Selonsertib in Combination With Prednisolone Versus Prednisolone Alone in Participants With Severe Alcoholic Hepatitis (AH)

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 (AH)

The primary objective of this study is to evaluate the safety and tolerability of selonsertib (GS-4997) in combination with prednisolone versus prednisolone alone in participants with severe alcoholic hepatitis (AH).

Study Overview

• Status: Completed
• Conditions: Alcoholic Hepatitis (AH)
• Intervention / Treatment: Drug: Selonsertib; Drug: Prednisolone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • Medizinische Universität Graz
  • Innsbruck, Austria
    • Universitätsklinik für Innere Medizin I
  • Vienna, Austria
    • Medical University Vienna
• Belgium
  • Brussels, Belgium
    • CUB Hôpital Erasme
  • Brussels, Belgium
    • Cliniques Universitaires Ucl Saint-Luc
  • Ghent, Belgium
    • Ghent University Hospital
  • Leuven, Belgium
    • Universitair Ziekenhuis Leuven
  • Liège, Belgium
    • Centre Hospitalier Universitaire de Liege
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • University of Calgary
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • University of Manitoba
  • Ontario
    • Toronto, Ontario, Canada
      • Toronto General Hospital
• France
  • Amiens, France
    • CHU Amiens Picardie
  • Angers, France
    • CHU Angers
  • Besançon, France
    • Hôpital Jean Minjoz
  • Caen, France
    • C.H.U. de Caen
  • Créteil, France
    • CHU Henri Mondor
  • La Tronche, France
    • CHU de Grenoble- Hopital Michallon
  • Lille, France
    • CHRU de Lille
  • Lyon, France
    • Hopital de La Croix Rousse
  • Paris, France
    • Hôpital La Pitié Salpêtrière
  • Villejuif, France
    • Hopital Paul Brousse
• Switzerland
  • Zurich, Switzerland
    • University of Zurich
• United Kingdom
  • Brighton, United Kingdom
    • Brighton & Sussex University Hospitals NHS Trust
  • Hull, United Kingdom
    • Hull and East Yorkshire Hospitals NHS Trust
  • Liverpool, United Kingdom
    • Royal Liverpool & Broadgreen University Hospitals NHS Trust
  • London, United Kingdom
    • Barts Health NHS Trust
  • London, United Kingdom
    • Imperial College
  • London, United Kingdom
    • Chelsea And Westminster Hospital
  • London, United Kingdom
    • Kings College Hospital NHS Trust
  • Newcastle, United Kingdom
    • Freeman Hospital
  • Nottingham, United Kingdom
    • Nottingham University Hospitals NHS Trust
  • Plymouth, United Kingdom
    • Derriford Hospital
  • Portsmouth, United Kingdom
    • Portsmouth Hospitals NHS Trust
• United States
  • Arkansas
    • Little Rock, Arkansas, United States
      • University of Arkansas for Medical Sciences
  • California
    • Coronado, California, United States
      • Southern California Research Centers
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
  • Florida
    • Weston, Florida, United States
      • Cleveland Clinic Florida
  • Louisiana
    • New Orleans, Louisiana, United States
      • Oschner Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States
      • University of Michigan
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • University of Pennsylvania
  • Texas
    • Dallas, Texas, United States
      • Methodist Healthcare Dallas - The Liver Institute
  • Virginia
    • Newport News, Virginia, United States
      • Liver Institute of Virginia
  • Washington
    • Seattle, Washington, United States
      • 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

Key Inclusion Criteria:

• 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)

• Clinical diagnosis of severe AH

  • Maddrey's Discriminant Function (DF) ≥ 32 at screening

Key Exclusion Criteria:

