| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes (T2DM) with Non-Alcoholic Steatohepatitis (NASH) |
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| E.1.1.1 | Medical condition in easily understood language |
| Type 2 Diabetes (T2DM) with Non-Alcoholic Steatohepatitis (NASH) |
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| 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 |
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| 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 |
Primary objective
To assess the effect of lanifibranor alone compared to placebo and the effect of lanifibranor in combination with empagliflozin compared to placebo on HbA1c after a 24-week treatment duration.
Secondary objectives
To assess the effect of lanifibranor alone compared to placebo and lanifibranor in combination with empagliflozin compared to placebo after a 24-week treatment duration on:
• Liver tests
• Markers of glycemic control and insulin resistance
• Inflammatory markers
• Lipid parameters
• Body weight and body composition
and
To assess the safety and tolerability of lanifibranor alone and in combination with empagliflozin during the 24-week treatment period and the 4-week follow-up period.
Exploratory objectives
To assess the effect of lanifibranor alone compared to placebo and lanifibranor in combination with empagliflozin compared to placebo after a 24 week treatment duration on hepatic fat content, steatosis, inflammation and fibrosis...
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives
To assess the effect of lanifibranor alone compared to placebo and lanifibranor in combination with empagliflozin compared to placebo after a 24-week treatment duration on: Liver tests, Markers of glycemic control and insulin resistance, Inflammatory markers, Lipid parameters , Body weight and body composition and
To assess the safety and tolerability of lanifibranor alone and in combination with empagliflozin during the 24-week treatment period and the 4-week follow-up period.
Exploratory objectives :
To assess the effect of lanifibranor alone compared to placebo and lanifibranor in combination with empagliflozin compared to placebo after a 24-week treatment duration on: Hepatic fat content ; Steatosis, inflammation and fibrosis ; NASH and fibrosis non-invasive biomarkers; Liver elasticity and tissue attenuation; Liver stiffness; The time to initiation of a rescue medication.
To perform population pharmacokinetic (popPK) modelling of lanifibranor
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For an eligible patient, all inclusion criteria must be answered “yes” at Screening and re-confirmed at the time of randomization procedure and at Baseline (i.e., before treatment initiation). Laboratory tests taken during the screening period will be used to determine eligibility. If information cannot be confirmed in the medical record, responses will be obtained in a patient interview:
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 is willing to continue on the study in case of moving or relocating to a different region/city where there would be no active study site
3. Able to communicate meaningfully with the Investigator and legally competent to provide written informed consent
4. Male or female, aged ≥ 18 years at the time of signing informed consent
5. Diagnosis of NASH
a. based on a historical (within 12 months prior to Screening) liver biopsy with a non-alcoholic fatty liver disease activity score (NAS) ≥ 4 with a score of one or more in each sub-component (steatosis, hepatocyte ballooning, lobular inflammation) and no documented cirrhosis in the last 12 months prior to Screening OR
b. NASH at Screening
b1. High Risk NASH defined as cT1 ≥ 875 ms assessed by LiverMultiScan® OR
b2. NASH defined as cT1 ≥ 825 ms assessed by LiverMultiScan® and hepatic fat content ≥ 10% assessed by MRI-PDFF
6. HbA1c at screening ≥ 7.0 and ≤ 10.0%, on diet alone, or on metformin (≥ 1,000 mg/day), and/or dipeptidyl peptidase 4 inhibitor (DPP-IVi) therapy. Doses have no qualitative change for 3 months prior to informed consent. These medicines will be continued at stable doses during the entire study.
7. Negative pregnancy test at Screening for females of childbearing potential or at least two-year post-menopausal. Women of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile) have to use a highly effective method of contraception throughout the study and for one month after treatment discontinuation. Highly effective contraceptive methods are defined as follows: combined (estrogen 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, vasectomized partner (provided he is her sole sexual partner and he has received medical assessment of the surgical success), and true sexual abstinence (when this is in line with the preferred and usual lifestyle of the patient) whereas periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
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| E.4 | Principal exclusion criteria |
A. Liver-related:
1. Documented causes of chronic liver disease other than NASH (see protocol for details, see exclusion criteria no 50 for autoimmune hepatitis)
2. Histologically documented liver cirrhosis (fibrosis F4); or diagnosis ofcirrhosis at Screening
3. History or current diagnosis of hepatocellular carcinoma (HCC)
4. History of or planned liver transplant
5. Documented history of HIV infection
6. ALT or AST > 5 × upper limit of normal (ULN) at Screening
7. Abnormal liver function as any :
a. Albumin < lower limit of normal range (LLN)
b. INR ≥ 1.3 (unless patient is on anticoagulants)
c. Total bilirubin level ≥ 1.5 mg/dL (25.7 μmol/L). Patients with Gilbert's syndrome can be enrolled if direct bilirubin is ≤ 0.45 mg/dL (7.7 μmol/L)
8. Hemoglobin < 110 g/L (11 g/dL) for females and < 120 g/L (12 g/dL) for males
9. White blood cell count < LLN or a lower count in patients with benignethnic neutropenia, if considered to be clinical insignificant by the investigator
