A Phase 3 Study Evaluating Long-term Efficacy and Safety of Lanifibranor in Adult Patients With (NASH) and Fibrosis 2 (F2)/Fibrosis 3 (F3) Stage of Liver Fibrosis

Overview

About this study

The purpose of this study is to evaluate the effectiveness and safety of lanifibranor (800 mg and 1200 mg administered once daily) compared to placebo in adult patients with NASH and F2/F3 liver fibrosis.
 

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Able to understand the nature of the study, willing and able to comply with the study procedures and restrictions, and willing to provide informed consent obtained before any study-related activities.
  • The patient will be willing to continue on the study in case of moving or relocation during the first 72 weeks of the study.
  • Male or female, aged ≥ 18 years at the time of signing informed consent
  • If biopsy performed before Screening, histological diagnosis of NASH with liver fibrosis made no more than 6 months before Screening
  • Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF):
    • Steatosis score ≥ 1;
    • Activity score: A3 or A4;
    • Fibrosis score: F2 or F3.
  • MELD score ≤ 12.
  • Stable dose for the specified period is required prior to the historical liver biopsy or before Screening visit (whichever is longer) until Baseline visit (Visit 0) for the drugs listed below:
    • Antidiabetic treatment if glucagon-like peptide-1 receptor agonists (GLP1 receptor agonists) or sodium-glucose co-transporter-2 inhibitors (SGLT2 inhibitors): Stable dose for at least 3 months;
    • Vitamin E (if at a dose ≥ 400 IU/day): Stable dose for at least 6 months;
    • Statins: Stable dose for at least 3 months.
  • All chronically administered drugs not covered by criterion #7 (including but not limited to antidiabetic treatments other than GLP1 receptor agonists and SGLT2 inhibitors, antihypertensives, antidepressants, cardiovascular, antihyperlipidemic, etc.) must be stable for at least 3 months prior to Screening.
  • History of at least 1 unsuccessful attempt to reduce body weight by diet and/or exercise within the past 6 years up to 6 months prior to Screening.
  • Weight stable for 6 months prior to Screening and between the qualifying liver biopsy and Baseline (no more than 5% change for both periods).
  • No attempt to change lifestyle (diet and/or exercise) during the 3 months prior to Screening.
  • Patient agrees to follow recommendations with lifestyle modifications, which will be monitored throughout the whole study period.
  • Negative serum pregnancy test at study Screening for females of childbearing potential confirmed by central laboratory. Females of childbearing potential must practice a consistent and proper use of highly effective method of contraception throughout the study and for 1 month after treatment discontinuation. Highly effective contraceptive methods are defined as follows: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, and sexual abstinence.

Exclusion Criteria:

