To validate the ability of the Methacetin Breath Test (MBT) to detect clinically significant portal hypertension (CSPH)/severe portal hypertension (SPH) defined as hepatic venous pressure gradient (HVPG) ≥ 10 mmHg and HVPG ≥ 12 mmHg respectively, in patients with non-alcoholic steatohepatitis (NASH) during the course of treatment with Conatus's investigational product emricasan/placebo.

This study is a companion protocol that will use the data generated by Conatus' study of emricasan under protocol IDN-6556-14 (NCT02960204).The IDN-6556-14 study is a Phase 2, multicenter, double-blind, randomized, placebo-controlled trial in subjects with non-alcoholic steatohepatitis (NASH) cirrhosis and severe portal hypertension.

As one of the Conatus' study exploratory objectives, this companion protocol is designed to assess whether emricasan compared to placebo improves liver metabolic function at Weeks 24 and 48 as assessed by the methacetin breath test (at select sites), if relevant.

Inclusion Criteria:

1. 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.
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.)
3. Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event.
4. Severe portal hypertension defined as HVPG ≥12 mmHg
5. 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
6. 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:

1. Evidence of severe decompensation
2. Severe hepatic impairment defined as a Child-Pugh score ≥10
3. ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening
4. Estimated creatinine clearance <30 mL/min
5. Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure
6. Known portal vein thrombosis
7. Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy, other definitive treatment (e.g. sphincterotomy), or medical management (e.g. ursodeoxycholic acid)
8. Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters
9. Alpha-fetoprotein >50 ng/mL
10. History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of >500 msec
11. History of or active malignancies, other than those successfully treated with curative intent and believed to be cured
12. Prior liver transplant
13. Change in diabetes medications or vitamin E within 3 months of screening
14. Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening
15. Significant systemic or major illness other than liver disease
16. HIV infection
17. Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening
18. If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding
19. Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1

Diagnostic endpoints used screening measurements taken prior to study drug administration, therefore no treatment effect was relevant. In addition, for the event prediction endpoints, the treatment covariate was tested for significance, and was found to be non-significant, thus removed from the final predicting model. As such, arms were combined.

Data was collected for a duration of approximately 1 year to observe the effect of the treatment. Additional MBTs after 24 and 48 weeks were performed to enable Conatus to assess the ability of MBT to identify improvement in liver function due to treatment, if relevant. Each MBT duration is 1 hour. The subsequent MBTs were not relevant to companion protocol primary and secondary efficacy diagnostic endpoints listed above, but additional safety information regarding these MBTs was collected.

Diagnostic endpoints used screening measurements taken prior to study drug administration, therefore no treatment effect was relevant. In addition, for the event prediction endpoints, the treatment covariate was tested for significance, and was found to be non-significant, thus removed from the final predicting model. As such, arms were combined.

The collaborator is responsible for the masking process.