Emricasan, an Oral Caspase Inhibitor, in Subjects With NASH Cirrhosis and Severe Portal Hypertension
Condition: Cirrhosis; Portal Hypertension; Non-alcoholic Steatohepatitis
MeSH terms: Liver Cirrhosis; Fatty Liver; Hypertension, Portal; Non-alcoholic Fatty Liver Disease; Hypertension; Fibrosis
Intervention: Emricasan; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 263.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cirrhosis; Portal Hypertension; Non-alcoholic Steatohepatitis; Liver cirrhosis

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.
    

Eligibility criteria:

        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