Emricasan, an Oral Caspase Inhibitor, in Subjects With NASH Cirrhosis and Severe Portal Hypertension

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, placebo-controlled trial involving subjects with NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg as determined by the central reader assigned to this study). Upon successful screening, subjects will be randomized to receive either emricasan 50 mg BID, 25 mg BID, or 5 mg BID or matching placebo BID.

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

Conditions
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Cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Emricasan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.) Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event Severe portal hypertension defined as HVPG ≥12 mmHg Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a stable dose for at least 3 months prior to Day 1 Willingness to utilize effective contraception (for both males and females of childbearing potential) from Screening to 4 weeks after the last dose of study drug Exclusion Criteria: Evidence of severe decompensation Severe hepatic impairment defined as a Child-Pugh score ≥10 ALT (alanine transaminase) > 3 times upper limit of normal (ULN) or AST (aspartate transaminase) >5 times ULN during screening Estimated creatinine clearance <30 mL/min Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure Known portal vein thrombosis Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters Alpha-fetoprotein >50 ng/mL History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of >500 msec History of or active malignancies, other than those successfully treated with curative intent and believed to be cured Prior liver transplant Change in diabetes medications or vitamin E within 3 months of screening Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening Significant systemic or major illness other than liver disease HIV infection Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1

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 (5 mg)<br>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day. | Drug: Emricasan<br> <br> |
| Active Comparator: Emricasan (25 mg)<br>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day. | Drug: Emricasan<br> <br> |
| Active Comparator: Emricasan (50 mg)<br>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day. | Drug: Emricasan<br> <br> |
| Placebo Comparator: Matching Placebo<br>Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Hepatic Venous Pressure Gradient (HVPG) | To assess the mean change from baseline to Week 24 in hepatic venous pressure gradient (HVPG) | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of HVPG Response Using a 20% Reduction From Baseline | To assess subjects who have at least a 20 percent reduction from baseline in HVPG | Baseline to Week 24 | 
| Caspase 3/7 | To assess whether number of Caspase 3/7 biomarkers is affected by emricasan as compared to placebo | Baseline to Week 24, Baseline to Week 48 | 
| Alanine Aminotransferase (ALT) | To assess whether amount of non-specific (ALT) biomarkers are affected by emricasan compared to placebo | Baseline to Week 24 and Baseline to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis, Liver cirrhosis