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

Phase 2

Completed

Conditions: Non-alcoholic Steatohepatitis
Cirrhosis
Portal Hypertension

Interventions: Drug: Placebo
Drug: Emricasan

Registration Number: NCT02960204

Lead Sponsor: Histogen

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 263

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Matching Placebo	Placebo	Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day.
Emricasan (5 mg)	Emricasan	Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day.
Emricasan (25 mg)	Emricasan	Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day.
Emricasan (50 mg)	Emricasan	Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day.

Primary Outcome Measures

Name	Time	Method
Mean Change in Hepatic Venous Pressure Gradient (HVPG)	Baseline to Week 24	To assess the mean change from baseline to Week 24 in hepatic venous pressure gradient (HVPG)

Secondary Outcome Measures

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

Trial Locations

Locations (30): Valencia
🇪🇸
Valencia, Spain
Barcelona
🇪🇸
Barcelona, Spain
Norfolk
🇺🇸
Norfolk, Virginia, United States
Santander
🇪🇸
Santander, Spain
Majadahonda
🇪🇸
Majadahonda, Spain
Pasadena
🇺🇸
Pasadena, California, United States
Rialto
🇺🇸
Rialto, California, United States
Palmetto Bay
🇺🇸
Palmetto Bay, Florida, United States
Clive
🇺🇸
Clive, Iowa, United States
Saint Paul
🇺🇸
Saint Paul, Minnesota, United States
Bonn
🇩🇪
Bonn, Germany
Halle (Saale)
🇩🇪
Halle (Saale), Germany
Leipzig
🇩🇪
Leipzig, Germany
Münster
🇩🇪
Münster, Germany
Mainz
🇩🇪
Mainz, Germany
Madrid
🇪🇸
Madrid, Spain
San Sebastian
🇪🇸
San Sebastian, Spain
Germantown
🇺🇸
Germantown, Tennessee, United States
Detroit
🇺🇸
Detroit, Michigan, United States
Rochester
🇺🇸
Rochester, Minnesota, United States
Kansas City
🇺🇸
Kansas City, Missouri, United States
Durham
🇺🇸
Durham, North Carolina, United States
Atlanta
🇺🇸
Atlanta, Georgia, United States
Baltimore
🇺🇸
Baltimore, Maryland, United States
Arlington
🇺🇸
Arlington, Texas, United States
Houston
🇺🇸
Houston, Texas, United States
San Antonio
🇺🇸
San Antonio, Texas, United States
Richmond
🇺🇸
Richmond, Virginia, United States
Seattle, Washington
🇺🇸
Seattle, Washington, United States
Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States