| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-alcoholic Steatohepatitis (NASH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-alcoholic Steatohepatitis (NASH) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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.
Other secondary objectives of both periods to assess the effect of lanifibranor on other key histological features of NASH*, on NASH resolution and improvement of fibrosis in diabetic patients*, on liver tests, glycaemic parameters, lipid parameters and liver stiffness and steatosis assessed by elastography, on health-related quality of life, on the safety,
To assess pop PK modelling through plasma levels of lanifibranor*
*only for DBPC period
During DBPC period, effect of the 2 doses of lanifibranor will be compared to placebo .
During ATE period, the effect of lanifibranor will be descriptively assessed between the 2 doses. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Optional Pharmacogenomic sub-study. |
|
| E.3 | Principal inclusion criteria |
1. Able to understand the nature of the study, willing and able to comply with the study procedures and restrictions, and ableto 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: any stage (F1 to F4)
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)
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)
11. Criterion removed from Version 3.0
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 (provided that partner is the sole sexual partner of the female patient and that the vasectomised partner has received medical assessment of the surgical success), or sexual abstinence (intended as true abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal are not acceptable methods of contraception). Female patients who are only in same-sex relationships are not required to use contraception. |
|
| E.4 | Principal exclusion criteria |
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
7.1. AST < 0.60 × ULN if the screening liver biopsy has to be performed in the scope of the study
7.2. Liver Stiffness Measurement (LSM) < 6 kPa by transient elastography (or equivalent) during screening if the screening liver biopsy has to be performed in the scope of the study.
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 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. Current treatment with insulin
19.Treatment with PPAR-gamma agonists 12 months before randomisation, or any history of stopping TZD due to safety reason
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 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. New participation in an organised weight-loss programme within 6 months of the study, or planned participation through Week 72 or current treatment with orlistat
Cardiovascular related:
22. History of heart failure with reduced left ventricular ejection fraction (LVEF) defined as any past measurement of LVEF ≤ 40%
23. Atrial fibrillation requiring anticoagulation
24.Unstable heart failure with preserved ejection fraction, defined as:
a)New York Heart Association (NYHA) class III-IV or,
b)Hospitalisation or emergency room visit for heart failure during the past 1 year or, c)Need for intravenous diuretics in the outpatient setting within 6
months of Screening or,
d) Concomitant treatment with high dose of diuretics
25. -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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| DBPC period main cohort: from date of randomisation until the date of biopsy at Week 72. |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
• 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
Other secondary endpoints:
• Improvement of NASH CRN fibrosis stage by at least 2 points and no worsening of NASH (no increase in scores for steatosis, ballooning, or lobular inflammation) at Week 72
• Resolution of fibrosis, defined as NASH CRN fibrosis stage 0, at Week 72
• Improvement of NAFLD activity score (NAS) by at least 2 points (at least a 1 point reduction in either lobular inflammation or hepatocellular ballooning) and no worsening of fibrosis, at Week 72
•Improvement of each histological feature of NASH by at least 1 point (steatosis, lobular inflammation, and hepatocellular ballooning) and no worsening of fibrosis at Week 72
• Resolution of NASH and no worsening of steatosis and improvement of fibrosis at Week 72, defined by NASH Clinical Research Network (NASH CRN) scores for ballooning of 0 and inflammation of 0 to 1, no increase of steatosis and fibrosis score ≥1 stage decrease compared to Baseline
• Resolution of NASH and no worsening of steatosis 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 steatosis or fibrosis scores when compared to Baseline
• Improvement of NAFLD activity score (NAS) by at least 2 points (at least a 1 point reduction in either lobular inflammation or hepatocellular
ballooning) and no worsening of steatosis and no worsening of fibrosis, at Week 72
• NASH resolution and improvement of fibrosis at Week 72 in the subgroup of diabetic patients
• Change from Baseline in liver stiffness by elastography and in steatosis by controlled attenuation parameter (CAP)
Refer to protocol for full list |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DBPC period main cohort: from date of randomisation until the date of biopsy at Week 72 visit.
DBPC and ATE periods main cohort (only non-histological endopoints): from date of randomisation until end of ATE period |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 124 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Chile |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Mexico |
| South Africa |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
|
| E.8.7 | Trial 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
|
A patient is considered to have completed the study if he or she has completed all parts of the study.
The End of Study will occur at the last patient last visit performed during the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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