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

Alcoholic Hepatitis (AH) Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02854631
• Other study ID #: GS-US-416-2124
• Secondary ID: 2016-000821-37
• Status: Completed
• Phase: Phase 2
• Start date: September 1, 2016
• Est. completion date: May 31, 2018

Study information

• Verified date: February 2019
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: May 31, 2018
• Est. primary completion date: February 16, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alcoholic Hepatitis (AH)
• Hepatitis
• Hepatitis A
• Hepatitis, Alcoholic

Intervention

Drug:
• Selonsertib
18 mg tablet administered orally once daily
• Prednisolone
40 mg (4 x 10 mg tablets) administered orally once daily
• Placebo
Selonsertib placebo tablet administered orally once daily

Locations

Country	Name	City	State
Austria	Medizinische Universitat Graz	Graz
Austria	Universitätsklinik für Innere Medizin I	Innsbruck
Austria	Medical University Vienna	Vienna
Belgium	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
Canada	University of Calgary	Calgary	Alberta
Canada	Toronto General Hospital	Toronto	Ontario
Canada	University of Manitoba	Winnipeg	Manitoba
France	CHU Amiens Picardie	Amiens
France	CHU Angers	Angers
France	Hôpital Jean Minjoz	Besançon
France	C.H.U. de Caen	Caen
France	CHU henri Mondor	Créteil
France	CHU de Grenoble- Hopital Michallon	La Tronche
France	CHRU de Lille	Lille
France	Hôpital de la Croix Rousse	Lyon
France	Hopital La Pitie Salpetriere	Paris
France	Hopital Paul Brousse	Villejuif
Switzerland	University of Zurich	Zurich
United Kingdom	Brighton & Sussex University Hospitals NHS Trust	Brighton
United Kingdom	Hull and East Yorkshire Hospitals NHS Trust	Hull
United Kingdom	Royal Liverpool & Broadgreen University Hospitals NHS Trust	Liverpool
United Kingdom	Barts Health NHS Trust	London
United Kingdom	Chelsea and Westminster Hospital	London
United Kingdom	Imperial College	London
United Kingdom	Kings College Hospital NHS Trust	London
United Kingdom	Freeman Hospital	Newcastle
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Portsmouth Hospitals NHS Trust	Portsmouth
United States	University of Michigan	Ann Arbor	Michigan
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Southern California Research Centers	Coronado	California
United States	Methodist Healthcare Dallas - The Liver Institute	Dallas	Texas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Oschner Medical Center	New Orleans	Louisiana
United States	Liver Institute of Virginia	Newport News	Virginia
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Washington	Seattle	Washington
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  France,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Percentage of Participants Who Died by Day 28	The percentage of participants who died by Day 28 was calculated.	Day 28
Secondary	Percentage of Participants Who Died by Week 8	The percentage of participants who died by Week 8 was calculated.	Week 8
Secondary	Percentage of Participants Who Died by Week 12	The percentage of participants who died by Week 12 was calculated.	Week 12
Secondary	Percentage of Participants Who Died by Week 24	The percentage of participants who died by Week 24 was calculated.	Week 24
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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