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

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 Study to Evaluate the Efficacy and Safety of GFT505 Once Daily on Steatohepatitis in Patients With Non-Alcoholic Steatohepatitis (NASH). A Multicentre, Randomized, Double Blind, Placebo-Controlled Study, With an Adaptive Design to Allow for Initial GFT505 80mg Dosing Versus Placebo, Followed by a Second Phase Including GFT505 120mg Dose, After Review of 6-month Safety Analysis of the 80mg Data on at Least 50% of Patients.

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines Liver Diseases

U.S. FDA Resources

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:	January 2015
Estimated Primary Completion Date:	October 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).
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 authorised. 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, neoplasic, 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

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

Contacts

Contact: GENFIT, Product Development department

contact@genfit.com

Show 58 Study Locations

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. Jeoffrey SCHOUTEN, M.D.	National Coordinator - Erasmus MC University Hospital - Rotterdam - 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:	March 20, 2013
Health Authority:	United States: Food and Drug Administration Belgium: Federal Agency for Medicinal Products and Health Products France: L’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
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on May 16, 2013