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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
NATURALPHA
PREMIER RESEARCH GROUP
Information provided by (Responsible Party):
Genfit
ClinicalTrials.gov Identifier:
NCT01694849
First received: September 24, 2012
Last updated: February 25, 2014
Last verified: February 2014
  Purpose

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 Intervention Phase
Non-Alcoholic Steatohepatitis (NASH)
Drug: GFT505 80mg
Drug: GFT505 120mg
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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).

Resource links provided by NLM:


Further study details as provided by Genfit:

Primary Outcome Measures:
  • Percentage of responders defined by the disappearance of steatohepatitis without worsening of fibrosis [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]

    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the percentage of responders from baseline to Week 52, defined by the disappearance of steatohepatitis (i.e. patients no longer meeting the criteria for steatohepatitis) without worsening of fibrosis.

    Worsening of fibrosis is evaluated using NASH CRN (Clinical Research Network) fibrosis staging system and defined as:

    • Progression to stage 3 or 4 for patients at stage 0, 1 or 2 on diagnostic liver biopsy
    • Progression to stage 4 for patients at stage 3 on diagnostic liver biopsy


Secondary Outcome Measures:
  • Percentage of responders, defined by the disappearance of steatohepatitis [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the percentage of responders from baseline to week 52, defined by the disappearance of steatohepatitis (i.e. patients no longer meeting the criteria for steatohepatitis).

  • NAS score (Non-alcoholic fatty liver disease Activity Score) [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the change from baseline to week 52, in NAS score (Non-alcoholic fatty liver disease Activity Score).

  • Stages of steatosis, hepatic activity [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in stages of steatosis, hepatic activity (lobular inflammation + ballooning).

  • Stages of fibrosis [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    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 (NASH CRN scoring = Non-Alcoholic Steatohepatitis Clinical Research Network scoring).

  • Area of fibrosis [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to Week 52, in area of fibrosis by morphometry

  • Liver enzymes [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in liver enzymes.

  • Non-invasive markers of fibrosis and steatosis [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in non-invasive markers of fibrosis and steatosis.

  • Lipid parameters [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in lipid parameters.

  • Body weight [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in body weight.

  • Insulin resistance [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in insulin resistance.

  • Inflammatory markers [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in inflammatory markers.

  • Safety markers [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in safety markers (renal or cardiac function parameters).

  • Cardiovascular risk profile [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    To evaluate after 52 weeks of daily administration of GFT505 80mg, or GFT505 120mg, the changes from baseline to week 52, in cardiovascular risk profile.


Estimated Enrollment: 270
Study Start Date: September 2012
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01694849

  Hide Study 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
Site 915
Miami, Florida, United States, FL 33136
United States, Georgia
Site 924
Atlanta, Georgia, United States, GA 30303
Site 917
Atlanta, Georgia, United States, GA 30322
United States, Indiana
Site 910
Indianapolis, Indiana, United States, IN 46202
United States, Kentucky
Site 904
Lexington, Kentucky, United States, KY 40536
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, Missouri
Site 922
St. Louis, Missouri, United States, MO 63110
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, Rhode Island
Site 918
Providence, Rhode Island, United States, RI 02903
United States, South Carolina
Site 925
Charleston, South Carolina, United States, SC 29425
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 101
Paris, France, 75651
Site 112
Paris, France, 75571
Site 107
Pessac, France, 33604
Germany
Site 403
Bochum, Germany, 44791
Site 405
Bonn, Germany, 53127
Site 401
Hannover, Germany, 30625
Site 404
Mainz, Germany, 55131
Site 402
Tübingen, Germany, 72076
Italy
Site 505
Bologna, Italy, 40138
Site 506
Bologna, Italy, 40138
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 601
Bucharest, Romania, 022328
Site 602
Bucharest, Romania, 022328
Site 603
Bucharest, Romania, 021105
Spain
Site 704
Alcorcón, Spain, 28922
Site 702
Aranjuez, Spain, 28300
Site 703
Barcelona, Spain, 08036
Site 707
Majadahonda, Spain, 28222
Site 705
Malaga, Spain, 29010
Site 709
Pontevedra, Spain, 36071
Site 706
Santander, Spain, 39008
Site 701
Sevilla, Spain, 41014
United Kingdom
Site 804
Birmingham, United Kingdom, B15 2TT
Site 802
Camberley, United Kingdom, GU16 7UJ
Site 809
Cambridge, United Kingdom, CB2 0QQ
Site 808
Hull, United Kingdom, HU3 2JZ
Site 807
London, United Kingdom, W2 1NY
Site 801
Newcastle Upon Tyne, United Kingdom, NE7 7DN
Site 803
Nottingham, United Kingdom, NG7 2UH
Site 810
Sheffield, United Kingdom, S10 2JF
Sponsors and Collaborators
Genfit
NATURALPHA
PREMIER RESEARCH GROUP
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

No publications provided

Responsible Party: Genfit
ClinicalTrials.gov Identifier: NCT01694849     History of Changes
Other Study ID Numbers: GFT505-212-7, 2012-000295-42
Study First Received: September 24, 2012
Last Updated: February 25, 2014
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicinal Products and Health Products
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Romania: National Agency for Medicines and Medical Devices
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Genfit:
PPARs
NASH
Non-Alcoholic Steatohepatitis
Liver Diseases
Fibrosis

Additional relevant MeSH terms:
Fatty Liver
Digestive System Diseases
Liver Diseases

ClinicalTrials.gov processed this record on October 22, 2014