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.

Study Overview

• Status: Withdrawn
• Conditions: Severe Alcoholic Hepatitis
• Intervention / Treatment: Drug: Placebo; Drug: GS-4997; Drug: Prednisolone; Device: HepQuant SHUNT Test

Detailed Description

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

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Dallas, Texas, United States, 75203
      • The Liver Institute at Methodist Dallas Medical Center
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at the Texas Liver Institute
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Liver Institute of Virginia
    • Richmond, Virginia, United States, 23226
      • Liver Institute of Virginia
    • Richmond, Virginia, United States, 23298
      • VCU Health System
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GS-4997 + Prednisolone; GS-4997 + Prednisolone for 28 days HepQuant SHUNT Test	Drug: GS-4997; Experimental drug; Drug: Prednisolone; Control drug that is also administered with the Experimental drug, GS-4997. This drug is used in both arms.; Device: HepQuant SHUNT Test; The HepQuant SHUNT Liver Diagnostic Kit is intended for use in the quantitative detection of 13C-cholate and d4-cholate in blood serum, collected after the intravenous administration of 13C-cholate and the oral ingestion of d4-cholate. The device is indicated to assess the severity of liver disease. For use by health care professionals. Administer the test under a physician's supervision. The HepQuant Analytical Testing Laboratory must analyze the serum samples.; Other Names: SHUNT
Placebo Comparator: Prednisolone + Placebo; Placebo + Prednisolone for 28 days HepQuant SHUNT Test	Drug: Placebo; Placebo; Drug: Prednisolone; Control drug that is also administered with the Experimental drug, GS-4997. This drug is used in both arms.; Device: HepQuant SHUNT Test; The HepQuant SHUNT Liver Diagnostic Kit is intended for use in the quantitative detection of 13C-cholate and d4-cholate in blood serum, collected after the intravenous administration of 13C-cholate and the oral ingestion of d4-cholate. The device is indicated to assess the severity of liver disease. For use by health care professionals. Administer the test under a physician's supervision. The HepQuant Analytical Testing Laboratory must analyze the serum samples.; Other Names: SHUNT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the change in (DSI ) Disease Severity Index between GS-4997 treatment and placebo arms	Using the SHUNT DSI to evaluate the liver, this outcome will compare the two arms to determine if SHUNT DSI is able to measure a change between the experimental and control groups.	HepQuant Shunt testing will be done at baseline (Day1), Week 1, Week 4, Week 12, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Outcome 1	To determine the relationship of baseline Disease Severity Index (DSI) to mortality risk;	HepQuant Shunt testing will be done at baseline (Day1), Week 1, Week 4, Week 12, Week 24
Secondary Outcome 2	To determine the relationship of change in Disease Severity Index (DSI) to mortality risk	HepQuant Shunt testing will be done at baseline (Day1), Week 1, Week 4, Week 12, Week 24
Secondary Outcome 3	To correlate baseline Disease Severity Index (DSI) with baseline Maddrey, MELD, and Lille scorestest with the pharmacokinetics of GS-4997	HepQuant Shunt testing will be done at baseline (Day1), Week 1, Week 4, Week 12, Week 24
Secondary Outcome 4	To determine the relationship between baseline Disease Severity Index (DSI), Maddrey, MELD, and Lille scores and mortality	HepQuant Shunt testing will be done at baseline (Day1), Week 1, Week 4, Week 12, Week 24

Collaborators and Investigators

• Sponsor: HepQuant, LLC
• Investigators: Principal Investigator: Greg Everson, MD, HepQuant, LLC

Study record dates

Study Major Dates

• Study Start (Anticipated): July 31, 2016
• Primary Completion (Actual): September 13, 2017
• Study Completion (Actual): September 13, 2017

Study Registration Dates

• First Submitted: March 9, 2017
• First Submitted That Met QC Criteria: March 16, 2017
• First Posted (Actual): March 23, 2017

Study Record Updates

• Last Update Posted (Actual): August 30, 2021
• Last Update Submitted That Met QC Criteria: August 27, 2021
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; Hepatitis; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Liver Diseases; Hepatitis, Alcoholic; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: HepQuant-002-2124

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes