Study to Evaluate the Effect of Elafibranor on Hepatic Lipid Composition in Subjects With Nonalcoholic Fatty Liver (NAFL)

Study Overview
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Brief Summary
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This randomized, double-blind, cross-over (placebo or elafibranor [GFT505]) placebo-controlled study, will evaluate the effect on hepatic lipid composition and safety of elafibranor 120 mg quaque die (QD) versus placebo in an adult NAFL population after 6 weeks of treatment with a 4-week wash-out period. This study will achieve mechanistic information about the mode of action of Elafibranor on the (lipid) metabolism in the human fatty liver

Official Title
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A Double-Blind, Placebo-Controlled, Cross-over Phase II Study to Evaluate the Effect of a 6-week Elafibranor (120mg) Treatment Administered Once Daily on Hepatic Lipid Composition in Subjects With Nonalcoholic Fatty Liver (NAFL)

Conditions
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Non-Alcoholic Fatty Liver

Intervention / Treatment
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* Drug: elafibranor 120mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or post-menopausal females aged from 40-75 years inclusive at first Screening Visit. (Post-menopausal defined as: subject should be surgically sterilized at least 6 months or no spontaneous menses for at least 1 year prior to screening) Must provide signed written informed consent and agrees to comply with the study protocol. Liver fat percentage ≥ 5 percent (as measured with Magnetic Resonance Spectroscopy) 25.0 ≤ BMI ≤ 38.0 kg/m^2 Stable dietary habits and physical activity pattern (over 3 months prior to Screening Visit) Subject agrees not to change dietary habits and physical activity pattern, to follow diet and lifestyle recommendations and not to consume or use illicit drugs during the study up to end of treatment. Exclusion Criteria: Medical history: Documented weight loss of more than 5 percent during the 6-month period prior to Screening Visit Contra-indications for magnetic resonance imaging / spectroscopy Known history of Type 1 and 2 diabetes Known chronic heart failure (Grade I to IV of New York Heart Association classification) History of clinically significant acute cardiac event within 6 months prior to Screening Visit such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial infarction, revascularization procedures) Uncontrolled hypertension despite optimal antihypertensive therapy Other well documented causes of chronic liver disease according to standard diagnostic procedures. Symptoms of clinical depression Other concurrent medical (e.g., immunological, neoplastic, endocrine, hematological, gastrointestinal or neurological) or psychiatric condition, which, in the opinion of the Investigator, would place the subject at increased risk, preclude obtaining voluntary consent/assent or compliance with required study procedures, or would confound the objectives of study Known hypersensitivity to the investigation product or any of its formulation excipients Concomitant medications and lifestyle: Fibrates are not permitted from 8 weeks before Screening up to end of treatment. Subjects taking statins or ezetimibe prior to Screening Visit 1 may participate if the dose has been stable for 3 months prior to Screening Visit 1 and no dose adjustments are anticipated 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 Subjects receiving thiazolidinediones (glitazones [pioglitazone, rosiglitazone]) 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 Any medication use known to interfere with glucose homeostasis/metabolism Smoking Current or recent history (<5years) 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 Subjects who have donated blood or blood products within the previous month prior to screening or who plan to donate blood or blood products at any time during the trial and in the month following the end of the study Is participating in any other study and have received any other investigational drug or device within 30 days prior to Screening or are taking part in a non-medication study which, in the opinion of the Investigator, would interfere with study compliance or outcome assessments Subjects who cannot be contacted in case of emergency In addition to the above criteria, subject should not present any of the following biological exclusion criteria: Positive anti-human immunodeficiency virus (HIV) antibody Positive hepatitis B surface antigen Positive hepatitis C Virus (HCV) antibody Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >5 x upper limit of normal (ULN) Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease subjects are allowed into the study International normalized ratio >1.40 due to altered hepatic function Platelet count <100,000/mm^3 due to portal hypertension Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as subjects with markers of kidney damage or estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m^2) Unexplained serum creatine phosphokinase (CPK) >2 x ULN. In case of explained elevated CPK >2 x ULN, the measurement can be repeated prior to Randomization. In this case, retest should be performed within 1 to 2 weeks after initial test. A CPK retest >2 x ULN leads to exclusion Hemoglobin A1c (HbA1C) > 6.4% and/or fasting plasma glucose (FGP) > 126 mg/dl

