| Outcome Measures: |
Main Objective: Primary objectives - surrogate endpoint<br>To evaluate the efficacy of elafibranor 120 mg QD versus placebo for 72 weeks vs placebo on resolution of NASH without worsening of fibrosis<br>?€? Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for steatohepatitis.<br>?€? Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging system and defined as progression of at least 1 stage.<br><br>Primary objectives - long-term endpoints<br>To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a composite endpoint composed of death due to any cause, histological liver cirrhosis and the full list of portal hypertension/cirrhosis related events (please refer to the protocol for a full list of events).;Secondary Objective: Key secondary objectives (at surrogate endpoint analysis)<br>To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the following endpoint:<br>?€? Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring.<br>To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints:<br>?€? Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients)<br><br>Other secondary objectives<br>?€? To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the endpoints listed in section 2.3 of the protocol<br>?€? To assess the endpoints listed in section 2.3 of the protocol at Week 72 and at the end of the LTTP<br>?€? To assess the onset to events listed in section 2.3 of the protocol;Primary end point(s): Primary endpoint:<br>Surrogate endpoint - resolution of NASH - To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening of fibrosis after 72 weeks of treatment.<br><br>Long-term endpoint ?€? clinical outcomes (at final analysis)<br>To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events:<br>?€? liver transplantation<br>?€? MELD score =15 for patients with a baseline MELD score =12<br>?€? the onset of:<br>o variceal bleed requiring hospitalization,<br>o hepatic encephalopathy defined as West Haven/Conn score =2 and requiring hospitalization,<br>o spontaneous bacterial peritonitis,<br>o ascites requiring treatment.<br>The final analysis will be performed when 456 patients experience an event listed above. This is expected to occur approximately 96 months after the first patient is randomized.;Timepoint(s) of evaluation of this end point: Primary Endpoint: Surrogate endpoint - Week 72<br>Primary Endpoint: Long-term endpoint - Monitored throughout the study. The final analysis will be done when 456 of these events occur. This is expected to occur approximately 96 months after the first patient is randomized <br>Secondary end point(s): Key secondary endpoint (at surrogate endpoint analysis)
<br>Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 weeks.
<br>Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients)
<br>Other secondary endpoints
<br>?€? To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the following endpoints:
<br>o percentage of patients with resolution of NASH without worsening of fibrosis (at the end of LTTP)
<br>o percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring (at the end of LTTP)
<br>o percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring without worsening of NASH
<br>o percentage of patients with no worsening of Fibrosis and no worsening of NASH
<br>o percentage of patients with resolution of NASH and improvement of Fibrosis
<br>o percentage of patients with at least 1 point improvement in histological scores (NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal inflammation
<br>o percentage of patients with improvement of NAS of at least 2 points
<br>o percentage of patients with improvement of NAS of at least 2 points and with at least 1 point improvement in hepatic ballooning
<br>o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activityfibrosis (SAF) scoring
<br>o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 point improvement in hepatic ballooning
<br>o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) scoring and with at least 1 point improvement in hepatic ballooning
<br>o percentage of patients with at least 2 points improvement in disease activity score according to NAS scoring and SAF scoring
<br>o changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score
<br>o changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry.
<br>?€? To assess the following endpoints at Week 72, and at the end of the LTTP:
<br>o changes in liver enzymes and liver markers
<br>o changes in noninvasive markers of fibrosis and steatosis
<br>o changes in lipid parameters
<br>o variation in body weight
<br>o changes in insulin resistance and glucose homeostasis markers
<br>o changes in inflammatory markers
<br>o changes in cardiovascular risk profile as assessed by Framingham scores
<br>o changes in liver stiffness by Fibroscan measurement
<br>o changes in quality of life (SF-36 questionnaire).
<br>?€? To assess the onset of:
<br>o histological liver cirrhosis
<br>o death of any cause
<br>o any portal hypertension or cirrhosis related events
<br>o cardiovascular events
<br>o liver-related death events.;Timepoint(s) of evaluation of this end point: Monitored throughout the study. The final analysis will be done when 456 of these events occur. This is expected to occur approximately 96 months after the first patient is randomized
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