Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis (NASH)

A Multicentre, Randomized, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GFT505 Once Daily on Steatohepatitis in Patients With Non-Alcoholic Steatohepatitis (NASH).

Abdominal obesity and type-2 Diabetes are associated with chronic liver disorders resulting from the accumulation of fat in the liver (steatosis), which may progress towards hepatitis and possibly lead to cirrhosis and liver cancer. NAFLD (Non Alcoholic Fatty Liver Disease) is considered as the most common form of chronic liver disease in adults in the United States, Australia, Asia and Europe. In the USA, the estimated prevalence of NAFLD is 20-30% of the adult population.

Non-alcoholic Steatohepatitis (NASH) is a progressing form of NAFLD, which corresponds to hepatic steatosis associated with inflammation and liver cell injury upon microscopic examination of a liver biopsy. This condition may lead to advanced fibrosis and cirrhosis and deserves serious medical management. Up to now, there is no effective drug which has clearly demonstrated therapeutic efficacy which may help lifestyle and dietary recommendations in the resolution of NASH.

In this context, GENFIT is developing a new liver targeted drug candidate, GFT505, for the treatment of NASH and the reduction of multiple cardiometabolic risk factors associated with the metabolic syndrome and type 2 Diabetes.

This phase IIb study will evaluate the efficacy and safety of GFT505 80mg and 120mg once daily for 52 weeks on the reversal of NASH without worsening of fibrosis, based on liver biopsy assessments.

Study Overview

• Status: Completed
• Conditions: Non-Alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Drug: Placebo; Drug: GFT505 80mg; Drug: GFT505 120mg

Detailed Description

The study duration per patient will be 80 weeks. A screening period (from 4 to 16 weeks) will precede a 52-week double-blind treatment period and a 3 months follow-up period.

The study will be conducted in 270 patients (90 patients in the placebo arm, 90 patients in the GFT505 80mg arm, and 90 patients in the GFT505 120mg arm).

Enrollment will be performed in two phases: during the first phase, the patients will receive either GFT505 at a dose of 80 mg either the placebo. An independent expert committee will review the safety data when 45 patients receiving the dose at 80 mg will have been treated for 6 months. The committee approval will be necessary to start the second phase, while the patients will receive either GFT505 at a dose of 80 mg, or GFT505 at a dose of 120 mg or the placebo.

• Study Type: Interventional
• Enrollment (Actual): 275
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • Site 205
  • Edegem, Belgium, B-2650
    • Site 201
  • Gent, Belgium, B-9000
    • Site 204
  • Haine-Saint-Paul, Belgium, 7100
    • Site 202
  • Leuven, Belgium, 3000
    • Site 203
• France
  • Amiens, France, 80054
    • Site 106
  • Angers, France, 49933
    • Site 102
  • Clichy, France, 92110
    • Site 114
  • Lille, France, 59037
    • Site 103
  • Lyon, France, 69317
    • Site 113
  • Marseille, France, 13285
    • Site 111
  • Montpellier, France, 34295
    • Site 108
  • Nantes, France, 44093
    • Site 104
  • Nice, France, 06202
    • Site 109
  • Paris, France, 75571
    • Site 112
  • Paris, France, 75651
    • Site 101
  • Pessac, France, 33604
    • Site 107
• Germany
  • Bonn, Germany, 53127
    • Site 405
  • Mainz, Germany, 55131
    • Site 404
• Italy
  • Milano, Italy, 20122
    • Site 507
  • Palermo, Italy, 90127
    • Site 503
  • Roma, Italy, 00133
    • Site 504
  • Torino, Italy, 10126
    • Site 501
• Netherlands
  • Amsterdam, Netherlands, 1100
    • Site 303
  • Nijmegen, Netherlands, 6500
    • Site 302
• Romania
  • Bucharest, Romania, 021105
    • Site 603
  • Bucharest, Romania, 022328
    • Site 601
  • Bucharest, Romania, 022328
    • Site 602
• Spain
  • Barcelona, Spain, 08036
    • Site 703
  • Majadahonda, Spain, 28222
    • Site 707
  • Malaga, Spain, 29010
    • Site 705
  • Santander, Spain, 39008
    • Site 706
  • Sevilla, Spain, 41014
    • Site 701
• United Kingdom
  • Camberley, United Kingdom, GU16 7UJ
    • Site 802
  • Hull, United Kingdom, HU3 2JZ
    • Site 808
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Site 801
  • Nottingham, United Kingdom, NG7 2UH
    • Site 803
• United States
  • California
    • Fresno, California, United States, CA 9372
      • Site 920
    • La Jolla, California, United States, CA 92037
      • Site 903
  • Colorado
    • Aurora, Colorado, United States, CO 80045
      • Site 911
  • Florida
    • Gainesville, Florida, United States, FL 32610-0277
      • Site 912
  • Georgia
    • Atlanta, Georgia, United States, GA 30303
      • Site 924
    • Atlanta, Georgia, United States, GA 30322
      • Site 917
  • Louisiana
    • New Orleans, Louisiana, United States, LA 70112-2600
      • Site 909
  • Massachusetts
    • Worcester, Massachusetts, United States, MA 01655
      • Site 921
  • Michigan
    • Detroit, Michigan, United States, MI 48202
      • Site 902
  • New York
    • New York, New York, United States, NY 10029-6574
      • Site 927
  • North Carolina
    • Durham, North Carolina, United States, NC 27710
      • Site 908
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, PA 19104
      • Site 919
  • Tennessee
    • Memphis, Tennessee, United States, TN 38104
      • Site 916
  • Texas
    • Fort Sam Houston, Texas, United States, TX 78234
      • Site 913
    • Houston, Texas, United States, TX 77030
      • Site 923
    • San Antonio, Texas, United States, TX 78215
      • Site 906
  • Utah
    • Salt Lake City, Utah, United States, UT 84132
      • Site 931
  • Virginia
    • Charlottesville, Virginia, United States, VA 22908
      • Site 930
    • Richmond, Virginia, United States, VA 23298
      • Site 901

