Evaluation of HepQuant SHUNT to Assess Liver Disease; Substudy Within GS-US-416-2124

Evaluation of HepQuant SHUNT to Assess Liver Disease; Substudy Within GS-US-416-2124

This clinical investigation is a substudy within GS-US-416-2124, IND 129570, which is A Phase 2, Double-Blind, Randomized Study Evaluating the Safety, Tolerability, and Efficacy of GS-4997 in Combination with Prednisolone versus Prednisolone Alone in Subjects with Severe Alcoholic Hepatitis. The use of the HepQuant SHUNT test is to assess liver disease severity before, during, and after treatment with GS-4997 or placebo, to assess liver disease severity.

The main study is a Phase 2, double blind, proof-of-concept, randomized study evaluating the safety, tolerability, and biological activity of GS-4997 in combination with prednisolone, compared to prednisolone alone, in subjects with severe, histologically-confirmed AH.

This substudy uses the HepQuant SHUNT Liver Diagnostic test to assess severity of disease at baseline and to track disease progression or improvement over the 24 weeks of the study. The HepQuant SHUNT test will be performed at baseline (Day 1) and at Weeks 1, 2, 4, 12, and 24 regardless of treatment Arm.

GS-4997 Dose and Mode of Administration. Subjects will be randomized 1:1 to either:

• Treatment Group A: GS-4997 18 mg (1 x 18 mg tablet) AND prednisolone 40 mg (4 x 10 mg tablets), both administered orally once daily
• Treatment Group B: GS-4997 placebo (1 tablet) AND prednisolone 40 mg (4 x 10 mg tablets), both administered orally once daily

Inclusion Criteria:

1. Willing and able to give informed consent prior to any study specific procedures being performed. In individuals with hepatic encephalopathy (HE) which may impair decision-making, consent will be obtained per hospital procedures (eg, by Legally Authorized Representative)
2. Clinical diagnosis of severe AH
3. Maddrey's DF ≥ 32 at screening

Exclusion Criteria:

Key Exclusion Criteria:

1. Pregnant or lactating females;
2. Other causes of liver disease including chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C (HCV RNA positive), acetaminophen hepatotoxicity, biliary obstruction, and autoimmune liver disease;
3. Serum AST >400 U/L or ALT >300 U/L;
4. MELD >30 at screening;
5. Maddrey's DF >60 at screening;
6. Grade 4 Hepatic Encephalopathy (HE) by West Haven criteria;
7. Concomitant or previous history of hepatocellular carcinoma;
8. History of liver transplantation;
9. HIV Ab positive;
10. Clinical suspicion of pneumonia;
11. Uncontrolled sepsis;
12. Uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding within 7 days of screening that was associated with shock or required transfusion of more than 3 units of blood;
13. Type 1 hepatorenal syndrome (HRS) or renal failure defined as a serum creatinine >221 μmol/L (>2.5 mg/dL) or the requirement for renal replacement therapy;
14. Individuals dependent on inotropic (eg, epinephrine or norepinephrine) or ventilatory support (ie, endotracheal intubation or positive-pressure ventilation);
15. Portal vein thrombosis;
16. Acute pancreatitis;
17. Cessation of alcohol consumption for more than 2 months before Baseline/ Day 1 NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.