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

• ClinicalTrials.gov Identifier: NCT01694849
• Recruitment Status: Completed
• First Posted: September 27, 2012
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022
• Sponsor: Genfit
• Collaborators: Naturalpha; Premier Research Group plc
• Information provided by (Responsible Party): Genfit

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Non-Alcoholic Steatohepatitis (NASH)	Drug: GFT505 80mg; Drug: GFT505 120mg; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 275 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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).
• Study Start Date: September 2012
• Actual Primary Completion Date: February 2015
• Actual Study Completion Date: December 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Percentage of Responders With Disappearance of Steatohepatitis Without Worsening of Fibrosis (ie, Participants no Longer Meeting the Criteria for Steatohepatitis) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

   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

Secondary Outcome Measures :

1. Change From Baseline to Week 52 in Non-alcoholic Fatty Liver Disease Activity Score [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

   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.

2. Number of Participants With Change From Baseline to Week 52 in Non-alcoholic Fatty Liver Disease Activity Score of at Least 2 Points [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

   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).

3. Number of Participants With Decrease in Steatosis Score of at Least 1 Point Between Baseline and Week 52 [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (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).

4. Number of Participants With Decrease in Lobular Inflammation Score of at Least 1 Point Between Baseline and Week 52 [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (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).

5. Title: Number of Participants With Decrease in Ballooning Score of at Least 1 Point Between Baseline and Week 52 [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (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).

6. Changes From Baseline to Week 52 in the Stages of Fibrosis [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

   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.

7. Changes From Baseline to Visit 8 (Week 52) in Liver Enzymes [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
   To evaluate after 52 weeks of daily administration of GFT505 80mg or GFT505 120mg the changes from baseline to week 52, in liver enzymes.
8. Changes From Baseline to Visit 8 (Week 52) in Aspartate Transaminase/Alanine Aminotransferase Ratio [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
   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
9. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: CK 18-M65 [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
   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).
10. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: CK18 M30 [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

11. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Adiponectin [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
12. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Ferritin [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

13. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: FG19 and FG21 [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
14. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Alpha2 Macroglobulin [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

15. 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) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
16. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fibrotest [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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.
17. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Steatotest [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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.
18. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Angulo Index or Non-Alcoholic Fatty Liver Disease Fibrosis Score [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

19. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Enhanced Liver Fibrosis (ELF) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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.
20. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fatty Liver Index (FLI) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

21. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fibrometer [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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.
22. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Total Bilirubin and Conjugated Bilirubin [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
23. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Prothrombin Ratio [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

24. Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: International Normalized Ratio (INR) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

25. Changes From Baseline to Week 52 in Lipid Parameters (Cardiovascular Risk Profile) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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)
26. Changes From Baseline to Week 52 in Outcomes Related to Biochemistry [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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
27. Changes From Baseline to Week 52 in Insulin Resistance: Leptin [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
28. Changes From Baseline to Week 52 in Insulin Resistance: Insulin [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

29. Changes From Baseline to Week 52 in Insulin Resistance: C Peptide [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

30. Changes From Baseline to Week 52 in Insulin Resistance: Homeostatic Model Assessment-insulin Resistance (HOMA-IR) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

31. Changes From Baseline to Week 52 in Insulin Resistance: Free Fatty Acids (FFA) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

32. Changes From Baseline to Week 52 in Insulin Resistance: Plasma Glucose [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

33. Changes From Baseline to Week 52 in Insulin Resistance: Glycosylated Haemoglobin A1c (HbA1c) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

34. Changes From Baseline to Week 52 in Insulin Resistance: Fructosamine [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
35. Changes From Baseline to Week 52 in Inflammatory Markers: Fibrinogen and Haptoglobin [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
36. Changes From Baseline to Week 52 in Inflammatory Markers: Tumour Necrosis Factor Alpha and Interleukine 6 [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
37. Changes From Baseline to Week 52 in Inflammatory Markers: Plasminogen Activator Inhibitor 1 (PAI-1) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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

38. Changes From Baseline to Week 52 in Inflammatory Markers: C-Reactive Protein (CRP) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
39. Changes From Baseline to Week 52 in Safety Markers: Creatinine (Renal Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
40. Changes From Baseline to Week 52 in Safety Markers: Creatinine Clearance (Renal Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
41. Changes From Baseline to Week 52 in Safety Markers: Uric Acid (Renal Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
42. Changes From Baseline to Week 52 in Safety Markers: Blood Urea Nitrogen (BUN; Renal Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    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).
43. Changes From Baseline to Week 52 in Safety Markers: Cystatin C (Renal Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

44. Changes From Baseline to Week 52 in Safety Markers: Beta2-microglobulin (Renal Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

45. Changes From Baseline to Week 52 in Safety Markers: N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP; Cardiac Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

46. Changes From Baseline to Week 52 in Safety Markers: Troponin T (Cardiac Function Parameter) [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]

    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.

