Study of IDN-6556 in Patients With Severe Alcoholic Hepatitis and Contraindications to Steroid Therapy

A Placebo-Controlled, Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Patients With Severe Alcoholic Hepatitis and Contraindications to Corticosteroid Therapy

The main purpose of the study is to test if taking a study drug called emricasan (also known as IDN-6556 and PF-03491390) will affect overall patient survival after one month of treatment.

The study will also see if overall patient survival is affected at 6 months, and if the study drug improves liver function.

Inclusion Criteria:

1. Able to provide written informed consent (either from patient or patient's legally acceptable representative), and understand and willing to comply with the requirements of the study

2. Male or female patients 21 years of age or older

3. Patients with alcoholic hepatitis defined as:

   1. History of heavy alcohol abuse use: >40 g/day in females and >60 g/day in males for most days in a minimum period of 6 months
   2. Consumed alcohol within 6 weeks of entry into the study
   3. Biochemical parameters of severe disease as evidenced by MELD score >20 but <35, or MELD score 35-40 if the SOFA score is <10

4. Willingness to utilize 2 reliable forms of contraception (for both males and females of childbearing potential) from screening to 1 month after the completion of study treatment

5. Patients with established contraindications to steroid use including but not limited to the following:

   1. GI bleed
   2. Active infection, including spontaneous bacterial peritonitis, based on positive blood culture, urine culture, or chest x-ray (if positive, must have been on antibiotics for at least 24 hours prior to study entry)
   3. Acute pancreatitis (increased lipase > 3x ULN or radiologic evidence)
   4. Positivity for hepatitis B (HBsAg+) or C virus (HCV+), and
   5. Renal failure

Exclusion Criteria:

1. Other or concomitant cause of liver disease as a result of:

   1. Autoimmune liver disease (positive anti-mitochondrial antibody and smooth muscle antibody, positive reading on anti-nuclear antibody titer >1:160)
   2. Metabolic liver disease (abnormal ceruloplasmin levels)
   3. Vascular liver disease
   4. Drug induced liver disease Note: Concurrent viral hepatitis is not excluded.

2. Co-infection with human immunodeficiency virus (HIV)

3. Sepsis as evidenced by positive blood or urine culture, or pneumonia as confirmed by x-ray

4. History of renal transplant and/or on dialysis at time of entry into study

5. Inflammatory bowel disease

6. Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA)

7. Hepatocellular carcinoma (HCC) at entry into the study

8. Active non-liver malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas)

9. Active tuberculosis on chest x-ray at study entry

10. History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QT or QTc interval of >480 milliseconds (msec)

11. Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the patient from participating in and completing the study

12. Patients requiring the use of vasopressors or inotropic support

13. Liver biopsy, if carried out, showing findings not compatible with alcoholic hepatitis

14. Any patient that has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device in the course of the study Note: Investigational drug includes any drug that is used off-label.

15. If female, known pregnancy, or has a positive urine or serum pregnancy test, or lactating/breastfeeding

16. If male, if partner is known to be pregnant at time of entry into study or becomes pregnant while patient is on study drug or up to 1 month after completion of study drug

17. Appropriate candidate for corticosteroid therapy

18. Treatment for alcohol hepatitis within 1 month of study entry with use of corticosteroids for >1 week or corticosteroid use at the time of entry into the study.