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

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ClinicalTrials.gov Identifier: NCT02854631
Recruitment Status : Completed
First Posted : August 3, 2016
Results First Posted : February 6, 2019
Last Update Posted : February 6, 2019
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Alcoholic Hepatitis (AH) Drug: Selonsertib Drug: Prednisolone Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 1, 2016
Actual Primary Completion Date : February 16, 2018
Actual Study Completion Date : May 31, 2018


Arm Intervention/treatment
Experimental: Selonsertib + Prednisolone
Selonsertib + prednisolone for 28 days
Drug: Selonsertib
18 mg tablet administered orally once daily
Other Name: 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




Primary Outcome Measures :
  1. 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 [ Time Frame: 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 :
  1. Percentage of Participants Who Died by Day 28 [ Time Frame: Day 28 ]
    The percentage of participants who died by Day 28 was calculated.

  2. Percentage of Participants Who Died by Week 8 [ Time Frame: Week 8 ]
    The percentage of participants who died by Week 8 was calculated.

  3. Percentage of Participants Who Died by Week 12 [ Time Frame: Week 12 ]
    The percentage of participants who died by Week 12 was calculated.

  4. Percentage of Participants Who Died by Week 24 [ Time Frame: Week 24 ]
    The percentage of participants who died by Week 24 was calculated.

  5. Percentage of Participants With Survival at Day 28 Using Kaplan-Meier [ Time Frame: Day 28 ]
    The percentage of participants with survival at Day 28 using Kaplan-Meier was calculated.

  6. Percentage of Participants With Survival at Week 8 Using Kaplan-Meier [ Time Frame: Week 8 ]
    The percentage of participants with survival at Week 8 using Kaplan-Meier was calculated.

  7. Percentage of Participants With Survival at Week 12 Using Kaplan-Meier [ Time Frame: Week 12 ]
    The percentage of participants with survival at Week 12 using Kaplan-Meier was calculated.

  8. Percentage of Participants With Survival at Week 24 Using Kaplan-Meier [ Time Frame: Week 24 ]
    The percentage of participants with survival at Week 24 using Kaplan-Meier was calculated.

  9. Percentage of Participants Who Received a Liver Transplant [ Time Frame: Day 28, Week 8, Week 12, and Week 24 ]
    The percentage of participants who received a liver transplant by week 24 was calculated.

  10. Percentage of Participants With Hepatorenal Syndrome (HRS) [ Time Frame: 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.

  11. Percentage of Participants With Infection [ Time Frame: 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).

  12. Length of Hospital Stay [ Time Frame: 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.

  13. Change From Baseline in Liver Biochemistry Tests: Alanine Aminotransferase (ALT) [ Time Frame: Baseline (Day 1) and up to 24 weeks ]
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.

  14. Change From Baseline in Liver Biochemistry Tests: Aspartate Aminotransferase (AST) [ Time Frame: Baseline (Day 1) and up to 24 weeks ]
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.

  15. Change From Baseline in Liver Biochemistry Tests: Gamma Glutamyl Transferase (GGT) [ Time Frame: Baseline (Day 1) and up to 24 weeks ]
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.

  16. Change From Baseline in Liver Biochemistry Tests: Alkaline Phosphatase [ Time Frame: Baseline (Day 1) and up to 24 weeks ]
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.

  17. Change From Baseline in Liver Biochemistry Tests: Bilirubin [ Time Frame: Baseline (Day 1) and up to 24 weeks ]
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.

  18. Change From Baseline in Liver Biochemistry Tests: Albumin [ Time Frame: Baseline (Day 1) and up to 24 weeks ]
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.

  19. Change From Baseline in Liver Biochemistry Tests: International Normalized Ratio (INR) [ Time Frame: Baseline (Day 1) and up to 24 weeks ]
    Change from Baseline was calculated as the value at endpoint minus the value at Baseline.

  20. Percentage of Participants With Lille Response (Score < 0.45) at Day 7 [ Time Frame: 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.

  21. Percentage of Participants With a Lille Null Response (Score ≥ 0.56) at Day 7 [ Time Frame: 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.

  22. Lille Score at Day 7 as a Continuous Variable [ Time Frame: 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.

  23. 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 [ Time Frame: 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.

  24. Change From Baseline in Prognostic Index: Model for End-Stage Liver Disease (MELD) Score [ Time Frame: 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.

  25. Change From Baseline in Prognostic Index: Child-Pugh-Turcotte (CPT) Score [ Time Frame: 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

  26. Change From Baseline in Prognostic Index: Maddrey Discriminant Function (DF) Score [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02854631


  Hide Study Locations
Locations
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United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
United States, California
Southern California Research Centers
Coronado, California, United States
Cedars Sinai Medical Center
Los Angeles, California, United States, 90048
United States, Florida
Cleveland Clinic Florida
Weston, Florida, United States
United States, Louisiana
Oschner Medical Center
New Orleans, Louisiana, United States
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States
United States, Texas
Methodist Healthcare Dallas - The Liver Institute
Dallas, Texas, United States
United States, Virginia
Liver Institute of Virginia
Newport News, Virginia, United States
United States, Washington
University of Washington
Seattle, Washington, United States
Austria
Medizinische Universitat Graz
Graz, Austria
Universitätsklinik für Innere Medizin I
Innsbruck, Austria
Medical University Vienna
Vienna, Austria
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, Belgium
Canada, Alberta
University of Calgary
Calgary, Alberta, Canada
Canada, Manitoba
University of Manitoba
Winnipeg, Manitoba, Canada
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada
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, France
Switzerland
University of Zurich
Zurich, Switzerland
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 Kingdom
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol: Original  [PDF] April 12, 2016
Study Protocol: Amendment 1  [PDF] June 2, 2016
Study Protocol: Amendment 2  [PDF] January 11, 2017
Study Protocol: Amendment 3  [PDF] August 4, 2017
Statistical Analysis Plan  [PDF] May 21, 2018


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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02854631     History of Changes
Other Study ID Numbers: GS-US-416-2124
2016-000821-37 ( EudraCT Number )
First Posted: August 3, 2016    Key Record Dates
Results First Posted: February 6, 2019
Last Update Posted: February 6, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gilead Sciences:
Cirrhosis
Prednisone
Jaundice
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis
Hepatitis, Alcoholic
Hepatitis, Viral, Human
Liver Diseases, Alcoholic
Liver Diseases
Digestive System Diseases
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Prednisolone
Methylprednisolone Acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antiemetics