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.
Brief Title
Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH)
Completion Date
Completion Date Type
Actual
Conditions
Nonalcoholic Steatohepatitis (NASH) With Fibrosis
Eligibility 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. 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
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
Inclusion 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. 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.
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.
Gender
All
Gender Based
false
Keywords
Elafibranor
NASH
Nonalcoholic steatohepatitis
Fatty liver disease
Fibrosis
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
75 Years
Minimum Age
18 Years
NCT Id
NCT02704403
Org Class
Industry
Org Full Name
Genfit
Org Study Id
GFT505-315-1
Overall Status
Terminated
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
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.
Outcome Measure
Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis Without Worsening of Fibrosis
Outcome Time Frame
Measurement at 72 weeks
Outcome Description
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.
Outcome Measure
Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes
Outcome 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)
Secondary Ids
Secondary Id
2015-005385-38
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Measurements at 72 weeks
Outcome Measure
Number of Elafibranor-treated Participants Relative to Placebo Achieving Improvement of Fibrosis of at Least 1 Stage
Outcome Description
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.
Outcome Time Frame
Measurements after 72 weeks of treatment and up to study termination
Outcome Measure
Change From Baseline of Hemoglobin A1c (HbA1c) in Diabetic Participants After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo
Outcome Description
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.
Outcome Time Frame
Measurements after 72 weeks of treatment and up to study termination
Outcome Measure
Change From Baseline of High-density Lipoprotein (HDL) Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo
Outcome Description
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.
Outcome Time Frame
Measurements after 72 weeks of treatment and up to study termination
Outcome Measure
Change From Baseline of Low-density Lipoprotein (LDL) Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo
Outcome Description
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.
Outcome Time Frame
Measurements after 72 weeks of treatment and up to study termination
Outcome Measure
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
Outcome Description
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.
Outcome Time Frame
Measurements after 72 weeks of treatment and up to study termination
Outcome Measure
Change From Baseline of Non-high Density Lipoprotein Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo
Outcome Description
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.
Outcome Time Frame
Measurements after 72 weeks of treatment and up to study termination
Outcome Measure
Change From Baseline of Triglycerides After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
75
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Samuel Sigal
Investigator Email
ssigal@montefiore.org
Investigator Phone
718-920-6240