A clinical study to assess the efficacy and safety of lanifibranor followed by an active treatment extension in adult patients with non-cirrhotic nonalcoholic steatohepatitis (NASH) and fibrosis 2 (F2)/fibrosis 3 (F3) stage of liver fibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Inventiva

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

26 Nov 2021 → ongoing

Decision date (initial)

2024-08-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Inventiva S.A., France

External identifiers

EU CT number

2023-508248-23-00

EudraCT number

2020-004986-38

ClinicalTrials.gov

NCT04849728

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacogenomic, Pharmacokinetic, Safety, Efficacy

The primary objectives of both periods in the main cohort are:
• Double-blind placebo-controlled (DBPC) period (Part A) To assess the effect of lanifibranor compared to placebo on NASH resolution and improvement of fibrosis assessed by liver histology.
• Double-blind active treatment extension (ATE) period (Part B) To assess the safety of lanifibranor beyond the DBPC period.

Secondary objectives 1

1. Key secondary objectives of DBPC period: •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.

Conditions and MedDRA coding

Non-alcoholic steatohepatitis (NASH)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1. Able to understand the nature of the study, willing and able to comply with the study procedures and restrictions, and able to provide signed, dated and written informed consent obtained before any study-related activities, sampling or analysis. 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 is performed before Screening, i.e. if a historical biopsy is available, a histological diagnosis of NASH with liver fibrosis must be made no more than 7 months before randomisation 5. Main cohort: Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF): a.Steatosis score ≥1 b.Activity score: A3 or A4 c.Fibrosis score: F2 or F3 Exploratory cohort: Patients who, upon central biopsy reading process, do not meet the eligibility criteria described above but fulfil the following criteria: diagnosis of NASH according to the Steatosis-Activity- Fibrosis (SAF): a) Steatosis score ≥1 b) Activity score ≥2 with SAF-Inflammation score ≥1 and SAF-Ballooning score ≥1 c) Fibrosis score: F1 to F3 6. Model for End-Stage Liver Disease (MELD) score ≤12 (unless patient is on anticoagulants) 7. For patients receiving the concomitant medications listed below: no qualitative change in dose are allowed (changes having minimal clinical impact like temporary cessation/change between class of drugs are allowed), for the specified period prior to the qualifying liver biopsy and dose must remain stable from the time of the liver biopsy until the Baseline visit (Visit 0): a. Antidiabetic treatment if glucagon-like peptide-1 receptor agonists (GLP1 receptor agonists including combinations) or sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors): for at least 3 months b. Vitamin E (if at a dose ≥400 IU/day): for at least 6 months c. Statins for at least 3 months d. Anti-obesity treatments for at least 6 months 8. For patients receiving concomitant medications not covered by criterion #7 and that may impact safety or efficacy evaluation (antidiabetic treatments other than GLP1 (or combinations) receptor agonists and SGLT2 inhibitors, antihypertensives, antidepressants, cardiovascular, antihyperlipidemic) no qualitative change in dose are allowed for at least 3 months prior to the Baseline visit (Visit 0) or for at least 8 weeks prior to Screening visit for herbal/dietary supplement with potential liver toxicity or those with unknown composition and dose must remain stable until the Baseline visit (Visit 0) 9. For overweight/obese patient, history of at least 1 unsuccessful attempt to reduce body weight by diet and/or exercise within the past 6 years 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) 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.

Exclusion criteria 1

1. Liver-related: 1.Documented causes of chronic liver disease other than NASH including, but not restricted to: a.Viral hepatitis b.Drug-induced liver disease c.Alcoholic liver disease d.Autoimmune hepatitis (See Exclusion criteria 44 for more information) e.Wilson's disease f.Haemochromatosis g.Primary biliary cholangitis h.Primary sclerosing cholangitis i.Alpha-1-antitrypsin deficiency j.Chronic portal vein thrombosis or splenic vein thrombosis 2.Histologically documented liver cirrhosis in the most recent historical biopsy (fibrosis stage F4) or suspicion at screening of cirrhosis based on clinic biochemical and imaging criteria 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) and at Week 72 6.Positive human immunodeficiency virus (HIV) serology 7.ALT or AST >5 × ULN 8.Abnormal synthetic liver function of any of the following: a.Albumin below the lower limit of the normal range b.International normalised ratio (INR) ≥1.3 (unless patient is on anticoagulants) c.Total bilirubin level ≥1.5 mg/dL (25.6 μmol/L) Patients with a history of Gilbert's syndrome can be enrolled if the direct bilirubin is ≤0.45 mg/dL (7.7 μmol/L) 9.Haemoglobin <110 g/L (11 g/dL) for females and <120 g/L (12 g/dL) for males 10.Leucocytes count < LLN. A lower count is acceptable in patients with benign ethnic neutropenia, if considered to be clinical insignificant by the investigator. 11.Platelet count <140,000/μL. 12.Alkaline phosphatase (ALP) >2 × ULN 13.Patient currently receiving any approved treatment for NASH 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 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 Glycaemia related: 16.HbA1c >9% at Screening 17.Diabetes mellitus other than type 2 18.-43. Refer to protocol for full list Autoimmune related: 44.Any patient with a predisposition to autoimmune liver disease, incl: a)Signs on liver biopsy suggestive of autoimmune liver disease b)Family history of autoimmune liver disease in a first degree relative c)Autoimmune thyroid disease 1.Diagnosis of autoimmune thyroid disease 2.Thyroid replacement hormone unless documented for reason of primary thyroid insufficiency 3.Positive autoimmune antibodies associated with abnormal thyroid function testing (TSH, T4 or free T3) i.Anti-thyroid peroxidase antibody (TPO) or ii.Anti-TSH receptor antibodies (TRAb) d)History of or positive testing at screening for: 1.Anti-nuclear antibodies (ANA) at a dilution of 1:320 or greater 2.Anti-mitochondrial antibodies (AMA) 3.Anti-smooth muscle antibodies (ASMA) at a dilution of 1:320 or greater 4.Anti-liver kidney microsomal type 1 antibodies (LKM1) 5.Anti-liver cytosol type 1 antibody (LC1)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 1

1. Resolution of NASH and no worsening of fibrosis at Week 72, defined by NASH CRN scores for ballooning of 0, inflammation of 0 to 1, and no increase in fibrosis score when compared to Baseline; Improvement of fibrosis and no worsening of NASH at Week 72, defined by a decrease in NASH CRN fibrosis score ≥1 stage from Baseline and no increase in scores for ballooning, inflammation, or steatosis

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Inventiva

Sponsor organisation

Inventiva

Address

50 Rue De Dijon

City

Daix

Postcode

21121

Country

France

Scientific contact point

Organisation

Inventiva

Contact name

Martine Baudin

Public contact point

Organisation

Inventiva

Contact name

Martine Baudin

Third parties 13

Locations

11 EU/EEA countries · 97 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 201 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

14 submissions — initial application plus substantial / non-substantial modifications