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

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

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02704403

Acronym

RESOLVE-IT

Enrollment

2157

Registered

2016-03-10

Start date

2016-03-31

Completion date

2020-10-28

Last updated

2022-03-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Nonalcoholic Steatohepatitis (NASH) With Fibrosis

Keywords

Elafibranor, NASH, Nonalcoholic steatohepatitis, Fatty liver disease, 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.

Interventions

DRUGElafibranor

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis Without Worsening of Fibrosis	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	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.

Secondary

Measure	Time frame	Description
Change From Baseline of High-density Lipoprotein (HDL) Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo	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	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.
Number of Elafibranor-treated Participants Relative to Placebo Achieving Improvement of Fibrosis of at Least 1 Stage	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 Non-high Density Lipoprotein Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo	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	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.
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	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 Hemoglobin A1c (HbA1c) in Diabetic Participants After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo	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.

Countries

Argentina, Australia, Belgium, Canada, Chile, Colombia, Czechia, Denmark, Finland, France, Germany, Italy, Mexico, Netherlands, Portugal, Puerto Rico, Romania, Russia, South Africa, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

The version 3 protocol for Brazil is included in the uploaded documents as it was part of the pre-specified plan, but this country was not used as part of the study.

Participants by arm

Arm	Count
120 mg Elafibranor Coated 120mg elafibranor tablets; oral administration; one tablet per day before breakfast with a glass of water	1,437
Placebo Coated placebo tablets; oral administration; one tablet per day before breakfast with a glass of water	720
Total	2,157

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Administrative reasons by sponsor	1,251	616
Overall Study	Adverse Event	2	0
Overall Study	Death	4	3
Overall Study	Endpoint event	52	24
Overall Study	Follow-up not possible	1	2
Overall Study	Investigator decision	1	1
Overall Study	Lost to Follow-up	22	11
Overall Study	Protocol Violation	15	15
Overall Study	Randomized and not treated (due to non-compliance with protocol)	4	3
Overall Study	Withdrawal by Subject	85	45

Baseline characteristics

Characteristic	Placebo	120 mg Elafibranor	Total
Age, Continuous	54.4 years STANDARD_DEVIATION 11.63	54.0 years STANDARD_DEVIATION 11.78	54.1 years STANDARD_DEVIATION 11.73
BMI	33.6 kg/m^2 STANDARD_DEVIATION 5.77	34.1 kg/m^2 STANDARD_DEVIATION 6.13	33.9 kg/m^2 STANDARD_DEVIATION 6.01
Child Bearing Potential Missing	0 Participants	1 Participants	1 Participants
Child Bearing Potential No	262 Participants	516 Participants	778 Participants
Child Bearing Potential Not applicable	412 Participants	815 Participants	1227 Participants
Child Bearing Potential Yes	46 Participants	105 Participants	151 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	177 Participants	336 Participants	513 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	532 Participants	1089 Participants	1621 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	11 Participants	12 Participants	23 Participants
Fibrosis Stage F1	69 Participants	135 Participants	204 Participants
Fibrosis Stage F2	302 Participants	603 Participants	905 Participants
Fibrosis Stage F3	349 Participants	699 Participants	1048 Participants
Height	168.8 cm STANDARD_DEVIATION 10.23	169.1 cm STANDARD_DEVIATION 10.48	169.0 cm STANDARD_DEVIATION 10.39
Model For End-Stage Liver Disease Score (categorical) Greater than or equal to 15	5 Participants	11 Participants	16 Participants
Model For End-Stage Liver Disease Score (categorical) Less than 15	715 Participants	1426 Participants	2141 Participants
Non-alcoholic fatty liver disease Activity Score Grouped Severity Score (categorical) Moderate (4-5)	317 Participants	663 Participants	980 Participants
Non-alcoholic fatty liver disease Activity Score Grouped Severity Score (categorical) Severe (greater than or equal to 6)	402 Participants	774 Participants	1176 Participants
Non-alcoholic fatty liver disease Activity Score Severity Score (categorical) 4	94 Participants	193 Participants	287 Participants
Non-alcoholic fatty liver disease Activity Score Severity Score (categorical) 5	223 Participants	470 Participants	693 Participants
Non-alcoholic fatty liver disease Activity Score Severity Score (categorical) 6	225 Participants	453 Participants	678 Participants
Non-alcoholic fatty liver disease Activity Score Severity Score (categorical) 7	154 Participants	271 Participants	425 Participants
Non-alcoholic fatty liver disease Activity Score Severity Score (categorical) 8	23 Participants	50 Participants	73 Participants
Non-alcoholic fatty liver disease Activity Score Severity Score (categorical) Missing	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	8 Participants	9 Participants
Race (NIH/OMB) Asian	27 Participants	53 Participants	80 Participants
Race (NIH/OMB) Black or African American	10 Participants	28 Participants	38 Participants
Race (NIH/OMB) More than one race	49 Participants	93 Participants	142 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	3 Participants	3 Participants	6 Participants
Race (NIH/OMB) Unknown or Not Reported	16 Participants	18 Participants	34 Participants
Race (NIH/OMB) White	614 Participants	1234 Participants	1848 Participants
Sex: Female, Male Female	308 Participants	622 Participants	930 Participants
Sex: Female, Male Male	412 Participants	815 Participants	1227 Participants
Type 2 Diabetes No	369 Participants	738 Participants	1107 Participants
Type 2 Diabetes Yes	351 Participants	699 Participants	1050 Participants
Waist Circumference	110.4 cm STANDARD_DEVIATION 13.48	111.9 cm STANDARD_DEVIATION 14.19	111.4 cm STANDARD_DEVIATION 13.97
Weight	96.3 kg STANDARD_DEVIATION 20.84	98.0 kg STANDARD_DEVIATION 21.9	97.4 kg STANDARD_DEVIATION 21.56