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, double-blind, cross-over (placebo or elafibranor [GFT505]) placebo-controlled study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: elafibranor 120mg followed by placebo<br>Participants will first receive elafibranor 120mg for 6 weeks. After a washout period of 4-6 weeks, they will then receive placebo for 6 weeks | Drug: elafibranor 120mg<br>* elafibranor 120mg is a coated tablet for oral administration, once daily<br>* Other names: GFT505;Drug: Placebo<br>* Placebo is a coated tablet for oral administration, once daily<br>|
| Placebo Comparator: placebo followed by elafibranor 120mg<br>Participants will first receive placebo for 6 weeks. After a washout period of 4-6 weeks, they will then receive elafibranor 120mg for 6 weeks | Drug: elafibranor 120mg<br>* elafibranor 120mg is a coated tablet for oral administration, once daily<br>* Other names: GFT505;Drug: Placebo<br>* Placebo is a coated tablet for oral administration, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in relative amount of saturated fatty acids in the liver | Relative amount of saturated fatty acids (SFA) in the liver measured by Magnetic Resonance Spectroscopy (1H-MRS) at the end of 6 weeks treatment period | After 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepatic insulin sensitivity | Hepatic insulin sensitivity measured by Hepatic Glucose Production (HGP) at the end of 6 weeks treatment period | After 6 weeks | 
| Glucose homeostasis markers | Fasting glycemia | After 6 weeks | 
| Glucose homeostasis markers | HbA1c | After 6 weeks | 
| Glucose homeostasis markers | Fasting insulinemia | After 6 weeks | 
| Glucose homeostasis markers | C-peptide | After 6 weeks | 
| Glucose homeostasis markers | Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index | After 6 weeks | 
| Glucose homeostasis markers | Fructosamine | After 6 weeks | 
| Lipid metabolism markers | Triglycerides (TG) | After 6 weeks | 
| Lipid metabolism markers | Total cholesterol (TC) | After 6 weeks | 
| Lipid metabolism markers | High density lipoprotein-cholesterol (HDL-C) | After 6 weeks | 
| Lipid metabolism markers | Low density lipoprotein-cholesterol (LDL-C) | After 6 weeks | 
| Lipid metabolism markers | Non-HDL-C | After 6 weeks | 
| Lipid metabolism markers | Free fatty acid (FFA) | After 6 weeks | 
| Inflammatory markers | High sensitivity C-reactive protein (hs-CRP) | After 6 weeks | 
| Inflammatory markers | Fibrinogen | After 6 weeks | 
| Inflammatory markers | Haptoglobin | After 6 weeks | 
| Liver function | Alanine aminotransferase (ALT) | After 6 weeks | 
| Liver function | Aspartate aminotransferase (AST) | After 6 weeks | 
| Liver function | Gamma glutamyl transferase (GGT) | After 6 weeks | 
| Liver function | Alkaline phosphatase (ALP) | After 6 weeks | 
| Liver function | Total and conjugated bilirubin | After 6 weeks | 
| Renal function | Creatinine | After 6 weeks | 
| Renal function | Estimated glomerular filtration rate (using Modification of Diet in Renal Disease (MDRD) formula) | After 6 weeks | 
| Renal function | Blood urea nitrogen | After 6 weeks | 
| Renal function | Albumin | After 6 weeks | 
| Renal function | Uric acid | After 6 weeks | 
| Renal function | Total proteins | After 6 weeks | 
| Body weight |  | After 6 weeks | 
| Body Mass Index |  | After 6 weeks | 
| Waist circumference |  | After 6 weeks | 
| Incidence and severity of treatment emergent adverse events (TEAEs) and their relationship to study drug |  | After 6 weeks | 
| Incidence of clinically meaningful changes from baseline in safety laboratory parameters, and vital signs |  | After 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic lipid composition, Elafibranor, Hepatic Glucose Production