  • Liver-related - Documented causes of chronic liver disease other than NASH including, but not restricted to:
    • Viral hepatitis, unless eradicated at least 3 years prior to Screening
      • Positive hepatitis B surface antigen (HBsAg);
      • Positive hepatitis C virus ribonucleic acid (RNA) (tested for in case of known cured hepatitis C virus [HCV] infection or positive HCV serology at Screening).
    • rug-induced liver disease;
    • Alcoholic liver disease: patients with a history of alcohol use who present an AST:ALT ratio of ≥ 2 and gamma-glutamyltransferase (GGT) > 2 × upper limit of normal (ULN) and macrocytosis with mean corpuscular volume (MCV) > 95 fL without known aetiology of Vitamin B12 insufficiency;
    • Autoimmune hepatitis;
    • Wilson’s disease;
    • Haemochromatosis;
    • Primary biliary cholangitis;
    • Primary sclerosing cholangitis;
    • Alpha-1-antitrypsin deficiency.
  • Histologically documented liver cirrhosis (fibrosis stage F4), either at Screening or in a historical biopsy or diagnosis of cirrhosis based on clinic biochemical and imaging criteria (FibroScan value confirmed ≥ 14 kPa and FIB-4 > 3.25 or ELF > 11.3, both provided to the site by the central lab).
  • History or current diagnosis of hepatocellular carcinoma (HCC).
  • History of or planned liver transplant.
  • Inability or unwillingness to undergo a liver biopsy at Screening (if a suitable historical biopsy is unavailable for central review), at Week 72, and after the non-invasive algorithm suggests high risk of progression to F4 OR at the End of Study.
  • Positive human immunodeficiency virus (HIV) serology.
  • ALT or AST > 5 × ULN.
  • Abnormal synthetic liver function as defined by Screening central laboratory evaluation of any of the following:
    • Albumin below the lower limit of the normal range;
    • International normalised ratio (INR) ≥ 1.3 (unless patient is on anticoagulants);
    • Total bilirubin level ≥ 1.3 mg/dL (22.2 μmol/L) (patients with a documented history of Gilbert’s syndrome can be enrolled if the direct bilirubin is within normal reference range).
  • Haemoglobin < 110 g/L (11g/dL) for females and <120 g/L (12g/dL) for males.
  • White blood cell (WBC) count < 5.0 × 10^9/L (5.0 × 10^3/μL).
  • Platelet count < 150,000/μL.
  • Alkaline phosphatase (ALP) > 2 × ULN.
  • Patient currently receiving any approved treatment for NASH or obesity.
  • Current or recent history (< 5 years) of significant alcohol consumption, which is typically defined as higher than 30 g pure alcohol per day for men and as higher than 20 g pure alcohol per day for women. No binge drinking during the last year. (Consuming 75 g pure alcohol (male), 60 g pure alcohol, or more in about 2 hours (female).
  • Treatment with drugs that may cause non-alcoholic fatty liver disease (NAFLD) administered for at least 2 weeks within 12 months prior to qualifying liver biopsy (e.g., valproic acid, tamoxifen, methotrexate, amiodarone, oral corticosteroids > 5 mg/day of prednisone equivalent [one short (< 2 weeks) course of oral corticosteroids, more than 3 months before the liver biopsy is allowed], or oestrogens [at doses greater than those used for contraception or hormone replacement]).
  • HbA1c > 9% at Screening.
  • Diabetes mellitus other than type 2 (e.g., type 1, endocrinopathy, and genetic syndromes).
  • Current treatment with insulin.
  • Previous or current treatment with PPAR-gamma agonists (e.g., thiazolidinediones [TZDs]).
  • Bariatric surgery: restrictive procedures (e.g., lap banding, intragastric balloon, sleeve gastrectomy) are allowed, if performed >6 months prior to the qualifying liver biopsy; malabsorptive procedures (e.g., biliopancreatic diversion) and procedures combining both restrictive and malabsorptive methods (e.g. Roux-en-Y gastric bypass, duodenal switch surgery) are not allowed within 5 years of the qualifying liver biopsy. Liposuction and/or abdominoplasty are allowed if performed > 6 months before qualifying liver biopsy. Planned bariatric surgery is not allowed.
  • Participation in an organised weight loss programme (e.g., Weight Watchers®, Jenny Craig®) within 3 months of the study, or planned participation through Week 72.
  • History of heart failure with reduced left ventricular ejection fraction (LVEF) defined as any past measurement of LVEF ≤ 40%.
  • N-terminal-prohormone B-type natriuretic peptide (NT-proBNP) >900 pg/mL.
  • Atrial fibrillation requiring anticoagulation.
  • Unstable heart failure with preserved ejection fraction, defined as:
    • New York Heart Association (NYHA) class III-IV; or
    • Hospitalisation or emergency room visit for heart failure during the past 1 year; or
    • Need for intravenous diuretics in the outpatient setting within 6 months of Screening; or
    • Concomitant treatment with high dose of diuretics (i.e. furosemide 80 mg/day or equivalent).
  • Any other clinical significant cardiovascular event requiring hospitalisation within 6 months before Screening.
  • Uncontrolled hypertension at Screening (values > 160/100 mm Hg).
  • Corrected QT interval by Fridericia (QTcF) > 480 ms
  • Based on the investigator’s evaluation, evidence of any other unstable or untreated clinically significant hepatic, pulmonary, immunological, endocrine, haematological, gastrointestinal, neurological, neoplastic (see also exclusion criterion #21), psychiatric disease, or any medical condition that may diminish life expectancy to less than 2 years.
  • Cancer: Presence or history of malignant neoplasm within 5 years prior to Screening. History of cancer is allowed only following 5 years of documented remission. History of HCC is exclusionary (see exclusion criterion #3). Basal and squamous cell skin cancer and any carcinoma are allowed in case of a resected, non-invasive lesion.
  • Major surgery scheduled for the first 72 weeks of study
  • Any condition which, in the investigator’s opinion, might jeopardise a patient’s safety or compliance with the protocol, or warrants exclusion from the study.
  • Women currently breastfeeding.
  • Known or suspected hypersensitivity to any of the excipients of lanifibranor/placebo or PPAR agonists.
  • Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
  • Previous exposure to lanifibranor.
  • Participation in any clinical trial of an approved or non-approved investigational medicinal product/device within 3 months from Screening or 5 half-lives from Screening, whichever is longer.
  • Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value < 60 mL/min/1.73 m^2.
  • Screening triglycerides > 500 mg/dL (0.45-1.81 mmol/L).
  • Concomitant treatment with PPAR-alpha agonists (fibrates); if treatment with PPAR-alpha agonist is discontinued before the Baseline visit, it should be anticipated that triglycerides should remain < 500 mg/dL during the study.
  • Current treatment with strong inducers of CYP3A4 and CYP2C8. However, if medically necessary, these drugs may be taken for a maximum duration of 3 weeks.
  • Current treatment with substrates of CYP2B6 and CYP2C8. 
  • Current SARS-CoV-2 infection confirmed by a validated test.
  • In the subgroup of 300 ECG patients:
    • Concomitant treatment known to be associated with a prolongation of QTcF > 480 ms.

Eligibility last updated 8/16/21. Questions regarding updates should be directed to the study team contact.

 

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Harmeet Malhi, M.B.B.S.

Contact us for the latest status

Contact information:

Harmeet Malhi M.B.B.S.

(507) 293-1537

Malhi.Harmeet@mayo.edu

More information

Publications

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CLS-20529328

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