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females (females must be either of non-child bearing potential or using an efficient double contraception). For male participants, contraceptive measures must be taken during the study, either by the male participant or his female partner.
• Body Mass Index ≤ 45 kg/m².
• Patients agree to have one liver biopsy during the screening period for diagnostic purpose (if no historical biopsy within 6 months before randomization is available) and one at the end of the treatment period for assessment of the treatment effects.
• For hypertensive patients, hypertension must be controlled by stable dose of anti-hypertensive medication for at least 2 months prior to screening (and the stable dose can be maintained throughout the study).
• Patients treated with vitamin E (>400IU/d), or Polyunsaturated fatty acids (>2g/day)or Ursodeoxycholic acid can be included if drugs are stopped at least 3 months prior to diagnostic liver biopsy and up to the end of the study.
• Histological confirmation of steatohepatitis on a diagnostic liver biopsy. Histological diagnostic is confirmed by central reading of the slides (steatosis > 5% + lobular inflammation, any grade + ballooning, any amount).
• For patients with Type 2 Diabetes, glycemia must be controlled (Glycosylated Haemoglobin A1c ≤8.5%). If glycemia is controlled by anti-diabetic drugs, qualitative change is not permitted within 6 months prior to randomization and should be avoided during the study. Treatments with metformin, Dipeptidyl Peptidase 4 inhibitors, Glucagon-like peptide-1 agonists, sulfamides, insulin are authorized. Sulfamides and insulin are permitted if glycemia is self-monitored by the patient.

Exclusion Criteria:

