Integrated Therapies for Alcohol Use in Alcohol-Associated Liver Disease
Raj Vuppalanchi, MD
Principal Investigator
Brief Description
- To determine whether interventions directed to treat AUD integrated with sAH therapies will improve a composite endpoint of alcohol and liver-related events at 6 months compared to usual care for AUD (primary endpoint)
- To compare 90-day survival in patients receiving F-652 with those receiving up to 28 days of prednisone using the Day-7 Lille score as a stopping rule (secondary endpoint)
- To compare one-year overall survival in patients receiving either IL-22 or prednisone with or without acamprosate (secondary endpoint).
Detailed Description
The study consists of a study treatment phase for approximately 180 days (6 months) and the follow-up phase for days 540 days (18 months).
During the study treatment phase, participants will be randomly placed by chance (like the flip of a coin) into one of four groups to receive study drug/placebo (an inactive substance), which they will take for approximately 180 days and counseling sessions or referral to a 12-step program. There are approximately 7 visits during this phase.
During the follow up phase, there are only two visits at Day 360 (1 year) and 720 (2 years). These will be done remotely through telehealth visit or medical record review and would not require an in-person visit.
During the entire study, participants' health will be closely monitored, and data will be collected from lab tests, physical exams, questionnaires, and Electrocardiograms (ECG - electrical tracings of the heartbeat).
Study participation will last approximately 720 days.
Eligibility of study
Inclusion Criteria
1. Age ≥18, 2. MELD 20-35 on day of randomization
3. Definitive or probable diagnosis as defined by the NIAAA criteria4, 5
A. Onset of jaundice (defined as serum total bilirubin >3 mg/dL) within the prior 8 weeks
B. Ongoing consumption of > 40 gm (for females) and > 60 gm (for males) alcohol daily for 6 months or more with less than 8 weeks of abstinence before onset of jaundice
C. AST > 50 IU/L,
D. AST: ALT > 1.5
E. ALT and AST values F. and/or histological evidence of AH*
*In patients with possible AH or AH with confounding factors such as possible ischemic hepatitis, possible DILI, uncertain history of alcohol use (e.g., patient denies excessive alcohol use), and atypical/abnormal laboratory tests (e.g., AST 400 IU/L, AST/ALT ratio 1:160 or SMA > 1:80, a standard of care liver biopsy may be performed during current hospital admission to confirm AH and exclude competing etiologies.
4. Females of childbearing (reproductive) potential must have a negative serum or urine pregnancy test at screening.
Exclusion Criteria
1. Active listing for liver transplantation before screening
2. MELD score 35
3. Uncontrolled infection (persistent positive blood or other body fluid cultures despite 48 hours of antibiotic therapy)
4. Progressive hemodynamic compromise requiring intravenous pressors
5. Pneumonia as evidenced by clinical and radiological examination
6. Renal failure defined by estimated GFR 7. Clinically active C. diff infection
8. Evidence of other liver diseases (such as autoimmune hepatitis, primary biliary cholangiopathy, primary sclerosing cholangitis, ischemic, sepsis- or drug-induced liver disease)
9. History or presence of cancer (including hepatocellular carcinoma) other than non- melanoma skin cancer
10. Prior exposure to systemic corticosteroid (glucocorticoid) or immunosuppressive therapy for more than 2 days within the previous 30 days
11. Current use of naltrexone or acamprosate.
12. Clinically significant pancreatitis- abdominal pain, elevated lipase (> 3 X ULN), and at least edema of pancreas with fat-stranding on CT scan
13. Active gastrointestinal bleeding defined as hematemesis or melena with a decrease in hemoglobin more than 2 g/dl in 24 hours due to gastrointestinal bleeding, or with a decrease in mean arterial BP to 14. Significant concomitant medical illnesses (such as uncontrolled congestive heart failure or COPD or progressive multi-organ failure) as determined by the study investigator
15. Uncontrolled mental illness as determined by the study investigator
16. Uncontrolled HBV, HIV, or HCV infection with persistent viremia. However, subjects with controlled (undetectable viral load) HIV and HBV on viral suppressive therapies will be enrolled and subjects with history of HCV will be enrolled if they have evidence of SVR one year prior to enrollment
17. Active illicit opiates, cocaine, ketamine, or methamphetamine use in the last 30 days.
18. Uncontrolled diabetes mellitus with A1c > 9
19. Pregnancy or breastfeeding
20. Known allergy or intolerance to therapeutic agents to be tested
21. Unwillingness to stop alcohol use and to undergo AUD treatment
22. Unwillingness to either abstain from sexual intercourse, or if sexually active, use a reliable method of birth control during the study and for at least 30 days after the last dose of the study medication. Examples of acceptable birth control methods include double barrier method such as condom and occlusive cap (diaphragm or cervical cap) with spermicidal foam/gel/film/cream/suppository; birth control pills, patches, injections, or implants; intrauterine device (IUD); vasectomy and tubal ligation.
23. Participant has any condition or circumstance that adversely affects the participant, could cause noncompliance with treatment or visits, may impact the interpretation of clinical data, could cause bias, or may otherwise contraindicate the participant’s participation in the study.