Emricasan, a Caspase Inhibitor, for Treatment of Subjects With Decompensated NASH Cirrhosis

Study Overview
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Brief Summary
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This is a multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of emricasan in improving event-free survival based on a composite clinical endpoint (where all-cause mortality, new decompensation events, and MELD score progression are events) in subjects with decompensated NASH cirrhosis.

Detailed Description
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The study treatment duration will be at least 48 weeks with study visits every 4 weeks up to Week 48 and every 8 weeks after Week 48. All subjects will continue treatment until the last subject in the study reaches 48 weeks in the study. At least 30% of subjects randomized should have baseline MELD score ≥15 and ≤20. For each subject, the study will consist of: Screening period of up to 4 weeks Randomized, double-blind treatment period of at least 48 weeks A follow-up visit 2 weeks after completion of study drug treatment The duration of each subject's participation will be at least 54 weeks for those completing the entire study.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in Subjects With Decompensated Non-Alcoholic Steatohepatitis (NASH) Cirrhosis

Conditions
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Decompensated Cirrhosis

Intervention / Treatment
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* Drug: Emricasan (25 mg)
* Drug: Emricasan (5 mg)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female subjects 18 years or older, able to provide written informed consent and able to understand and willing to comply with the requirements of the study. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.) At least one of the following: a) history of variceal hemorrhage (more than 3 months prior to day 1) documented on endoscopy and requiring blood transfusion, b) history of at least moderate ascites (on physical exam or imaging) currently treated with diuretics. MELD score ≥12 and ≤20 during screening Albumin ≥2.5 g/dL during screening Serum creatinine ≤1.5 mg/dL during screening Key Exclusion Criteria: Evidence of severe decompensation Non-cirrhotic portal hypertension Child-Pugh score ≥10 Current use of anticoagulants that affect prothrombin time or international normalized ratio ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening Initiation or discontinuation of non-selective beta blockers within 1 month of screening Transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure within 1 year of screening or previously requiring revision Alpha-fetoprotein >50 ng/mL in the last year History of hepatocellular carcinoma (HCC) or evidence of HCC History of malignancies other than HCC, unless successfully treated with curative intent and believed to be cured Prior liver transplant Uncontrolled diabetes mellitus (HbA1c >9%) Change in diabetes medications or vitamin E within 3 months of screening Restrictive bariatric surgery or bariatric device within 1 year of screening or prior malabsorptive bariatric surgery Symptoms of biliary colic unless resolved following cholecystectomy History of significant alcohol consumption within the past 5 years Current use of medications that are considered inhibitors of organic anion transporting polypeptide OATP1B1 and OATP1B3 transporters Prolongation of screening (pre-treatment) QTcF interval of >500 msecs, or history or presence of clinically concerning cardiac arrhythmias Significant systemic or major illness other than liver disease Human immunodeficiency virus infection Use of alcohol, controlled substances (including inhaled or injected drugs), or non-prescribed use of prescription drugs within 1 year of screening to the point of interfering with the subject's ability to comply with study procedures and study drug administration in the investigator's judgement

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Emricasan (25 mg)<br>Emricasan 25 mg | Drug: Emricasan (25 mg)<br>* 25 mg emricasan<br>* Other names: IDN-6556;|
| Active Comparator: Emricasan (5 mg)<br>Emricasan 5mg | Drug: Emricasan (5 mg)<br>* 5 mg emricasan<br>* Other names: IDN-6556;|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Placebo<br>* Matching Placebo<br>* Other names: Matching placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the effect of emricasan on improving event-free survival relative to placebo, based on a composite clinical endpoint |  | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in MELD score | The effect of emricasan on improving MELD score relative to placebo | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 
| Improvement in Child-Pugh scores | The effect of emricasan on improving the Child-Pugh score relative to placebo | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 
| Reduction of the proportion of subjects with MELD score progression | The effect of emricasan on reducing the proportion of patients with MELD score progression (≥4 point increase at any study visit) relative to placebo | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 
| Decrease in new decompensation events | The effect of emricasan on decreasing new decompensation events relative to placebo | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 
| Decrease in liver transplantation rates | The effect of emricasan on decreasing liver transplantation rates (in association with MELD score ≥25) relative to placebo | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 
| Decrease in all-cause and liver specific mortality | The effect of emricasan on decreasing all-cause and liver specific mortality relative to placebo | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 
| Improvement in health-related quality of life (QOL) as measured by Short Form-36 |  | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 
| Improvement in liver metabolic function as measured by Methacetin Breath Test (MBT) |  | Baseline - Final Treatment Visit (at least 48 weeks to a max of 120 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cirrhosis, NASH Cirrhosis, Decompensated NASH cirrhosis, Cirrhosis, Liver, Non-Alcoholic Fatty Liver Disease