• Known heart failure (Grade I to IV of New York Heart Association classification).
• Weight loss of more than 5% within 6 months prior to randomization.
• History of bariatric surgery.
• Uncontrolled Blood Pressure.
• Type 1 diabetes patients.
• Patients who had an acute cardiovascular episode within the 6 months prior to screening, or with a history of coronary angioplasty, history of stroke, Transient Ischemic Attack, Coronary Heart Disease.
• Compensated and uncompensated cirrhosis. Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded.
• Known alcohol and/or any other drug abuse or dependence in the last five years.
• Pregnant or lactating females.
• Other well documented causes of chronic liver disease
• Known intolerance or contra-indication to the list of excipients of GFT505.
• Evidence of any other unstable or, untreated clinically significant immunological, neoplastic, endocrine, haematological, gastrointestinal, neurological or psychiatric disorder.
• Positive HBsAg (Hepatitis B Surface Antigen), Positive anti-HIV, positive HCV-RNA (Hepatitis C Virus).
• Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone > 2X the upper limit of normal (ULN). Thyroid dysfunction controlled for at least 6 months prior to screening is permitted.
• Significant renal disease, including nephritic syndrome, chronic renal failure (defined as creatinine clearance < 60 mL/mn and serum creatinine >180 μmol/L).
• Unexplained serum creatine phosphokinase (CPK) > 3X the upper limit of normal (ULN). Patients with a reason for CPK elevation may have the measurement repeated prior to randomization; a CPK retest > 3X ULN leads to exclusion.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GFT505 80mg; Hard gelatin capsules dosed at 40mg, oral administration, 3 capsules per day before breakfast with a glass of water.	Drug: GFT505 80mg
Experimental: GFT505 120mg; Hard gelatin capsules dosed at 40mg, oral administration, 3 capsules per day before breakfast with a glass of water.	Drug: GFT505 120mg
Placebo Comparator: Placebo; hard gelatin capsules, oral administration, 3 capsules per day before breakfast with a glass of water.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Responders With Disappearance of Steatohepatitis Without Worsening of Fibrosis (ie, Participants no Longer Meeting the Criteria for Steatohepatitis)	Percentage of responders from baseline to Week 52 defined by the disappearance of steatohepatitis (ie, participants no longer meeting the criteria for steatohepatitis) without worsening of fibrosis. Worsening of fibrosis was evaluated using Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) fibrosis staging system and defined as: Progression to stage 3 or 4 for participants at stage 0, 1 or 2 on diagnostic liver biopsy; Progression to stage 4 for participants at stage 3 on diagnostic liver biopsy	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 52 in Non-alcoholic Fatty Liver Disease Activity Score	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg the change from baseline to Week 52, in Non-alcoholic Fatty Liver Disease Activity Score (NAS score). NAS score is a composite score equal to the sum of the steatosis grade (0 to 3), lobular inflammation grade (0 to 3) and hepatocellular ballooning grade (0 to 2). The overall scale of the NAS is 0 to 8, with higher scores indicating more severe disease. The outcome measure, change from baseline in NAFLD Activity Score (NAS), has a possible range from -8 to +8, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Number of Participants With Change From Baseline to Week 52 in Non-alcoholic Fatty Liver Disease Activity Score of at Least 2 Points	To evaluate the number of participants with at least a 2 point decrease from baseline in Non-alcoholic Fatty Liver Disease Activity Score (NAS) after 52 weeks of daily administration of GFT505 80mg or 120mg. The NAS refers to the severity of ongoing liver injury as assessed by a liver biopsy and is used to assess the activity of the disease. It is based on the NASH CRN methodology for scoring the severity of steatosis (score of 0 to 3), inflammation (score of 0 to 3), and hepatocellular ballooning (score of 0 to 2), with a maximum score of 8. A total NAS score of five or greater correlates with the diagnosis of steatohepatitis. In table below for raw "Mild (Nonalcoholic Fatty Liver Disease Activity Score 3)" and the column "GFT505 80mg" the result should be read as : 2 participants (out of 10 participants analysed with a baseline NAS at 3) had at Least 2 points decrease on their NAS after 52 weeks of daily administration of GFT505 80mg. It corresponds to 20% (2 out of 10).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Number of Participants With Decrease in Steatosis Score of at Least 1 Point Between Baseline and Week 52	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, number of participants with a decrease in steatosis score of at least 1 point between baseline and Week 52. Steatosis is assessed by a liver biopsy and evaluated on a scale of 0 to 3 with higher scores indicating more severe steatosis. A score of 0 indicating a lower severity with low parenchymal involvement (<5%), while a score of 3 is indicative of higher involvment/severity (> 66%). In below table and for helping how results are reported, as an example for raw "Mild (Nonalcoholic Fatty Liver Disease Activity Score 3)" and the column "GFT505 80mg" the result should be read as : 1 participants (out of 10 participants analysed with a baseline NAS at 3) had at least 1 point decrease Steatosis Score after 52 weeks of daily administration of GFT505 80mg. It corresponds to 10% (1 out of 10).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Number of Participants With Decrease in Lobular Inflammation Score of at Least 1 Point Between Baseline and Week 52	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, number of participants with a decrease in lobular inflammation score of at least 1 point between baseline and Week 52. Lobular inflammation is assessed by a liver biopsy and evaluated on a scale of 0 to 3. A score of 0 indicating the absence of inflammation loci, while a score of 3 is indicative of a higher degree of inflammation with more than 4 inflammation loci 200 x field. In below table and for helping how results are reported, as an example for raw "Mild (Nonalcoholic Fatty Liver Disease Activity Score 3)" and the column "GFT505 80mg" the result should be read as : 1 participants (out of 10 participants analysed with a baseline NAS at 3) had at least 1 point decrease of Lobular Inflammation Score after 52 weeks of daily administration of GFT505 80mg. It corresponds to 10% (1 out of 10).