Selonsertib in Combination With Prednisolone Versus Prednisolone Alone in Participants With Severe Alcoholic Hepatitis (AH)
- Conditions
- Alcoholic Hepatitis (AH)
- Interventions
- Registration Number
- NCT02854631
- Lead Sponsor
- Gilead Sciences
- Brief Summary
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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 104
-
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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Prednisolone Placebo Selonsertib placebo + prednisolone for 28 days Prednisolone Prednisolone Selonsertib placebo + prednisolone for 28 days Selonsertib + Prednisolone Prednisolone Selonsertib + prednisolone for 28 days Selonsertib + Prednisolone Selonsertib Selonsertib + prednisolone for 28 days
- Primary Outcome Measures
Name Time Method 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 Up to Day 28 plus 30 days 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Who Died by Day 28 Day 28 The percentage of participants who died by Day 28 was calculated.
Percentage of Participants With Survival at Day 28 Using Kaplan-Meier Day 28 The percentage of participants with survival at Day 28 using Kaplan-Meier was calculated.
Percentage of Participants With Survival at Week 8 Using Kaplan-Meier Week 8 The percentage of participants with survival at Week 8 using Kaplan-Meier was calculated.
Percentage of Participants With Survival at Week 12 Using Kaplan-Meier Week 12 The percentage of participants with survival at Week 12 using Kaplan-Meier was calculated.
Percentage of Participants Who Died by Week 8 Week 8 The percentage of participants who died by Week 8 was calculated.
Percentage of Participants Who Died by Week 12 Week 12 The percentage of participants who died by Week 12 was calculated.
Percentage of Participants Who Died by Week 24 Week 24 The percentage of participants who died by Week 24 was calculated.
Percentage of Participants With Survival at Week 24 Using Kaplan-Meier Week 24 The percentage of participants with survival at Week 24 using Kaplan-Meier was calculated.
Percentage of Participants Who Received a Liver Transplant Day 28, Week 8, Week 12, and Week 24 The percentage of participants who received a liver transplant by week 24 was calculated.
Percentage of Participants With Hepatorenal Syndrome (HRS) Up to 24 weeks 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.
Change From Baseline in Liver Biochemistry Tests: Alkaline Phosphatase Baseline (Day 1) and up to 24 weeks Change from Baseline was calculated as the value at endpoint minus the value at Baseline.
Percentage of Participants With Infection Up to 24 weeks 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).
Length of Hospital Stay Up to 24 weeks 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.
Change From Baseline in Liver Biochemistry Tests: Alanine Aminotransferase (ALT) Baseline (Day 1) and up to 24 weeks Change from Baseline was calculated as the value at endpoint minus the value at Baseline.
Change From Baseline in Liver Biochemistry Tests: Aspartate Aminotransferase (AST) Baseline (Day 1) and up to 24 weeks Change from Baseline was calculated as the value at endpoint minus the value at Baseline.
Change From Baseline in Liver Biochemistry Tests: Gamma Glutamyl Transferase (GGT) Baseline (Day 1) and up to 24 weeks Change from Baseline was calculated as the value at endpoint minus the value at Baseline.
Change From Baseline in Prognostic Index: Maddrey Discriminant Function (DF) Score Baseline (Day 1) and up to 24 weeks 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.
Change From Baseline in Liver Biochemistry Tests: Bilirubin Baseline (Day 1) and up to 24 weeks Change from Baseline was calculated as the value at endpoint minus the value at Baseline.
Change From Baseline in Liver Biochemistry Tests: Albumin Baseline (Day 1) and up to 24 weeks Change from Baseline was calculated as the value at endpoint minus the value at Baseline.
Change From Baseline in Liver Biochemistry Tests: International Normalized Ratio (INR) Baseline (Day 1) and up to 24 weeks Change from Baseline was calculated as the value at endpoint minus the value at Baseline.
Percentage of Participants With Lille Response (Score < 0.45) at Day 7 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.
Percentage of Participants With a Lille Null Response (Score ≥ 0.56) at Day 7 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.
Lille Score at Day 7 as a Continuous Variable 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.
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 Baseline and Day 7 Time Points used to calculate Overall Mortality Risk at Months 2 and 6 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.
Change From Baseline in Prognostic Index: Model for End-Stage Liver Disease (MELD) Score Baseline (Day 1) and up to 24 weeks 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.
Change From Baseline in Prognostic Index: Child-Pugh-Turcotte (CPT) Score Baseline (Day 1) and up to 24 weeks 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
Trial Locations
- Locations (44)
University of Washington
🇺🇸Seattle, Washington, United States
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Methodist Healthcare Dallas - The Liver Institute
🇺🇸Dallas, Texas, United States
Liver Institute of Virginia
🇺🇸Newport News, Virginia, United States
Medizinische Universitat Graz
🇦🇹Graz, Austria
Universitätsklinik für Innere Medizin I
🇦🇹Innsbruck, Austria
Medical University Vienna
🇦🇹Vienna, Austria
Cliniques Universitaires UCL Saint-Luc
🇧🇪Brussels, Belgium
CUB Hopital Erasme
🇧🇪Brussels, Belgium
Ghent University Hospital
🇧🇪Ghent, Belgium
Universitair Ziekenhuis Leuven
🇧🇪Leuven, Belgium
Centre Hospitalier Universitaire de Liege
🇧🇪Liège, Belgium
University of Calgary
🇨🇦Calgary, Alberta, Canada
CHU Angers
🇫🇷Angers, France
C.H.U. de Caen
🇫🇷Caen, France
CHU henri Mondor
🇫🇷Créteil, France
CHRU de Lille
🇫🇷Lille, France
Hôpital de la Croix Rousse
🇫🇷Lyon, France
Hopital La Pitie Salpetriere
🇫🇷Paris, France
Hopital Paul Brousse
🇫🇷Villejuif, France
University of Zurich
🇨🇭Zurich, Switzerland
Hull and East Yorkshire Hospitals NHS Trust
🇬🇧Hull, United Kingdom
Chelsea and Westminster Hospital
🇬🇧London, United Kingdom
Royal Liverpool & Broadgreen University Hospitals NHS Trust
🇬🇧Liverpool, United Kingdom
Imperial College
🇬🇧London, United Kingdom
Freeman Hospital
🇬🇧Newcastle, United Kingdom
Kings College Hospital NHS Trust
🇬🇧London, United Kingdom
Nottingham University Hospitals NHS Trust
🇬🇧Nottingham, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Southern California Research Centers
🇺🇸Coronado, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
University of Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Brighton & Sussex University Hospitals NHS Trust
🇬🇧Brighton, United Kingdom
Barts Health NHS Trust
🇬🇧London, United Kingdom
Portsmouth Hospitals NHS Trust
🇬🇧Portsmouth, United Kingdom
CHU de Grenoble- Hopital Michallon
🇫🇷La Tronche, France
Cleveland Clinic Florida
🇺🇸Weston, Florida, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Oschner Medical Center
🇺🇸New Orleans, Louisiana, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
CHU Amiens Picardie
🇫🇷Amiens, France
Hôpital Jean Minjoz
🇫🇷Besançon, France