Clinical trial NCT01694849: Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis (NASH)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis (NASH)
Keywords: PPARs
NASH
Non-Alcoholic Steatohepatitis
Liver Diseases
Fibrosis
Lead sponsor: Genfit
Sponsor class: INDUSTRY
Collaborators: name: Naturalpha
name: Premier Research Group plc
First posted: 2012-09-27
Enrollment: 275
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Percentage of Responders With Disappearance of Steatohepatitis Without Worsening of Fibrosis (ie, Participants no Longer Meeting the Criteria for Steatohepatitis)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Secondary outcomes:
measure: Change From Baseline to Week 52 in Non-alcoholic Fatty Liver Disease Activity Score
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Number of Participants With Change From Baseline to Week 52 in Non-alcoholic Fatty Liver Disease Activity Score of at Least 2 Points
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Number of Participants With Decrease in Steatosis Score of at Least 1 Point Between Baseline and Week 52
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Number of Participants With Decrease in Lobular Inflammation Score of at Least 1 Point Between Baseline and Week 52
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Title: Number of Participants With Decrease in Ballooning Score of at Least 1 Point Between Baseline and Week 52
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in the Stages of Fibrosis
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Visit 8 (Week 52) in Liver Enzymes
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Visit 8 (Week 52) in Aspartate Transaminase/Alanine Aminotransferase Ratio
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: CK 18-M65
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: CK18 M30
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Adiponectin
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Ferritin
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: FG19 and FG21
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Alpha2 Macroglobulin
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: 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)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fibrotest
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Steatotest
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Angulo Index or Non-Alcoholic Fatty Liver Disease Fibrosis Score
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Enhanced Liver Fibrosis (ELF)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fatty Liver Index (FLI)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Fibrometer
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Total Bilirubin and Conjugated Bilirubin
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: Prothrombin Ratio
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Non-invasive Markers of Fibrosis and Steatosis: International Normalized Ratio (INR)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Lipid Parameters (Cardiovascular Risk Profile)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Outcomes Related to Biochemistry
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: Leptin
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: Insulin
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: C Peptide
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: Homeostatic Model Assessment-insulin Resistance (HOMA-IR)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: Free Fatty Acids (FFA)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: Plasma Glucose
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: Glycosylated Haemoglobin A1c (HbA1c)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Insulin Resistance: Fructosamine
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Inflammatory Markers: Fibrinogen and Haptoglobin
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Inflammatory Markers: Tumour Necrosis Factor Alpha and Interleukine 6
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Inflammatory Markers: Plasminogen Activator Inhibitor 1 (PAI-1)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Inflammatory Markers: C-Reactive Protein (CRP)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: Creatinine (Renal Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: Creatinine Clearance (Renal Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: Uric Acid (Renal Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: Blood Urea Nitrogen (BUN; Renal Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: Cystatin C (Renal Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: Beta2-microglobulin (Renal Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP; Cardiac Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Safety Markers: Troponin T (Cardiac Function Parameter)
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
measure: Changes From Baseline to Week 52 in Body Weight
timeFrame: Baseline (Visit 2; Week 0) to Visit 8 (Week 52)
Other outcomes:
Locations:
city: Fresno
country: United States
facility: Site 920
state: California
city: La Jolla
country: United States
facility: Site 903
state: California
city: Aurora
country: United States
facility: Site 911
state: Colorado
city: Gainesville
country: United States
facility: Site 912
state: Florida
city: Atlanta
country: United States
facility: Site 924
state: Georgia
city: Atlanta
country: United States
facility: Site 917
state: Georgia
city: New Orleans
country: United States
facility: Site 909
state: Louisiana
city: Worcester
country: United States
facility: Site 921
state: Massachusetts
city: Detroit
country: United States
facility: Site 902
state: Michigan
city: New York
country: United States
facility: Site 927
state: New York
city: Durham
country: United States
facility: Site 908
state: North Carolina
city: Philadelphia
country: United States
facility: Site 919
state: Pennsylvania
city: Memphis
country: United States
facility: Site 916
state: Tennessee
city: Fort Sam Houston
country: United States
facility: Site 913
state: Texas
city: Houston
country: United States
facility: Site 923
state: Texas
city: San Antonio
country: United States
facility: Site 906
state: Texas
city: Salt Lake City
country: United States
facility: Site 931
state: Utah
city: Charlottesville
country: United States
facility: Site 930
state: Virginia
city: Richmond
country: United States
facility: Site 901
state: Virginia
city: Brussels
country: Belgium
facility: Site 205
city: Edegem
country: Belgium
facility: Site 201
city: Gent
country: Belgium
facility: Site 204
city: Haine-Saint-Paul
country: Belgium
facility: Site 202
city: Leuven
country: Belgium
facility: Site 203
city: Amiens
country: France
facility: Site 106
city: Angers
country: France
facility: Site 102
city: Clichy
country: France
facility: Site 114
city: Lille
country: France
facility: Site 103
city: Lyon
country: France
facility: Site 113
city: Marseille
country: France
facility: Site 111
city: Montpellier
country: France
facility: Site 108
city: Nantes
country: France
facility: Site 104
city: Nice
country: France
facility: Site 109
city: Paris
country: France
facility: Site 112
city: Paris
country: France
facility: Site 101
city: Pessac
country: France
facility: Site 107
city: Bonn
country: Germany
facility: Site 405
city: Mainz
country: Germany
facility: Site 404
city: Milano
country: Italy
facility: Site 507
city: Palermo
country: Italy
facility: Site 503
city: Roma
country: Italy
facility: Site 504
city: Torino
country: Italy
facility: Site 501
city: Amsterdam
country: Netherlands
facility: Site 303
city: Nijmegen
country: Netherlands
facility: Site 302
city: Bucharest
country: Romania
facility: Site 603
city: Bucharest
country: Romania
facility: Site 601
city: Bucharest
country: Romania
facility: Site 602
city: Barcelona
country: Spain
facility: Site 703
city: Majadahonda
country: Spain
facility: Site 707
city: Malaga
country: Spain
facility: Site 705
city: Santander
country: Spain
facility: Site 706
city: Sevilla
country: Spain
facility: Site 701
city: Camberley
country: United Kingdom
facility: Site 802
city: Hull
country: United Kingdom
facility: Site 808
city: Newcastle Upon Tyne
country: United Kingdom
facility: Site 801
city: Nottingham
country: United Kingdom
facility: Site 803
Study officials:
affiliation: Development Director Genfit, France
name: Rémy HANF, PhD
role: STUDY_DIRECTOR
affiliation: International Coordinator - La Pitié-Salpêtrière Hospital - Paris 13, France
name: Pr. Vlad RATZIU, M.D.
role: STUDY_CHAIR
affiliation: National Coordinator -Virginia Commonwealth University - Richmond - USA
name: Pr. Arun SANYAL, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinator - UZA - Edegem - Belgium
name: Dr. Sven FRANCQUE, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinator - UMC St Radboud Nijmegen - Nijmegen - The Netherlands
name: Dr. Jost PH DRENTH, MD, Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinator - Medical School of Hannover - Hannover - Germany
name: Pr. Michael Manns, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinator - University of Torino - S. Giovanni Battista Hospital - Torino - Italy
name: Pr. Elisabetha BUGIANESI, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinator - Center of Internal Medicine, Fundeni Clinical Institute - Bucharest - Romania
name: Pr. Mihai VOICULESCU, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinator - Valme University hospital - Sevilla - Spain
name: Pr. Manuel ROMERO-GOMEZ, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinator - Freeman Hospital - Newcastle - UK
name: Pr. Quentin M. ANSTEE, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.