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Title: Number of Participants With Decrease in Ballooning Score of at Least 1 Point Between Baseline and Week 52	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, number of participants with a decrease in ballooning score of at least 1 point between baseline and Week 52. Ballooning is assessed by a liver biopsy and evaluated on a scale of 0 to 2 with higher scores indicating more severe ballooning (0: No ballooned cells, 1: Few [rare but definite] ballooned hepatocytes; 2: Many ballooned cells/prominent ballooning). In below table and for helping how results are reported, as an example for raw "Mild (Nonalcoholic Fatty Liver Disease Activity Score 3)" and the column "GFT505 80mg" the result should be read as : 4 participants (out of 10 participants analysed with a baseline NAS at 3) had at least 1 point decrease of Ballooning Score after 52 weeks of daily administration of GFT505 80mg. It corresponds to 10% (1 out of 10).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in the Stages of Fibrosis	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in stages of fibrosis (based on Non-Alcoholic Steatohepatitis Clinical Research Network [NASH CRN] scoring). Fibrosis is assessed on a scale of 0 to 4 with higher scores indicating more severe fibrosis.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Visit 8 (Week 52) in Liver Enzymes	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to week 52, in liver enzymes.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Visit 8 (Week 52) in Aspartate Transaminase/Alanine Aminotransferase Ratio	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to week 52, in aspartate transaminase/alanine aminotransferase ratio	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: CK 18-M65	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in CK 18-M65 (non-invasive markers of fibrosis and steatosis).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: CK18 M30	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in CK18 M30 (non-invasive markers of fibrosis and steatosis). Participants with missing data for CK18 M30 at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Adiponectin	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in adiponectin (non-invasive markers of fibrosis and steatosis).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Ferritin	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in ferritin (non-invasive markers of fibrosis and steatosis). Participants with missing data for Ferritin at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: FG19 and FG21	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in FG19 and FG21 (non-invasive markers of fibrosis and steatosis).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Alpha2 Macroglobulin	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in alpha2 macroglobulin (a non-invasive marker of fibrosis and steatosis). Participants with missing data for Alpha2 Macroglobulin at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Hyaluronic Acid, N-terminal Pro-peptide of Collagen Type III (PIIINP), and Tissue Inhibitor of Matrix Metalloprotease-1 (TIMP-1)	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in hyaluronic acid, N-terminal pro-peptide of collagen type III (PIIINP), and tissue inhibitor of matrix metalloprotease-1 (TIMP-1) (non-invasive markers of fibrosis and steatosis).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fibrotest	Fibrotest combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT with adjustment for age and gender. Fibrotest is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e^-z). Calculated score range from 0 (no fibrosis) to 1 (severe fibrosis or cirrhosis) In below table for "Fibrotest" and for column "GFT505 80mg" the result should be read as: the mean of change from baseline to week 52 of Fibrotest calculated in 81 participants is -0.06 with a standard deviation of 0.08.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Steatotest	SteatoTest combines α2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT, fasting glucose, triglycerides, cholesterol, and ALT, adjusted for patient's age, sex, weight, and height. Patented formula. Calculated score range from 0 (no steatosis) to 1 (severe steatosis) In below table for "Steatotest" and for column "GFT505 80mg" the result should be read as: the mean of change from baseline to week 52 of Steatotest calculated in 81 participants is -0.09 with a standard deviation of 0.11.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Angulo Index or Non-Alcoholic Fatty Liver Disease Fibrosis Score	Angulo Index or Non-Alcoholic Fatty Liver Disease Fibrosis Score is based on age, hyperglycemia, BMI, platelet count, albumin level, and AST/ALT ratio. Score is calculated using the following formula: -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m^2) + 1.13 × IFG/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio - 0.013 × platelet (×10^9/l) - 0.66 × albumin (g/dl). A score of <-1.455 indicates no advanced fibrosis and a score of >0.676 indicates liver fibrosis. In below table for "Angulo index" and for column "GFT505 80mg" the result should be read as: the mean of change from baseline to week 52 of Angulo index calculated in 82 participants is 0.06 with a standard deviation of 0.53.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Enhanced Liver Fibrosis (ELF)	Enhanced Liver Fibrosis (ELF) combines measurements of tissue inhibitor of metalloprotein-ases-1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and hyaluronic acid (HA) . The ELF score is calculated as : 2.278 + 0.851 ln (HA) + 0.751 ln (PIIINP) + 0.394 ln (TIMP-1). ELF score range from An ELF score of less than 7.7 indicates no fibrosis. An ELF score greater than or equal to 9.8 indicates severe fibrosis. An ELF score of 11.3 or greater indicates cirrhosis. A decrease in ELF score represents a positive outcome In below table for "Enhanced Liver Fibrosis" and for column "GFT505 80mg" the result should be read as : the mean of change from baseline to week 52 of Enhanced Liver Fibrosis calculated in 81 analysed participants is -0.01 with a standard deviation of 0.54.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fatty Liver Index (FLI)	The Fatty Liver Index (FLI) combines triglycerides, BMI, GGT and Waist circumference. FLI is calculated as : (e0.953×loge[triglycerides]+0.139× Body Mass Index[BMI]+0.718×loge Gamma- Glutamyl Transferase [GGT]+0.053×waistcircumference-15.745)/ (1 +e0.953×loge[triglycerides]+0.139×BMI+0.718×loge [GGT]+0.053×waistcircumference-15.745) × 100. Calculated index range from 0 to 100. FLI score below 30 indicate absence of Fatty Liver and FLI Score of 60 and above indicates presence of Fatty Liver. In below table for "Fatty Liver Index" and for column "GFT505 80mg" the result should be read as : the mean of change from baseline to week 52 of Fatty Liver Index calculated in 82 analysed participants is -7.94 with a standard deviation of 11.74.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fibrometer	Fibrometer combines Platelets, AST, ALT, ferritin, glucose (fasting plasma), Weight and gender. Patented formula. Score ranges from 0 (no fibrosis) to 1 (severe fibrosis or cirrhosis) In below table for "Fibrometer" and for column "GFT505 80mg" the result should be read as : the mean of change from baseline to week 52 of Fibrometer calculated in 81 analysed participants is 0.04 with a standard deviation of 0.23.