberIVA_01_337_HNAS_16_002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorInventiva S.A.
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportInventiva S.A.
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINVENTIVA S.A.
    B.5.2Functional name of contact pointMathilde Merot, Reguatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address50, Rue de Dijon
    B.5.3.2Town/ cityDaix
    B.5.3.3Post code21121
    B.5.3.4CountryFrance
    B.5.4Telephone number +33 0 380 447 589
    B.5.5Fax number +33 0 380 447 561
    B.5.6E-mailmathilde.merot@inventivapharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLanifibranor
    D.3.2Product code IVA337
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLanifibranor
    D.3.9.1CAS number 927961-18-0
    D.3.9.2Current sponsor codeIVA337
    D.3.9.3Other descriptive name1-(6-BENZOTHIAZOLYLSULFONYL)-5-CHLORO-1H-INDOLE-2-BUTANOIC ACID
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Nonalcoholic steatohepatitis (NASH)
    E.1.1.1Medical condition in easily understood language
    Nonalcoholic steatohepatitis (NASH)
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and the efficacy on the activity part of the Steatosis Activity Fibrosis histological score (inflammation and ballooning) of a 24-week treatment with two doses of Lanifibranor (800, 1200 mg/24h) in NASH adult patients.
    E.2.2Secondary objectives of the trial
    Pharmacokinetics.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Adult subjects, age ≥18 years.
    -NASH histological diagnosis according to the currently accepted definition of both EASL and AASLD (1–3), requiring the combined presence of steatosis (any degree ≥ 5%) + lobular inflammation of any degree + liver cell ballooning of any amount, on a liver biopsy performed ≤ 6 months before screening in the study or at screening, and confirmed by central reading during the screening period and
    a.SAF Activity score of 3 or 4 (>2)
    b.SAF Steatosis score ≥ 1
    c.SAF Fibrosis score: < 4
    -Subject agrees to have a liver biopsy performed after 24 weeks of treatment
    -Compensated liver disease with the following hematologic and biochemical criteria before randomization:
    oALT < 10xULN
    oHemoglobin ≥ 110 g/L (11 g/dL) for females and ≥ 120 g/L (12 g/dL) for males
    oWhite blood cell (WBC) > 2.5 10^9/L (2.5 10^3/µL)
    oNeutrophil count > 1.5 10^9/L (1.5 10^3/µL)
    oPlatelets > 100 10^9/L (100 10^3/µL)
    oTotal bilirubin < 35µmol/L(2.06 mg/dL). Patients with bilirubin ≥ 35µmol/L(2.06 mg/dL) can be included if non-conjugated bilirubin in the setting of a Gilbert syndrome.
    oAlbumin > 36 g/L(3.6 g/dL)
    oInternational Normalized Ratio (INR) < 1.4
    oSerum creatinin < 115 µmol/L (1.3 mg/dL) (men) or < 97 µmol/L (1.1 mg/dL) (women) or estimated glomerular filtration rate ≥ 60 mL/min/1.73m2
    -No other cause of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, HCV, Wilson’s, α-1-antitrypsin deficiency, hemochromatosis etc…)considered to have an impact on the patient's safety or on the efficacy evaluation
    -If applicable, have a stable type 2 diabetes, defined as HbA1c ≤ 8.5% and fasting glycemia <10 mmol/L(180 mg/dL), no introduction of new medication in the previous 6 months, and no new symptoms associated with decompensated diabetes in the previous 3 months. Minor modifications of anti-diabetic treatments or dosages are allowed if done in a context of stable type 2 diabetes, i.e. HbA1c ≤ 8.5% in the previous 6 months.
    -Have a stable weight since the liver biopsy was performed defined by no more than a 5 % loss of initial body weight Negative pregnancy test or post menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progestogen containing) hormonal/ progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner). The contraceptive method will have to be followed for at least one menstruation cycle after the end of the study
    - Subjects having given her/his written informed consent.
    E.4Principal exclusion criteria
    -Evidence of another form of liver disease,considered to have an impact
    on the patient's safety or on the efficacy evaluation.
    -History of sustained excess alcohol ingestion in the year before the pre-study
    treatment biopsy: daily alcohol consumption > 30 g/day (3 drinks per day) for males and > 20 g/day (2 drinks/day) for females.
    -Unstable metabolic condition: Weight change > 5% in the last three months, diabetes with poor glycemic control (HbA1c > 8.5%), introduction of an antidiabetic or of an anti-obesity drug or restrictive bariatric (weight loss) surgery in the past 6 months prior to screening.
