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

Sponsor

Genfit (Industry)

Overall Status

Completed

CT.gov ID

NCT01694849

Collaborator

Naturalpha (Industry), Premier Research Group plc (Industry)

270

Enrollment

Locations

Arms

Duration (Months)

4.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

Actual Enrollment :

270 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 :

Sep 1, 2012

Actual Primary Completion Date :

Feb 1, 2015

Actual Study Completion Date :

Dec 1, 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

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

Percentage of responders defined by the disappearance of steatohepatitis without worsening of fibrosis [52 weeks]
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 [52 weeks]
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) [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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 [52 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	Site 920	Fresno	California	United States	CA 9372
2	Site 903	La Jolla	California	United States	CA 92037
3	Site 911	Aurora	Colorado	United States	CO 80045
4	Site 912	Gainesville	Florida	United States	FL 32610-0277
5	Site 924	Atlanta	Georgia	United States	GA 30303
6	Site 917	Atlanta	Georgia	United States	GA 30322
7	Site 909	New Orleans	Louisiana	United States	LA 70112-2600
8	Site 921	Worcester	Massachusetts	United States	MA 01655
9	Site 902	Detroit	Michigan	United States	MI 48202
10	Site 927	New York	New York	United States	NY 10029-6574
11	Site 908	Durham	North Carolina	United States	NC 27710
12	Site 919	Philadelphia	Pennsylvania	United States	PA 19104
13	Site 916	Memphis	Tennessee	United States	TN 38104
14	Site 913	Fort Sam Houston	Texas	United States	TX 78234
15	Site 923	Houston	Texas	United States	TX 77030
16	Site 906	San Antonio	Texas	United States	TX 78215
17	Site 931	Salt Lake City	Utah	United States	UT 84132
18	Site 930	Charlottesville	Virginia	United States	VA 22908
19	Site 901	Richmond	Virginia	United States	VA 23298
20	Site 205	Brussels		Belgium	1070
21	Site 201	Edegem		Belgium	B-2650
22	Site 204	Gent		Belgium	B-9000
23	Site 202	Haine-Saint-Paul		Belgium	7100
24	Site 203	Leuven		Belgium	3000
25	Site 106	Amiens		France	80054
26	Site 102	Angers		France	49933
27	Site 114	Clichy		France	92110
28	Site 103	Lille		France	59037
29	Site 113	Lyon		France	69317
30	Site 111	Marseille		France	13285
31	Site 108	Montpellier		France	34295
32	Site 104	Nantes		France	44093
33	Site 109	Nice		France	06202
34	Site 112	Paris		France	75571
35	Site 101	Paris		France	75651
36	Site 107	Pessac		France	33604
37	Site 405	Bonn		Germany	53127
38	Site 404	Mainz		Germany	55131
39	Site 507	Milano		Italy	20122
40	Site 503	Palermo		Italy	90127
41	Site 504	Roma		Italy	00133
42	Site 501	Torino		Italy	10126
43	Site 303	Amsterdam		Netherlands	1100
44	Site 302	Nijmegen		Netherlands	6500
45	Site 603	Bucharest		Romania	021105
46	Site 601	Bucharest		Romania	022328
47	Site 602	Bucharest		Romania	022328
48	Site 703	Barcelona		Spain	08036
49	Site 707	Majadahonda		Spain	28222
50	Site 705	Malaga		Spain	29010
51	Site 706	Santander		Spain	39008
52	Site 701	Sevilla		Spain	41014
53	Site 802	Camberley		United Kingdom	GU16 7UJ
54	Site 808	Hull		United Kingdom	HU3 2JZ
55	Site 801	Newcastle Upon Tyne		United Kingdom	NE7 7DN
56	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