10. Platelet count < 140,000/μL
11. Alkaline phosphatase (ALP) > 2 × ULN
12. Patient currently receiving any approved treatment for NASH or obesity
13. Current or recent history (< 5 years) of significant alcohol consumption. No binge drinking during the last year.
14. Administration of drugs known to produce hepatic steatosis in the 6 months prior to Screening
B. Diabetes related (see protocol/synopsis for details)
C. Obesity related (see protocol/synopsis for details)
20. BMI > 45 kg/m2 at Screening
21. Weight change > 5% in 3 months prior to Screening
22. Introduction of anti-obesity drug or restrictive bariatric surgery in past 12 months prior to Screening or planned bariatric surgery throughWeek 24
23. Participation in an organized weight loss program in past 6 months prior to Screening or planned participation through Week 24
D. Cardiovascular related (see protocol/synopsis for details)
E. General safety:
30. Significant systemic or major illnesses other than liver disease that would preclude treatment with lanifibranor and/or empagliflozin
31. Any condition which might jeopardize a patient’s safety or compliance with the protocol, or warrants exclusion from the study
32. Cancer: Presenceor history of malignancy within 5 years prior to Screening and/or active neoplasm at Screening.
33. History of bladder disease and/or persistent hematuria within 6 months prior to Screening or current hematuria unless due to a urinary tract infection
34. Renal impairment measured as eGFR < 60 mL/min as determined by MDRD
35. Total creatine kinase > 1.5 x ULN
36. History of pancreatitis, or confirmed pancreatic lipase > 1.3 x ULN, or > 2.0 x ULN upon repeated test within 3 weeks if on a DPP-IVi
37. Concomitant treatment with PPAR-⍺ agonists (fibrates);
38. Patients on Vitamin E at doses ≥ 400 IU/day; unless no qualitative change in dose
39. SARS-CoV-2 infections requiring hospitalization in the last 3 months or current SARS-CoV-2 infection confirmed by a validated test.
40. Major surgery scheduled during the study
41. Hypersensitivity to any of the ingredients of the IMPs
42. Galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
43. Previous exposure to lanifibranor or empagliflozin
44. Osteopenia, or any otherbone disease.
45. Claustrophobia that prevents tolerance of MRI scanning procedure.
46. Metallic implant that prevents MRI examination or any other contraindication to MRI
47. Pregnancy/lactation or inability to adhere to adequate contraception
48. Treatment with strong inducers or inhibitors of CYP2C8. Prior administration of other drugs as per Section 13.2.
49. Participation in clinical trial of IMP/device within 3 months from Screening or 5 half-lives of the IMP from Screening,
F. Autoimmune related:
50. Predisposition to autoimmune liver disease, incl.
a. Signs on previous liver biopsy suggestive of autoimmune liver disease (autoimmune hepatitis, immune cholangitis or overlap syndrome)
b. Family history of autoimmune liver disease in a first degree relative
c. Autoimmune thyroid disease:
i. Known diagnosis of autoimmune thyroid disease
ii. Thyroid replacement hormone unless documented for reason of primary thyroid insufficiency (e.g. due to thyroidectomy, radiation therapy, etc.)