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Total Bilirubin and Conjugated Bilirubin	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in total bilirubin and conjugated bilirubin (non-invasive markers of fibrosis and steatosis).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Prothrombin Ratio	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in prothrombin ratio (non-invasive marker of fibrosis and steatosis). The Prothrombin ratio is the ratio of a participants measured prothrombin time (in seconds) to the normal laboratory reference prothrombin time. Participants with missing data for Prothrombin ratio at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: International Normalized Ratio (INR)	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg, the changes from baseline to week 52, in international normalized ratio (INR; non-invasive marker of fibrosis and steatosis). Participants with missing data for International Normalized Ratio (INR) at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Lipid Parameters (Cardiovascular Risk Profile)	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to week 52, in lipid parameters (used to assess cardiovascular risk)	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Outcomes Related to Biochemistry	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to week 52, in secondary outcomes related to biochemistry	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: Leptin	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in leptin (to assess insulin resistance).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: Insulin	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in insulin (to assess insulin resistance). Participants with missing data for Insulin at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: C Peptide	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in C peptide (to assess insulin resistance). Participants with missing data for C Peptide at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: Homeostatic Model Assessment-insulin Resistance (HOMA-IR)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in homeostatic model assessment-insulin resistance (HOMA-IR; to assess insulin resistance). The HOMA-IR is expressed as the following: HOMA-IR = fasting serum insulin (μU/ml) x fasting plasma glucose (mmol/l) / 22.5 A decrease in HOMA-IR indicates a positive outcome. HOMA-IR values of greater than 1.9 indicates early insulin resistance and levels above 2.9 indicate significant insulin resistance. Participants with missing data for HOMA-IR at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: Free Fatty Acids (FFA)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in free fatty acids (FFA; to assess insulin resistance). Participants with missing data for Free Fatty Acids (FFA) at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: Plasma Glucose	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in plasma glucose (to assess insulin resistance). Participants with missing data for Plasma Glucose at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: Glycosylated Haemoglobin A1c (HbA1c)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in glycosylated haemoglobin A1c (HbA1c; to assess insulin resistance). Participants with missing data for Haemoglobin A1c (HbA1c) at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Insulin Resistance: Fructosamine	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in Fructosamine (to assess insulin resistance).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Inflammatory Markers: Fibrinogen and Haptoglobin	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to Week 52, in fibrinogen and haptoglobin (inflammatory markers).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Inflammatory Markers: Tumour Necrosis Factor Alpha and Interleukine 6	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to Week 52, in tumour necrosis factor alpha and interleukine 6 (inflammatory markers).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Inflammatory Markers: Plasminogen Activator Inhibitor 1 (PAI-1)	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to Week 52, in plasminogen activator inhibitor 1 (PAI-1; inflammatory marker). Participants with missing data for Plasminogen Activator Inhibitor 1 (PAI-1) at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Inflammatory Markers: C-Reactive Protein (CRP)	To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to Week 52, in C-Reactive Protein (CRP; inflammatory marker).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: Creatinine (Renal Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in creatinine (safety markers; renal function parameter).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: Creatinine Clearance (Renal Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in creatinine clearance (safety marker; renal function parameter).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: Uric Acid (Renal Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in uric acid (safety marker; renal function parameter).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: Blood Urea Nitrogen (BUN; Renal Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in blood urea nitrogen (BUN; safety marker; renal function parameter).	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: Cystatin C (Renal Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in cystatin C (safety marker; renal function parameter). Participants with missing data for Cystatin C at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: Beta2-microglobulin (Renal Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in beta2-microglobulin (safety marker; renal function parameter). Participants with missing data for Beta2-microglobulin at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP; Cardiac Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in N-terminal prohormone of brain natriuretic peptide (NT-proBNP; safety marker; cardiac function parameter). Participants with missing data for NT-proBNP at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Safety Markers: Troponin T (Cardiac Function Parameter)	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in troponin T (safety marker; cardiac function parameter). Participants with missing data for Troponin T at baseline (Visit 2) or Visit 8 were not imputed in the analysis explaining the difference with the number of participants reported in the "Efficacy Evaluable Set" of the Participant Flow.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Changes From Baseline to Week 52 in Body Weight	To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in body weight.	Baseline (Visit 2; Week 0) to Visit 8 (Week 52)