    -History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or ingestion of drugs known to produce hepatic steatosis including oral corticosteroids (at dose >5mg/day prednisone equivalent), estrogens (at doses greater than those used for contraception or hormone replacement), tamoxifen, methotrexate, tetracycline or amiodarone in the previous 6 months.Corticosteroids
    administered by routes other than oral are allowed. One short (<2 weeks) course of oral corticosteroids, more than 3 months before the pre-study treatment biopsy is also allowed.
    -Significant systemic or major illnesses other than liver disease, including congestive heart failure (class C and D of the AHA), unstable coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator, would preclude treatment with lanifibranor and/or adequate follow up.
    -HB antigen >0, HCV PCR >0 (patients with a history of HCV infection can be included if HCV PCR is negative since more than 3 years), HIV infection.
    -Pregnancy or lactation or inability to adhere to adequate contraception in women of child-bearing potential.
    -Active malignancy except cutaneous basocellular carcinoma.
    -Any other condition which, in the opinion of the investigator would impede competence or compliance or possibly hinder completion of the study
    -Body mass index (BMI) >45 kg/m2.
    -Type 1 diabetes and type 2 diabetic patient on insulin.
    -Diabetic ketoacidosis
    -Fasting Triglycerides > 300 mg/dL (3.39 mmol/L).
    -Hemostasis disorders or current treatment with anticoagulants.
    -Contra-indication to liver biopsy.
    -History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease event, including myocardial infarction, except patients with only well controlled hypertension. Any clinically significant ECG abnormality reported by central ECG reading, confirmed by the Investigator to be Clinically Significant.
    -Participation in any other investigational drug study within the previous
    3 months.
    -Have a known hypersensitivity to any of the ingredients or excipients of
    the IMP including: Lactose monohydrate, Hypromellose, Sodium laurilsulfate, Sodium starch glycolate (type A), Magnesium stearate, Opadry™ II 85F18422
    -Be possibly dependent on the Investigator or the sponsor (e.g.,including, but not limited to, affiliated employee).
    -Creatine phosphokinase (CPK)>5 x ULN
    -Patient with history of well documented osteopenia. Patient treated with vitamin D and/or Calcium based supplements for preventive reasons can be included.

    (The criteria below are applicable only for patients who will undergo a MRI/LMS in selected centers)
    - Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation is permitted at discretion of investigator.
    - Metallic implant of any sort that prevents MRI examination including, but not limited to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural stimulator, metallic contraceptive device, tattoo, body piercing that cannot be removed, cochlear implant; or any other contraindication to MRI examination.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is a binary outcome (responder / non responder). A responder is defined as a decrease from baseline to week 24 of at least 2 points of the SAF activity score combining hepatocellular inflammatory and ballooning score without fibrosis progression. Responder rates will be compared between the placebo and IMP groups at the end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on diabetes.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the treatment period (week 24)
    E.5.2Secondary end point(s)
    The following changes from baseline to 24 weeks of treatment will be evaluated:
    •NASH improvers defined as subjects with a decrease of at least 2 points in NAS, and no worsening in fibrosis in NASH from baseline to end of treatment (week 24).
    •Percent of patients with reversal of NASH (Steatosis without ballooning and with or without mild inflammation and no worsening of fibrosis) from baseline to end of treatment (week 24).
    •Percent of patients with a change in components of SAF score from baseline to end of treatment (week 24):
    -Steatosis: -1 point
    -Lobular inflammation: -1 point
    -Balloonning: -1 point
    • Percent of patients with at least 1- 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).
    •Change in fibrosis score on a 4-point scale (SAF) and modified Ishak: - 1 point from baseline to end of treatment (week 24). Comparison of mean change in fibrosis area assessed by morphometry (CPA) from baseline to end of treatment (week 24).
    •Liver enzymes (ALT, AST, γGT) change from baseline to end of treatment (week 24).
    •Inflammatory markers (fibrinogen, hs-CRP, alpha2 macroglobulin and haptoglobin levels) change from baseline to end of treatment (week 24).
    •Glucose metabolism (fasting glucose and insulin, HOMA index and, in subjects with T2DM, HbA1c) change from baseline to end of treatment (week 24).
    •Main plasma lipids levels (TC, HDL-C, calculated LDL-C, TG and apoA1) change from baseline to end of treatment (week 24).
    •Adiponectin change from baseline to end of treatment (week 24).
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline to 24 weeks of treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Italy
    Mauritius
    Netherlands
    Poland
    Portugal
    Spain
    Switzerland
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 270
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 165
    F.4.2.2In the whole clinical trial 225
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The trial treatment is stopped after V3.
    After the follow-up, the investigator/hepatologists/general prationer will decide, according to each patient, the need to use the lifestyle changes recommendations whenever appropriate and treatment of comorbidities which may play a role in NASH such as, for example, diabetes and hyperlipidaemia.
    If the study is positive there will be further trials for which these patients may be eligible.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-03-16
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