47. Changes From Baseline to Week 52 in Body Weight [ Time Frame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52) ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in body weight.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Site 920

Fresno, California, United States, CA 9372

Site 903

La Jolla, California, United States, CA 92037

United States, Colorado

Site 911

Aurora, Colorado, United States, CO 80045

United States, Florida

Site 912

Gainesville, Florida, United States, FL 32610-0277

United States, Georgia

Site 924

Atlanta, Georgia, United States, GA 30303

Site 917

Atlanta, Georgia, United States, GA 30322

United States, Louisiana

Site 909

New Orleans, Louisiana, United States, LA 70112-2600

United States, Massachusetts

Site 921

Worcester, Massachusetts, United States, MA 01655

United States, Michigan

Site 902

Detroit, Michigan, United States, MI 48202

United States, New York

Site 927

New York, New York, United States, NY 10029-6574

United States, North Carolina

Site 908

Durham, North Carolina, United States, NC 27710

United States, Pennsylvania

Site 919

Philadelphia, Pennsylvania, United States, PA 19104

United States, Tennessee

Site 916

Memphis, Tennessee, United States, TN 38104

United States, Texas

Site 913

Fort Sam Houston, Texas, United States, TX 78234

Site 923

Houston, Texas, United States, TX 77030

Site 906

San Antonio, Texas, United States, TX 78215

United States, Utah

Site 931

Salt Lake City, Utah, United States, UT 84132

United States, Virginia

Site 930

Charlottesville, Virginia, United States, VA 22908

Site 901

Richmond, Virginia, United States, VA 23298

Belgium

Site 205

Brussels, Belgium, 1070

Site 201

Edegem, Belgium, B-2650

Site 204

Gent, Belgium, B-9000

Site 202

Haine-Saint-Paul, Belgium, 7100

Site 203

Leuven, Belgium, 3000

France

Site 106

Amiens, France, 80054

Site 102

Angers, France, 49933

Site 114

Clichy, France, 92110

Site 103

Lille, France, 59037

Site 113

Lyon, France, 69317

Site 111

Marseille, France, 13285

Site 108

Montpellier, France, 34295

Site 104

Nantes, France, 44093

Site 109

Nice, France, 06202

Site 112

Paris, France, 75571

Site 101

Paris, France, 75651

Site 107

Pessac, France, 33604

Germany

Site 405

Bonn, Germany, 53127

Site 404

Mainz, Germany, 55131

Italy

Site 507

Milano, Italy, 20122

Site 503

Palermo, Italy, 90127

Site 504

Roma, Italy, 00133

Site 501

Torino, Italy, 10126

Netherlands

Site 303

Amsterdam, Netherlands, 1100

Site 302

Nijmegen, Netherlands, 6500

Romania

Site 603

Bucharest, Romania, 021105

Site 601

Bucharest, Romania, 022328

Site 602

Bucharest, Romania, 022328

Spain

Site 703

Barcelona, Spain, 08036

Site 707

Majadahonda, Spain, 28222

Site 705

Malaga, Spain, 29010

Site 706

Santander, Spain, 39008

Site 701

Sevilla, Spain, 41014

United Kingdom

Site 802

Camberley, United Kingdom, GU16 7UJ

Site 808

Hull, United Kingdom, HU3 2JZ

Site 801

Newcastle Upon Tyne, United Kingdom, NE7 7DN

Site 803

Nottingham, United Kingdom, NG7 2UH

Sponsors and Collaborators

Genfit

Naturalpha

Premier Research Group plc

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Genfit
• ClinicalTrials.gov Identifier: NCT01694849
• Other Study ID Numbers: GFT505-212-7; 2012-000295-42 ( EudraCT Number )
• First Posted: September 27, 2012
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022
• Last Verified: November 2022

Keywords provided by Genfit:

PPARs; NASH; Non-Alcoholic Steatohepatitis; Liver Diseases; Fibrosis

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases; Digestive System Diseases