Collaborators and Investigators

• Sponsor: Genfit
• Collaborators: Premier Research Group plc; Naturalpha
• Investigators: Study Director: Rémy HANF, PhD, Development Director Genfit, France; Study Chair: Pr. Vlad RATZIU, M.D., International Coordinator - La Pitié-Salpêtrière Hospital - Paris 13, France; Principal Investigator: Pr. Arun SANYAL, M.D., National Coordinator -Virginia Commonwealth University - Richmond - USA; Principal Investigator: Dr. Sven FRANCQUE, M.D., National Coordinator - UZA - Edegem - Belgium; Principal Investigator: Dr. Jost PH DRENTH, MD, Ph.D, National Coordinator - UMC St Radboud Nijmegen - Nijmegen - The Netherlands; Principal Investigator: Pr. Michael Manns, M.D., National Coordinator - Medical School of Hannover - Hannover - Germany; Principal Investigator: Pr. Elisabetha BUGIANESI, M.D., National Coordinator - University of Torino - S. Giovanni Battista Hospital - Torino - Italy; Principal Investigator: Pr. Mihai VOICULESCU, M.D., National Coordinator - Center of Internal Medicine, Fundeni Clinical Institute - Bucharest - Romania; Principal Investigator: Pr. Manuel ROMERO-GOMEZ, M.D., National Coordinator - Valme University hospital - Sevilla - Spain; Principal Investigator: Pr. Quentin M. ANSTEE, M.D., National Coordinator - Freeman Hospital - Newcastle - UK

Publications and helpful links

General Publications

• Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee QM, Hum D, Hanf R, Roudot A, Megnien S, Staels B, Sanyal A; GOLDEN-505 Investigator Study Group. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016 May;150(5):1147-1159.e5. doi: 10.1053/j.gastro.2016.01.038. Epub 2016 Feb 11. Erratum In: Gastroenterology. 2017 Jun;152(8):2084.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: September 24, 2012
• First Submitted That Met QC Criteria: September 26, 2012
• First Posted (Estimate): September 27, 2012

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Fibrosis; NASH; Liver Diseases; Non-Alcoholic Steatohepatitis; PPARs
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: GFT505-212-7; 2012-000295-42 (EudraCT Number)