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

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)

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

Study Overview

• Status: Terminated
• Conditions: Non-Alcoholic Fatty Liver
• Intervention / Treatment: Drug: elafibranor 120mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • NUTRIM School of Nutrition and Translational Research in Metabolism

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: elafibranor 120mg followed by placebo; 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; elafibranor 120mg is a coated tablet for oral administration, once daily; Other Names: GFT505; Drug: Placebo; Placebo is a coated tablet for oral administration, once daily
Placebo Comparator: placebo followed by elafibranor 120mg; 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; elafibranor 120mg is a coated tablet for oral administration, once daily; Other Names: GFT505; Drug: Placebo; Placebo is a coated tablet for oral administration, once daily

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Genfit

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2019
• Primary Completion (Actual): March 11, 2020
• Study Completion (Actual): July 14, 2020

Study Registration Dates

• First Submitted: May 15, 2019
• First Submitted That Met QC Criteria: May 15, 2019
• First Posted (Actual): May 16, 2019

Study Record Updates

• Last Update Posted (Actual): August 31, 2020
• Last Update Submitted That Met QC Criteria: August 27, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Elafibranor; Hepatic lipid composition; Hepatic Glucose Production
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: GFT505-219-8; 2019-000645-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No