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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02704403
Recruitment Status : Terminated (Study did not meet the predefined primary surrogate efficacy endpoint, no safety issues identified)
First Posted : March 10, 2016
Results First Posted : March 23, 2022
Last Update Posted : March 23, 2022
Sponsor:
Information provided by (Responsible Party):
Genfit

Tracking Information
First Submitted Date  ICMJE February 16, 2016
First Posted Date  ICMJE March 10, 2016
Results First Submitted Date  ICMJE January 7, 2022
Results First Posted Date  ICMJE March 23, 2022
Last Update Posted Date March 23, 2022
Study Start Date  ICMJE March 2016
Actual Primary Completion Date October 28, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2022)
  • Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis 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) participants with fibrosis by assessing the following endpoint: The number of Elafibranor-treated participants relative to placebo achieving NASH resolution without worsening of fibrosis. This outcome measure is for the surrogate endpoint analysis.
  • Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes [ Time Frame: From first randomization up to early termination of the study corresponding to 54 months (54 months being the longest duration for any given participant) ]
    Composite long-term outcome measured by the number of participants with the onset of any of the adjudicated events, composed of death due to any cause, histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events as follows: liver transplantation; model for end stage liver disease (MELD) score greater than or equal to 15 for participants with baseline score less than or equal to 12, and onset of variceal bleeding requiring hospitalization, hepatic encephalopathy with West Haven/Conn score greater than or equal to 2 and requiring hospitalization, spontaneous bacterial peritonitis, and ascites requiring treatment. The MELD scale ranges from 6 to 40, showing how much a participant needs a liver transplant: higher number is more urgent. The West Haven/Conn scale is 5-point (0 to 4) grading severity of hepatic encephalopathy: higher score means worse hepatic encephalopathy. This outcome measure is for the long-term endpoint analysis.
Original Primary Outcome Measures  ICMJE
 (submitted: March 4, 2016)
  • 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.
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2022)
  • Number of Elafibranor-treated Participants Relative to Placebo Achieving Improvement of Fibrosis of at Least 1 Stage [ Time Frame: Measurements at 72 weeks ]
    To evaluate the effect of Elafibranor compared to placebo on liver histology in nonalcoholic steatohepatitis (NASH) participants by assessing the following endpoint: The number of Elafibranor-treated participants relative to placebo achieving improvement of liver fibrosis of at least 1 stage according to NASH Clinical Research Network (CRN) Scoring. As the primary efficacy objective was not met, the secondary efficacy endpoints were not formally tested. This outcome measure is for the surrogate endpoint analysis.
  • Change From Baseline of Hemoglobin A1c (HbA1c) in Diabetic Participants After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo [ Time Frame: Measurements after 72 weeks of treatment and up to study termination ]
    Hemoglobin A1c (HbA1c) were tested at Week 72. Changes from baseline in HbA1c at Week 72 were evaluated. As the primary efficacy objective was not met, the secondary efficacy endpoints were not formally tested. This outcome measure is for the surrogate endpoint analysis.
  • Change From Baseline of High-density Lipoprotein (HDL) Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo [ Time Frame: Measurements after 72 weeks of treatment and up to study termination ]
    High-density lipoprotein (HDL) cholesterol was tested at Week 72. Changes from baseline in HDL cholesterol were evaluated at Week 72. As the primary efficacy objective was not met, the secondary efficacy endpoints were not formally tested. This outcome measure is for the surrogate endpoint analysis.
  • Change From Baseline of Low-density Lipoprotein (LDL) Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo [ Time Frame: Measurements after 72 weeks of treatment and up to study termination ]
    Low-density lipoprotein (LDL) cholesterol was tested at Week 72. Changes from baseline in LDL cholesterol were evaluated at Week 72. As the primary efficacy objective was not met, the secondary efficacy endpoints were not formally tested. This outcome measure is for the surrogate endpoint analysis.
  • Change From Baseline of Homeostatic Model Assessment-IR (HOMA-IR) After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo in Non-diabetic Participants [ Time Frame: Measurements after 72 weeks of treatment and up to study termination ]
    Homeostatic model assessment-IR (HOMA-IR) was tested at Week 72. Changes from baseline in HOMA-IR were evaluated at Week 72. As the primary efficacy objective was not met, the secondary efficacy endpoints were not formally tested. This outcome measure is for the surrogate endpoint analysis.
  • Change From Baseline of Non-high Density Lipoprotein Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo [ Time Frame: Measurements after 72 weeks of treatment and up to study termination ]
    Non-high density lipoprotein (HDL) cholesterol was tested at Week 72. Changes from baseline in non-HDL cholesterol were evaluated at Week 72. As the primary efficacy objective was not met, the secondary efficacy endpoints were not formally tested. This outcome measure is for the surrogate endpoint analysis.
  • Change From Baseline of Triglycerides After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo [ Time Frame: Measurements after 72 weeks of treatment and up to study termination ]
    Triglycerides was tested at Week 72. Changes from baseline in triglycerides were evaluated at Week 72. As the primary efficacy objective was not met, the secondary efficacy endpoints were not formally tested. This outcome measure is for the surrogate endpoint analysis.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 4, 2016)
  • 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.
  • 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
  • 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)
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH)
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Nonalcoholic Steatohepatitis (NASH) With Fibrosis
Intervention  ICMJE
  • Drug: Elafibranor
    Other Name: GFT505
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: 120 mg Elafibranor
    Coated tablets dosed at 120mg Elafibranor; oral administration; one tablet per day before breakfast with a glass of water
    Intervention: Drug: Elafibranor
  • Placebo Comparator: Placebo
    Coated placebo tablets; oral administration; one tablet per day before breakfast with a glass of water
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 26, 2020)
2157
Original Estimated Enrollment  ICMJE
 (submitted: March 4, 2016)
2000
Actual Study Completion Date  ICMJE October 28, 2020
Actual Primary Completion Date October 28, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. Females participating in this study must be of nonchildbearing potential or using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as described below:

    1. Cessation of menses for at least 12 months due to ovarian failure,
    2. Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure
    3. If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
    4. Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, vasectomized partner, or intra-uterine device)
    5. Double contraception with barrier AND highly effective hormonal method of contraception (oral, intravaginal, or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation; oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; or intrauterine hormone-releasing system). The hormonal contraception must be started at least 1 month prior to Randomization.
  4. 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).
  5. NAS score ≥4.
  6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
  7. Stable dose of vitamin E, polyunsaturated fatty acids, or ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy
  8. For participants with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, change in anti-diabetic therapy must follow these requirements:

    1. No qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., implementation of a new anti-diabetic therapy) for participants treated with metformin, gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose in the 6 months prior to diagnostic liver biopsy.
    2. No implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment (Visit 7).

Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians' judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the end of treatment.

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 during the Screening Period despite optimal antihypertensive therapy
  4. Type 1 diabetes participants .
  5. Participants with decompensated diabetes (HbA1c>9%).
  6. Participants 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. Participants 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.
  17. Participants with biological criteria exclusion as per effective protocol
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Canada,   Chile,   Colombia,   Czechia,   Denmark,   Finland,   France,   Germany,   Italy,   Mexico,   Netherlands,   Portugal,   Puerto Rico,   Romania,   Russian Federation,   South Africa,   Spain,   Sweden,   Switzerland,   Turkey,   United Kingdom,   United States
Removed Location Countries Brazil,   Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02704403
Other Study ID Numbers  ICMJE GFT505-315-1
2015-005385-38 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party Genfit
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Genfit
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Carol Addy, MD MMSc Genfit
PRS Account Genfit
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP