| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Alcoholic Steatohepatitis (NASH) and fibrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-alcoholic liver disease and fibrosis |
|
| 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 | 20.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| 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 120 mg QD versus placebo 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 120 mg QD versus placebo on clinical outcomes described as a composite endpoint composed of death due to any cause, histological liver cirrhosis and the full list of portal hypertension/cirrhosis related events (please refer to the protocol for a full list of events) |
|
| 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.
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints:
• Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients)
Other secondary objectives
• To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the endpoints listed in section 2.3 of the protocol
• To assess the endpoints listed in section 2.3 of the protocol at Week 72 and at the end of the LTTP
• To assess the onset to events listed in section 2.3 of the protocol |
|
| 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. Females participating in this study must be of nonchildbearing potential or using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as described below:
o Cessation of menses for at least 12 months due to ovarian failure
o Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure
o If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
o Using a highly effective nonhormonal method of contraception
(bilateral tubal occlusion, vasectomized partner, or intra-uterine device)
o Double contraception with barrier AND highly effective hormonal method of contraception (oral, intravaginal, or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation; oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; or intrauterine hormone-releasing system). The hormonal contraception must be started at least 1 month prior to Randomization.
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3).
5. NAS ≥4.
6. 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 ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal value of ALT within the past year), obesity defined by a BMI ≥ 30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6.
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:
o 1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy within 6 months before Screening is available)
o 1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH
o a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has already been performed within the past year
o 1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological confirmation)
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic liver biopsy is required.
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, change in anti-diabetic therapy must follow these requirements:
o no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose in the 6 months prior to diagnostic liver biopsy.
o no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment (V7).
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians' judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the end of treatment. |
|
| E.4 | Principal exclusion criteria |
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification).
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the course of the study.
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy.
4. Type 1 diabetes patients.
5. Patients with 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 (glitazones [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: 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. Pregnant or lactating females or females planning to become pregnant during the study period.
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to:
o positive hepatitis B surface antigen
o positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or positive HCV Ab at Screening)
o suspicion of drug-induced liver disease
o alcoholic liver disease
o autoimmune hepatitis
o Wilson's disease
o primary biliary cirrhosis, primary sclerosing cholangitis
o genetic homozygous hemochromatosis
o known or suspected hepatocellular carcinoma (HCC)
o history or planned liver transplant, or current MELD score >12
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the recommendations of National Law in force applicable to clinical trials.
14. Patients who cannot be contacted in case of emergency.
15. Known hypersensitivity to the investigation product or any of its formulation excipients.
16. Patients with previous exposure to elafibranor.
17. Patients who are currently participating in, plan to participate in, or have participated in an investigational drug trial or medical device trial containing active substance within 30 days or five half-lives, whichever is longer, prior to Screening.
Concomitant medications:
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept constant for at least 2 months prior to Screening.
19. 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 and up to end of treatment.
20. 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 until end of treatment.
Associated illnesses or conditions:
21. Any medical conditions that may diminish life expectancy to less than 2 years including known cancers.
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease
23. 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:
24. Positive anti-human immunodeficiency virus antibody.
25. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN).
26. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function
Note: Gilbert Disease patients are allowed into the study.
27. International normalized ratio >1.40 due to altered hepatic function.
28. Platelet count <100,000/mm3 due to portal hypertension.
Please refer to the protocol for a full list of the exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint:
Surrogate endpoint - resolution of NASH - To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening of fibrosis after 72 weeks of treatment.
Long-term endpoint – clinical outcomes (at final analysis)
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a composite endpoint composed of death due to any cause, histological liver cirrhosis and the full list of portal hypertension/cirrhosis related events:
• liver transplantation
• MELD score ≥15 for patients with a baseline MELD score ≤12
• the onset of:
o variceal bleed requiring hospitalization
o hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring hospitalization
o spontaneous bacterial peritonitis
o ascites requiring treatment
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. |
|
| 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 96 months after the first patient is randomized
|
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint (at surrogate endpoint analysis)
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 weeks.
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients)
Other secondary endpoints
• To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the following endpoints:
o percentage of patients with resolution of NASH without worsening of fibrosis (at the end of LTTP)
o percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring (at the end of LTTP)
o percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring without worsening of NASH
o percentage of patients with no worsening of Fibrosis and no worsening of NASH
o percentage of patients with resolution of NASH and improvement of Fibrosis
o percentage of patients with at least a 1 point improvement in histological scores (NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal inflammation
o percentage of patients with improvement of NAS of at least 2 points
o percentage of patients with improvement of NAS of at least 2 points and with at least 1 point improvement in hepatic ballooning
o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activityfibrosis (SAF) scoring
o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 point improvement in hepatic ballooning
o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) scoring and with at least 1 point improvement in hepatic ballooning
o percentage of patients with at least 2 points improvement in disease activity score according to NAS scoring and SAF scoring
o changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score
o changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry.
• To assess the following endpoints at Week 72, and at the end of the LTTP:
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 liver stiffness by Fibroscan measurement
o changes in quality of life (SF-36 questionnaire).
• To assess the onset of:
o histological liver cirrhosis
o death of any cause
o any portal hypertension or cirrhosis related events
o cardiovascular events
o liver-related death events. |
|
| 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 96 months after the first patient is randomized |
|
| 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 | No |
| 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
| 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 | 93 |
| 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 |
|
| 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). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| 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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