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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
104
18 mg tablet administered orally once daily
40 mg (4 x 10 mg tablets) administered orally once daily
Selonsertib placebo tablet administered orally once daily
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.
Time frame: Up to Day 28 plus 30 days
Percentage of Participants Who Died by Day 28
The percentage of participants who died by Day 28 was calculated.
Time frame: Day 28
Percentage of Participants Who Died by Week 8
The percentage of participants who died by Week 8 was calculated.
Time frame: Week 8
Percentage of Participants Who Died by Week 12
The percentage of participants who died by Week 12 was calculated.
Time frame: Week 12
Percentage of Participants Who Died by Week 24
The percentage of participants who died by Week 24 was calculated.
Time frame: 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.
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University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Southern California Research Centers
Coronado, California, United States
Cedars Sinai Medical Center
Los Angeles, California, United States
Cleveland Clinic Florida
Weston, Florida, United States
Oschner Medical Center
New Orleans, Louisiana, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
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
...and 34 more locations
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Week 24
Percentage of Participants Who Received a Liver Transplant
The percentage of participants who received a liver transplant by week 24 was calculated.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: Baseline (Day 1) and up to 24 weeks