iii. Positive autoimmune antibodies associated with abnormal thyroid function testing (TSH, T4 or free T3) (1) Anti-thyroid peroxidase antibody (TPO)
iv. Anti-TSH receptor antibodies (TRAb)
d. History of or positive testing at screening for: i. Anti-nuclear antibodies (ANA) at a dilution of 1:320 or greater
一 ii. Anti-mitochondrial antibodies (AMA)
一 iii. Anti-smooth muscle antibodies (ASMA) at a dilution of 1:320 or greater
一 iv. Anti-liver kidney microsomal type 1 antibodies (LKM1)
一 v. Anti-liver cytosol type 1 antibody (LC1)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
• Absolute change in HbA1c from baseline (Week 0) to Week 24
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Change from baseline (Week 0) to Week 24 |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints
The following endpoints will be evaluated at Week 24:
• Change from baseline to Week 24 in liver tests (alanine aminotransferase [ALT], AST, gamma-glutamyl transferase (GGT), alkaline phosphatase [ALP], total and direct bilirubin)
• Change from baseline to Week 24 in markers of glycemic control and insulin resistance (determination of hepatic insulin sensitivity, Homeostatic Model Assessment for insulin resistance [HOMA-IR], fasting insulin, fasting plasma glucose [FPG], fructosamine, adiponectin)
• Binary endpoint defined as reaching HbA1c < 7.0% at Week 24, and no new antidiabetic treatment or increase in dosages of antidiabetic treatments
• Binary endpoint defined as reaching HbA1c decrease ≥ 0.5% at Week 24, and no new antidiabetic treatment or increase in dosages of antidiabetic treatments
• Change from baseline to Week 24 in inflammatory markers (high-sensitivity C-reactive protein [hsCRP], Interleukin IL-6, Interleukin IL-1β)
• Change from baseline to Week 24 in lipid parameters (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides [TG])
• Change from baseline to Week 24 in body weight
• Binary endpoint defined as reaching body weight increase ≥ 5% at Week 24
• Change from baseline to Week 24 in body composition as determined by MRI (including but not limited to visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT] and thigh SAT)
Safety endpoints
• Adverse events (AEs)
• Adverse Events of Special Interest (AESIs): anemia, heart failure, aminotransferase elevation, bone fracture, peripheral edema, cholelithiasis, hypoglycemia and ovulation resumption
• Serious adverse events (SAEs) including major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, hospitalization for acute coronary syndrome)
• Physical examination
• Vital signs (systolic and diastolic blood pressure [SBP, DBP], waist circumference)
• Electrocardiogram (ECG)
• Safety laboratory evaluations including N-terminal prohormone B-type natriuretic peptide (NT-pro-BNP)
Exploratory endpoints
• Absolute change from baseline to Week 24 in liver fat content (MRI-PDFF)
• Binary endpoint where a responder is defined reaching a relative decrease in MRI-PDFF of ≥ 30% at Week 24
• Binary endpoint where a responder is defined as reaching an absolute decrease in MRI-PDFF of ≥ 5% at Week 24
• Binary endpoint where a responder is defined as reaching ≤ 5.0% MRI-PDFF at Week 24 (i.e., non-alcoholic fatty liver disease (NAFLD) resolution)
• Changes from baseline to Week 24 in corrected T1 relaxation time (cT1) assessed by LiverMultiScan®
• Binary endpoint defined as reaching cT1 decrease > 80 ms at Week 24
• Binary endpoints defined as reaching cT1 < 800 ms at Week 24, and reaching cT1 < 875 ms at Week 24 (among patients with baseline cT1≥875 ms)
• Changes from baseline to Week 24 in non-invasive biomarkers related to NASH and fibrosis (included but not limited to: TIMP-1, hyaluronic acid, P3NP, cytokeratin CK18M30 and M65, proC3)
• Changes from baseline to Week 24 in VelacurTM ultrasound measures of liver elasticity (kPa) and attenuation (dB/m) (only applies to sites where VelacurTM is available)
• Changes from baseline to Week 24 in FibroScan® measures of LSM (kPa), CAP (dB/m) and FAST score (only applies to sites where FibroScan® is available)
• Time from baseline to initiation of a rescue medication (weeks)
Pharmacokinetic (PK) endpoints
• PopPK modelling of trough plasma levels of lanifibranor and its metabolites using a sparse sampling scheme (PK parameters include Cmax, Tmax, AUC, T1/2, CL/F, Vd/F)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Change from baseline (Week 0) to Week 24 (and intothe 4-week follow-up period specfically for safety and tolerability ) |
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| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-blinded with regards to lanifibranor, open-label with regards to empagliflozin |
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| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| United Kingdom |
| United States |
| Belgium |
| France |
| Netherlands |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| The Sponsor considers there is no need to have an Data Monitoring Committee (DMC) in this study due to the limited study duration (treatment duration of only 24 weeks), the short period of enrolment (estimated 6 months) and the limited number of subjects to be included (n=63). Rigorous medical monitoring will be conducted by investigators and medical monitors from the CRO/Sponsor and according to the measures detailed hereafter in the study protocol, Section 8.2. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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