| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Alcoholic Steatohepatitis (NASH) and fibrosis |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-alcoholic liver disease and fibrosis |
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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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016642 |
| E.1.2 | Term | Fibrosis |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| 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 |
Primary objectives - surrogate endpoint
To evaluate the efficacy of elafibranor QD for 72 weeks vs placebo on resolution of NASH without worsening of fibrosis
• Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for steatohepatitis
• Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging system and defined as progression of at least 1 stage.
Primary objectives - long-term endpoint
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events (please refer to the protocol for a full list of events)
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| E.2.2 | Secondary objectives of the trial |
Key secondary objective
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the following endpoint parameter:
• Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring.
Other secondary objectives
• To assess histological changes after 72 weeks of treatment and follow-up biopsy on the parameters listed in section 2.3 of the protocol
• To assess the endpoints listed in section 2.3 of the protocol in elafibranor treated patients relative to placebo, at Week 72 and at the end of the Long-term Treatment Period |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit.
2. Must provide signed written informed consent and agree to comply with the study protocol.
3. BMI ≤45 kg/m².
4. Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal contraception (including patch, contraceptive ring, etc), intra-uterine device, or other mechanical contraception method + condom or diaphragm or spermicide for the full duration of the study and for 1 month after the end of treatment
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3).
6. NAS score ≥4.
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6.
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of treatment (V13), unless a biopsy has already been performed within the year.
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy.
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, no change in anti-diabetic therapy is allowed within 6 months prior to diagnostic liver biopsy, under the following conditions:
• No change in dose for patients treated by glucagon-like peptide 1 agonists
• No qualitative change (i.e. implementation of a new anti-diabetic therapy) for patients treated by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, sulfamides, or insulin.
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| E.4 | Principal exclusion criteria |
1. Known heart failure (Grade I to IV of New York Heart Association classification).
2. History of efficient bariatric surgery within 5 years prior to Screening.
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy.
4. Type 1 diabetes patients.
5. Patients with decompensated diabetes ((hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion.
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at least 6 months before the diagnostic liver biopsy.
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial infarction, revascularization procedures).
8. Weight loss of more than 5% within 6 months prior to Randomization.
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded.
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically defined as higher than 20 g pure alcohol per day.
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to donate blood or blood products at any time during the trial and in the 2 months following the end of the study.
12. Pregnant or lactating females or females planning to become pregnant during the study period.
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to:
- positive hepatitis B surface antigen
- positive hepatitis C Virus RNA)
- suspicion of drug-induced liver disease
- alcoholic liver disease
- autoimmune hepatitis
- Wilson’s disease hemochromatosis
- primary biliary cirrhosis, primary sclerosing cholangitis
- genetic hemochromatosis
- Known or suspected HCC
- history or planned liver transplant, or current MELD score >12.
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the recommendations of National Law in force.
15. Patients who cannot be contacted in case of emergency.
16. Known hypersensitivity to the investigation product or any of its formulation excipients.
17. Patients with previous exposure to elafibranor.
18. Patients who are currently participating in, plan to participate in, or have participated in an investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior to Screening.
Concomitant medications:
19. Fibrates are not permitted 2 months before Randomization. Patients that used statins or ezetimibe before Screening may participate if the dosage has been kept constant for the past 2 months prior to Screening.
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to Screening.
21. Currently taking any medication that could interfere with study medication absorption, distribution, metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. indomethacin, which are not permitted from Randomization.
Associated illnesses or conditions:
22. Any medical conditions that may diminish life expectancy to less than 2 years including known cancers.
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric disease.
24. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.
In addition to the above criteria, patient should not present any of the following biological exclusion criteria:
25. Positive anti-human immunodeficiency virus antibody.
26. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN).
27. Total bilirubin >25 µmol/L (1.5 mg/dL).
28. International normalized ratio >1.4.
29. Platelet count <100,000/mm3.
30. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in females.
Please refer to the protocol for a full list of the exclusion criteria
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint:
Surrogate endpoint - resolution of NASH - The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor.
Long-term endpoint – time to clinical event/death -
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events:
• liver transplantation
• MELD score ≥15
• HCC
• hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of:
o variceal bleed
o hepatic encephalopathy
o spontaneous bacterial peritonitis
o uncontrolled ascites
o hepatorenal syndrome
o hepatopulmonary syndrome
o chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to hospitalization or transfusion).
The final analysis will be performed when 456 patients experience an event listed above. This is expected to occur approximately 72 months after the first patient is randomized.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Endpoint: Surrogate endpoint - Week 72
Primary Endpoint: Long-term endpoint - Monitored throughout the study. The final analysis will be done when 456 of these events occur. This is expected to occur approximately 72 months after the first patient is randomized
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| E.5.2 | Secondary end point(s) |
Key secondary endpoint:
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 weeks.
Other secondary endpoints
• To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following parameters:
o percentage of patients with resolution of NASH without worsening of fibrosis (follow-up biopsy)
o percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring (follow-up biopsy)
o percentage of patients with at least 1 point improvement in histological scores (NASH CRN scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal inflammation
o percentage of patients improvement of NAS score of at least 2 points
o percentage of patients with at least a 1 point improvement in SAF activity score
o mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF score, and activity score
o changes in area of fibrosis by morphometry
o mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring.
• To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, and at the end of the Long-term Treatment Period:
o cardiovascular events
o liver-related death events
o changes in liver enzymes and liver markers
o changes in noninvasive markers of fibrosis and steatosis
o changes in lipid parameters
o variation in body weight
o changes in insulin resistance and glucose homeostasis markers
o changes in inflammatory markers
o changes in cardiovascular risk profile as assessed by Framingham scores
o changes in quality of life (SF-36 questionnaire).
• Time to first occurrence of:
o liver cirrhosis
o death of any cause
o any portal hypertension or cirrhosis related events. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study. The final analysis will be done when 456 of these events occur. This is expected to occur approximately 72 months after the first patient is randomized |
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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 | No |
| 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 | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Mexico |
| Netherlands |
| Portugal |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Turkey |
| United Kingdom |
| United States |
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| 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
|
| The study will terminate upon the 456th patient (excluding exploratory F1 arm) experiencing an event (all-cause mortality, progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related events). |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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