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	6 / 1,437	3 / 720
other Total, other adverse events	1,227 / 1,433	601 / 717
serious Total, serious adverse events	190 / 1,433	95 / 717

Outcome results

Primary

Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis Without Worsening of Fibrosis

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 frame: Measurement at 72 weeks

Population: Intent-to-treat Set: a cohort of randomized F2 to F3 participants who completed the Week 72 treatment period or discontinued the study treatment early.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
120 mg Elafibranor	Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis Without Worsening of Fibrosis	138 Participants
Placebo	Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis Without Worsening of Fibrosis	52 Participants

Comparison: The null hypothesis was that there was no difference in response rates between the elafibranor and placebo treatment groups. The alternative hypothesis was that there was a difference in the response rates between the elafibranor and placebo treatment groups.p-value: 0.065995% CI: [-0.003, 0.09]Regression, Logistic

Primary

Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes

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.

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)

Population: Full Intent-to-Treat Set: All randomized participants. Participants were analyzed according to their randomized treatment.

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	18 months	No events or not censored	1010 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	Baseline	Censored	0 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	24 months	Events	56 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	Baseline	No events or not censored	1437 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	24 months	Censored	609 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	42 months	No events or not censored	83 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	24 months	No events or not censored	772 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	6 months	No events or not censored	1388 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	30 months	Events	57 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	6 months	Censored	48 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	30 months	Censored	778 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	42 months	Events	61 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	30 months	No events or not censored	602 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	54 months	No events or not censored	0 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	36 months	Events	60 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	12 months	Events	1 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	36 months	Censored	1049 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	12 months	Censored	159 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	36 months	No events or not censored	328 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	6 months	Events	1 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	12 months	No events or not censored	1277 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	48 months	Events	61 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	Baseline	Events	0 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	48 months	Censored	1374 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	18 months	Events	53 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	48 months	No events or not censored	2 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	18 months	Censored	374 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	54 months	Events	61 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	42 months	Censored	1293 Participants
120 mg Elafibranor	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	54 months	Censored	1376 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	48 months	Events	32 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	12 months	Events	1 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	18 months	Events	28 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	42 months	Events	32 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	42 months	No events or not censored	36 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	54 months	Censored	688 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	54 months	No events or not censored	0 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	Baseline	Events	0 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	Baseline	No events or not censored	720 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	6 months	Events	1 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	6 months	Censored	26 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	6 months	No events or not censored	693 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	12 months	Censored	82 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	12 months	No events or not censored	637 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	18 months	Censored	195 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	18 months	No events or not censored	497 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	24 months	Events	31 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	24 months	Censored	301 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	24 months	No events or not censored	388 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	30 months	Events	31 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	30 months	Censored	393 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	30 months	No events or not censored	296 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	36 months	Events	32 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	36 months	Censored	531 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	36 months	No events or not censored	157 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	42 months	Censored	652 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	Baseline	Censored	0 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	48 months	Censored	687 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	48 months	No events or not censored	1 Participants
Placebo	Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes	54 months	Events	32 Participants

95% CI: [0.619, 1.457]

Secondary

Change From Baseline of Hemoglobin A1c (HbA1c) in Diabetic Participants After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo

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.