Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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 (NATiV3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04849728
Recruitment Status : Recruiting
First Posted : April 19, 2021
Last Update Posted : August 16, 2021
Sponsor:
Information provided by (Responsible Party):
Inventiva Pharma

Brief Summary:
This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage 2 or 3

Condition or disease Intervention/treatment Phase
NASH - Nonalcoholic Steatohepatitis Fibrosis Drug: Lanifibranor Phase 3

Detailed Description:

Primary objectives

This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage 2 or 3 and consists of 2 parts - Part 1 and Part 2, with the following primary objectives:

Part 1 To assess the effect of lanifibranor compared to placebo on NASH resolution and improvement of fibrosis assessed by liver histology.

Part 2 To assess the effect of lanifibranor compared to placebo on delaying NASH disease progression measured by a composite endpoint that includes progression to cirrhosis, liver-related clinical outcome events, or all-cause death.

Secondary objectives

Key secondary objectives of Part 1:

  • To assess the effect of lanifibranor compared to placebo on NASH resolution and no worsening of fibrosis
  • To assess the effect of lanifibranor compared to placebo on improvement of fibrosis with no worsening of NASH

Other secondary objectives of both Part 1 and Part 2:

  • To assess the effect of lanifibranor compared to placebo on other key histological features of NASH
  • To assess the effect of lanifibranor compared to placebo on NASH resolution and improvement of fibrosis in diabetic patients
  • To assess the effect of lanifibranor compared to placebo on liver function tests
  • To assess the effect of lanifibranor compared to placebo on glycaemic parameters
  • To assess the effect of lanifibranor compared to placebo on lipid parameters
  • To assess the effect of lanifibranor compared to placebo on liver stiffness
  • To assess the effect of lanifibranor compared to placebo on health-related quality of life
  • To assess the long-term safety (up to 7 years) of lanifibranor
  • To assess population PK modeling of lanifibranor using sparse sampling scheme

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomised, Double-blind, Placebo-controlled, Multicentre, Phase 3 Study Evaluating Long-term Efficacy and Safety of Lanifibranor in Adult Patients With Non-cirrhotic Non-alcoholic Steatohepatitis (NASH) and Fibrosis 2 (F2)/Fibrosis 3 (F3) Stage of Liver Fibrosis
Estimated Study Start Date : August 2021
Estimated Primary Completion Date : February 2024
Estimated Study Completion Date : September 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lanifibranor (800 mg/day) Drug: Lanifibranor
A total of 2000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part 1 and Part 2.

Experimental: Lanifibranor (1200 mg/day) Drug: Lanifibranor
A total of 2000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part 1 and Part 2.

Placebo Comparator: Matching placebo Drug: Lanifibranor
A total of 2000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part 1 and Part 2.




Primary Outcome Measures :
  1. Resolution of NASH [ Time Frame: Date of randomisation until the date of biopsy at Week 72 ]
    Resolution of NASH and improvement of fibrosis at Week 72, defined by NASH CRN scores for ballooning of 0 and inflammation of 0 to 1, and fibrosis score ≥1 stage decrease compared to Baseline



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. The patient will be willing to continue on the study in case of moving or relocation during the first 72 weeks of the study.
  3. Male or female, aged ≥18 years at the time of signing informed consent
  4. If biopsy performed before Screening, histological diagnosis of NASH with liver fibrosis made no more than 6 months before Screening
  5. Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF):

    1. Steatosis score ≥1
    2. Activity score: A3 or A4
    3. Fibrosis score: F2 or F3
  6. Model for End-Stage Liver Disease (MELD) score ≤12
  7. 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:

    1. 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
    2. Vitamin E (if at a dose ≥400 IU/day): Stable dose for at least 6 months
    3. Statins: Stable dose for at least 3 months
  8. 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
  9. 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
  10. Weight stable for 6 months prior to Screening and between the qualifying liver biopsy and Baseline (no more than 5% change for both periods)
  11. No attempt to change lifestyle (diet and/or exercise) during the 3 months prior to Screening
  12. Patient agrees to follow recommendations with lifestyle modifications, which will be monitored throughout the whole study period.
  13. 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:

  1. Documented causes of chronic liver disease other than NASH including, but not restricted to:

    a. Viral hepatitis, unless eradicated at least 3 years prior to Screening i. Positive hepatitis B surface antigen (HBsAg) ii. 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) b. Drug-induced liver disease c. 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 d. Autoimmune hepatitis e. Wilson's disease f. Haemochromatosis g. Primary biliary cholangitis h. Primary sclerosing cholangitis i. Alpha-1-antitrypsin deficiency