• Pregnant or lactating females;
• 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;
• Serum aspartate aminotransferase (AST) >400 U/L or alanine aminotransferase (ALT) >300 U/L;
• Model for End Stage Liver Disease (MELD) >30 at screening;
• Maddrey's DF >60 at screening;
• Grade 4 Hepatic Encephalopathy (HE) by West Haven criteria;
• Concomitant or previous history of hepatocellular carcinoma;
• History of liver transplantation;
• HIV Ab positive;
• Clinical suspicion of pneumonia;
• Uncontrolled sepsis;
• 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;
• 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;
• Individuals dependent on inotropic (eg, epinephrine or norepinephrine) or ventilatory support (ie, endotracheal intubation or positive-pressure ventilation);
• Portal vein thrombosis;
• Acute pancreatitis;
• 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: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Selonsertib + Prednisolone; Selonsertib + prednisolone for 28 days	Drug: Selonsertib; 18 mg tablet administered orally once daily; Other Names: GS-4997; Drug: Prednisolone; 40 mg (4 x 10 mg tablets) administered orally once daily
Placebo Comparator: Prednisolone; Selonsertib placebo + prednisolone for 28 days	Drug: Prednisolone; 40 mg (4 x 10 mg tablets) administered orally once daily; Drug: Placebo; Selonsertib placebo tablet administered orally once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-Emergent (TE) Adverse Events (AE), Serious AEs (SAE), AEs Leading to Premature Study Drug Discontinuation, and Grade 3 or 4 Laboratory Abnormalities	An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.	Up to Day 28 plus 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Died by Day 28	The percentage of participants who died by Day 28 was calculated.	Day 28
Percentage of Participants Who Died by Week 8	The percentage of participants who died by Week 8 was calculated.	Week 8
Percentage of Participants Who Died by Week 12	The percentage of participants who died by Week 12 was calculated.	Week 12
Percentage of Participants Who Died by Week 24	The percentage of participants who died by Week 24 was calculated.	Week 24
Percentage of Participants With Survival at Day 28 Using Kaplan-Meier	The percentage of participants with survival at Day 28 using Kaplan-Meier was calculated.	Day 28
Percentage of Participants With Survival at Week 8 Using Kaplan-Meier	The percentage of participants with survival at Week 8 using Kaplan-Meier was calculated.	Week 8
Percentage of Participants With Survival at Week 12 Using Kaplan-Meier	The percentage of participants with survival at Week 12 using Kaplan-Meier was calculated.	Week 12
Percentage of Participants With Survival at Week 24 Using Kaplan-Meier	The percentage of participants with survival at Week 24 using Kaplan-Meier was calculated.	Week 24
Percentage of Participants Who Received a Liver Transplant	The percentage of participants who received a liver transplant by week 24 was calculated.	Day 28, Week 8, Week 12, and Week 24
Percentage of Participants With Hepatorenal Syndrome (HRS)	The occurrence of HRS was confirmed based on the following diagnostic criteria from the International Ascites Club (IAC): 1) Cirrhosis with ascites, 2) Diagnosis of acute kidney injury (AKI) according to the ICA-AKI criteria, 3) Absence of shock, 4) No current or recent treatment with nephrotoxic drugs, and 5) Absence of parenchymal renal disease as indicated by proteinuria >500 mg/day, microhematuria (> 50 red blood cells per high power field) and/or abnormal renal ultrasonography.	Up to 24 weeks
Percentage of Participants With Infection	The occurrence of bacterial, fungal, or viral infections was recorded. An infection was considered definite in participants with clinical evidence of infection and a positive culture from a normally sterile source (with the exception of spontaneous bacterial peritonitis).	Up to 24 weeks
Length of Hospital Stay	Length of initial hospital stay from first dose date of study drug was calculated for participants who were released from initial hospitalization separately from those who died during their initial hospitalization.	Up to 24 weeks
Change From Baseline in Liver Biochemistry Tests: Alanine Aminotransferase (ALT)	Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Liver Biochemistry Tests: Aspartate Aminotransferase (AST)	Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Liver Biochemistry Tests: Gamma Glutamyl Transferase (GGT)	Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Liver Biochemistry Tests: Alkaline Phosphatase	Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Liver Biochemistry Tests: Bilirubin	Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Liver Biochemistry Tests: Albumin	Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Liver Biochemistry Tests: International Normalized Ratio (INR)	Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Percentage of Participants With Lille Response (Score < 0.45) at Day 7	The Lille score is a tool used to predict which participants with severe alcoholic hepatitis (AH) were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). The Lille score was calculated using baseline factors: age, albumin, total bilirubin, serum creatinine, prothrombin time; and the change in total bilirubin between baseline (Day 1) and Day 7. Lille response was defined as having a Lille score < 0.45.	Day 7
Percentage of Participants With a Lille Null Response (Score ≥ 0.56) at Day 7	The Lille score is a tool used to predict which participants with severe AH were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). The Lille score was calculated using baseline factors: age, albumin, total bilirubin, serum creatinine, prothrombin time; and the change in total bilirubin between baseline (Day 1) and Day 7. Lille null response was defined as having a Lille score ≥ 0.56.	Day 7
Lille Score at Day 7 as a Continuous Variable	The Lille score is a tool used to predict which participants with severe AH were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). The Lille score was calculated using baseline factors: age, albumin, total bilirubin, serum creatinine, prothrombin time; and the change in total bilirubin between baseline (Day 1) and Day 7.	Day 7
Percentage of Participants With Estimated Mortality at Month 2 and Month 6: Combined Scoring Including Lille Score at Day 7 and Baseline Model for End-Stage Liver Disease (MELD) Score	The Lille score is a tool used to predict which participants with severe AH were not responding to corticosteroid therapy. It ranges between 0 and 1, with low scores (< 0.16) indicating complete response or positive response to steroids (continue therapy) and high scores (≥ 0.56) indicating no response or poor response to steroids (stop therapy). MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity. A scoring system combining the Lille score at Day 7 and the baseline MELD score was used to calculate the percentage of participants expected to die by Month 2 and by Month 6.	Baseline and Day 7 Time Points used to calculate Overall Mortality Risk at Months 2 and 6
Change From Baseline in Prognostic Index: Model for End-Stage Liver Disease (MELD) Score	MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity. Change from Baseline was calculated as the value at endpoint minus the value at Baseline.	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Prognostic Index: Child-Pugh-Turcotte (CPT) Score	CPT scores are used to assess the severity of cirrhosis. Scores can range from 5 to 15, with higher scores indicating a greater severity of disease	Baseline (Day 1) and up to 24 weeks
Change From Baseline in Prognostic Index: Maddrey Discriminant Function (DF) Score	Baseline Maddrey DF score is a prognostic tool used to determine the next step of treatment based on the severity of AH. Maddrey DF score of < 32 indicates mild to moderate AH and a lower chance of death in the next few months. Maddrey DF score of ≥ 32 indicates severe AH and a higher chance of death in the next few months. The score has no bounds.	Baseline (Day 1) and up to 24 weeks

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2016
• Primary Completion (Actual): February 16, 2018
• Study Completion (Actual): May 31, 2018

Study Registration Dates

• First Submitted: July 29, 2016
• First Submitted That Met QC Criteria: August 2, 2016
• First Posted (Estimate): August 3, 2016

Study Record Updates

• Last Update Posted (Actual): February 6, 2019
• Last Update Submitted That Met QC Criteria: February 5, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Cirrhosis; Jaundice; Prednisone
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis; Hepatitis A; Hepatitis, Alcoholic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Prednisolone; Selonsertib
• Other Study ID Numbers: GS-US-416-2124; 2016-000821-37 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No