Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH) (RESOLVE-IT)

• Sponsor: Genfit
• Information provided by (Responsible Party): Genfit

Study Description

Brief Summary:

The primary objectives of this study are to evaluate the effect of Elafibranor treatment compared to placebo on 1) histological improvement and 2) all-cause mortality and liver-related outcomes in patients with nonalcoholic steatohepatitis (NASH) and fibrosis.

Condition or disease	Intervention/treatment	Phase
Nonalcoholic Steatohepatitis (NASH) With Fibrosis	Drug: Elafibranor; Drug: Placebo	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	2000 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and Safety of Elafibranor in Patients With Nonalcoholic Steatohepatitis (NASH) and Fibrosis
Study Start Date :	March 2016
Estimated Primary Completion Date :	December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 120 mg Elafibranor; Coated tablets dosed at 120mg Elafibranor; oral administration; one tablet per day before breakfast with a glass of water	Drug: Elafibranor; Other Name: GFT505
Placebo Comparator: Placebo; Coated placebo tablets; oral administration; one tablet per day before breakfast with a glass of water	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Proportion of Elafibranor treated patients relative to placebo achieving resolution of NASH without worsening of fibrosis [ Time Frame: Measurement at 72 weeks ]
   To evaluate the effect of Elafibranor compared to placebo on liver histology in nonalcoholic steatohepatitis (NASH) subjects with fibrosis by assessing the following endpoint: The proportion of Elafibranor treated patients relative to placebo achieving NASH resolution without worsening of fibrosis.
2. Composite long-term outcome composed of all-cause mortality, cirrhosis, and liver-related clinical outcomes [ Time Frame: Time to accrue a pre-specified number of adjudicated events, estimated to be 4 years ]
   To evaluate the effect of Elafibranor compared to placebo on composite long-term outcome measured by the number of patients with the onset of any of the adjudicated events, composed of cirrhosis, all-cause mortality, liver-related clinical outcomes.

Secondary Outcome Measures :

1. Proportion of Elafibranor treated patients relative to placebo achieving improvement of fibrosis [ Time Frame: Measurements at 72 weeks ]
   To evaluate the effect of Elafibranor compared to placebo on liver histology in nonalcoholic steatohepatitis (NASH) subjects by assessing the following endpoint: The proportion of Elafibranor treated patients relative to placebo achieving improvement of liver fibrosis of at least one stage.
2. Proportion of Elafibranor treated patients relative to placebo achieving improvement in histological scores in NASH [ Time Frame: Measurements after 72 weeks of treatment and up to study completion estimated at 4 years of treatment ]
   • Percentage of patients with resolution of NASH without worsening of fibrosis (study completion)
   • Percentage of patients with improvement of fibrosis of at least 1 stage
   • Percentage of patients with at least 1 point improvement in histological scores in NASH
3. Proportion of Elafibranor treated patients relative to placebo with improvement in cardiometabolic and liver markers and liver markers [ Time Frame: Measurements at Week 72, and at the end of the Long-term Treatment Period estimated at 4 years ]

   To assess the following endpoints in Elafibranor treated patients relative to placebo, at Week 72 and at the end of the Long-term Treatment Period, estimated at 4 years:

   • cardiovascular events
   • changes in liver enzymes and liver markers
   • changes in non-invasive markers of fibrosis and steatosis
   • changes in lipid parameters
   • variation in body weight
   • changes in insulin resistance and glucose homeostasis markers
   • changes in inflammatory markers
   • changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire)
4. Proportion of Elafibranor treated patients relative to placebo having a liver-related death [ Time Frame: Measurements at Week 72, and at the end of the Long-term Treatment Period estimated at 4 years ]

   To assess the following endpoints in Elafibranor treated patients relative to placebo, at Week 72 and at the end of the Long-term Treatment Period, estimated at 4 years:

   o liver-related death

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Males or females aged from 18 to 75 years inclusive at first screening visit.
2. Must provide signed written informed consent and agree to comply with the study protocol.
3. BMI ≤45 kg/m².
4. Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal contraception (including patch, contraceptive ring, etc.), intra-uterine device, or other mechanical contraception method + condom or diaphragm or spermicide for the full duration of the study and for 1 month after the end of treatment.
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides (biopsy obtained within 6 months prior to randomization or during the screening period) with at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3).
6. NAS score ≥4.
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
8. Stable dose of vitamin E, polyunsaturated fatty acids, or ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy
9. No change in antidiabetic therapy within 6 months prior to liver biopsy

Exclusion Criteria:

1. Known heart failure (Grade I to IV of New York Heart Association classification).
2. History of efficient bariatric surgery within 5 years prior to screening.
3. Uncontrolled hypertension
4. Type 1 diabetes patients.
5. Patients with decompensated diabetes (HbA1c>9%).
6. Patients with a history of clinically significant acute cardiac event within 6 months prior to screening
7. Weight loss of more than 5% within 6 months prior to randomization
8. Compensated and decompensated cirrhosis
9. Current or recent history (<5 years) of significant alcohol consumption
10. Pregnant or lactating females or females planning to become pregnant during the study period.
11. Other well documented causes of chronic liver disease according to standard diagnostic procedures
12. Patients with previous exposure to Elafibranor
13. Prohibited concomitant medication
14. Any medical conditions that may diminish life expectancy to less than 2 years including known cancers.
15. Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric disease.
16. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.

Contacts and Locations

Contacts

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Contact: GENFIT		clinicaltrial@genfit.com

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Sponsors and Collaborators

Genfit

Investigators

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Study Director:	Pascal BIRMAN, MD	Genfit

More Information

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Responsible Party:	Genfit
ClinicalTrials.gov Identifier:	NCT02704403 History of Changes
Other Study ID Numbers:	GFT505-315-1; 2015-005385-38 ( EudraCT Number )
First Posted:	March 10, 2016
Last Update Posted:	February 4, 2019
Last Verified:	January 2018

Keywords provided by Genfit:

Elafibranor; NASH; Nonalcoholic steatohepatitis; Fatty liver disease; Fibrosis

Additional relevant MeSH terms:

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Fibrosis; Fatty Liver; Non-alcoholic Fatty Liver Disease	Pathologic Processes; Liver Diseases; Digestive System Diseases