  2. 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)
  3. History or current diagnosis of hepatocellular carcinoma HCC
  4. History of or planned liver transplant
  5. 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)
  6. Positive human immunodeficiency virus (HIV) serology
  7. ALT or AST >5 × ULN
  8. Abnormal synthetic liver function as defined by Screening central laboratory evaluation of any of the following:

    1. Albumin below the lower limit of the normal range
    2. International normalised ratio (INR) ≥1.3 (unless patient is on anticoagulants)
    3. 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)
  9. Haemoglobin <110 g/L (11 g/dL) for females and <120 g/L (12 g/dL) for males
  10. White blood cell (WBC) count <5.0 × 10^9/L (<5.0 × 10^3/µL)
  11. Platelet count <150,000/µL
  12. Alkaline phosphatase (ALP) >2 × ULN
  13. Patient currently receiving any approved treatment for NASH or obesity
  14. 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 (please also refer to Section 12.1). No binge drinking during the last year. (Consuming 75 g pure alcohol (male), 60 g pure alcohol or more in about 2 hours (female).
  15. 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])

    Glycaemia related:

  16. HbA1c >9% at Screening
  17. Diabetes mellitus other than type 2 (e.g. type 1, endocrinopathy, and genetic syndromes)
  18. Current treatment with insulin
  19. Previous or current treatment with PPAR-gamma agonists (thiazolidinediones [TZDs])

    Obesity related:

  20. 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
  21. 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

    Cardiovascular related:

  22. History of heart failure with reduced left ventricular ejection fraction (LVEF) defined as any past measurement of LVEF ≤ 40%
  23. N-terminal-prohormone B-type natriuretic peptide (NT-proBNP) >900 pg/mL
  24. Atrial fibrillation requiring anticoagulation
  25. Unstable heart failure with preserved ejection fraction, defined as:

    1. New York Heart Association (NYHA) class III-IV or,
    2. Hospitalisation or emergency room visit for heart failure during the past one year or,
    3. Need for intravenous diuretics in the outpatient setting within 6 months of Screening or,
    4. Concomitant treatment with high dose of diuretics (i.e. furosemide 80 mg/day or equivalent)
  26. Any other clinical significant cardiovascular event requiring hospitalisation within 6 months before Screening
  27. Uncontrolled hypertension at Screening (values >160/100 mm Hg)
  28. Corrected QT interval by Fridericia (QTcF) >480 ms

    General safety:

  29. 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
  30. 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
  31. Major surgery scheduled for the first 72 weeks of study
  32. 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
  33. Women currently breastfeeding
  34. Known or suspected hypersensitivity to any of the excipients of lanifibranor/placebo or PPAR agonists
  35. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
  36. Previous exposure to lanifibranor
  37. 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
  38. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value <60 mL/min/1.73 m2.
  39. Screening triglycerides >500 mg/dL (0.45-1.81 mmol/L)
  40. 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
  41. 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 (See Section 6.7 and Section 12.2).
  42. Current treatments with substrates of CYP2B6 and CYP2C8 See Section 6.7 and Section 12.2).
  43. Current SARS-CoV-2 infection confirmed by a validated test.

    In the subgroup of 300 ECG patients:

  44. Concomitant treatment known to be associated with a prolongation of QTcF >480 ms.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04849728


Contacts
Layout table for location contacts
Contact: Michael Cooreman, MD 380447500 ext +33 Michael.COOREMAN@inventivapharma.com

Locations
Layout table for location information
United States, California
Fomatmedicalresearch Recruiting
Camarillo, California, United States, 93011
Contact: Karen Simon, Doctor    805-483-1185    ksimon@fomatmedical.com   
Contact: Anthony Sana    8052361732    asana@fomatmedical.com   
Sponsors and Collaborators
Inventiva Pharma
Layout table for additonal information
Responsible Party: Inventiva Pharma
ClinicalTrials.gov Identifier: NCT04849728    
Other Study ID Numbers: 337HNAS20011
First Posted: April 19, 2021    Key Record Dates
Last Update Posted: August 16, 2021
Last Verified: August 2021

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Inventiva Pharma:
Phase III
Additional relevant MeSH terms:
Layout table for MeSH terms
Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Cirrhosis
Fibrosis
Pathologic Processes
Liver Diseases
Digestive System Diseases