Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis

Indiana University147 enrolled

Overview

This multicenter, randomized, double blinded, placebo-controlled clinical trial is focused on novel treatments for severe alcoholic hepatitis (AH), a life-threatening stage of alcoholic liver injury that has a short-term mortality rate much higher than that of other liver diseases. The primary objective of the study is to determine the clinical efficacy and safety of Anakinra (plus zinc) compared to the current standard medical treatment consisting of prednisone in participants with clinically severe AH. Key secondary objectives broadly are as follows: (a) to evaluate the use of biomarkers to assess disease severity and treatment response; and (b) to develop novel endpoints to overcome the limitations of current assessment strategies for severe AH.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

147

Conditions

Alcoholic Hepatitis

Interventions

Anakinra is indicated for reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis. It has been previously studied in AH. Zinc is a nutritional supplement. Zinc supplementation reverses the clinical signs of zinc deficiency in participants with alcoholic liver disease.

Eligibility

Sex: ALLMin age: 21 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. AH, as defined by the NIAAA pan-consortia for AH: 1. Onset of jaundice (defined as serum total bilirubin \>3 mg/dL) within the prior 8 weeks to screening visit 2. Regular consumption of alcohol with an intake of \> 40 gm daily or \>280gm weekly on average for women and \> 60 gm daily or \>420gm weekly on average for men for 6 months or more, with less than 8 weeks of abstinence before onset of jaundice 3. AST \> 50 IU/l 4. AST:ALT \> 1.5 and both values \< 400 IU/l 5. and/or histological evidence of AH\* 2. MELD 20-35 on day of randomization. 3. Ages \>21 * 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 \< 50 IU/L or \> 400 IU/L, AST/ALT ratio \< 1.5), antinuclear antibody \> 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 Exclusion Criteria 1. MELD SCORE \<20 or \> 35 2. Active sepsis (positive blood or ascitic cultures) with Systemic Inflammatory Response Syndrome (SIRS) or hemodynamic compromise requiring intravenous pressors to maintain tissue perfusion 3. Pneumonia as evidenced by radiological exam 4. Multi-organ failure 5. Renal failure defined by GFR \<35 mL/min by CKD-EPI. 6. Clinically active C. diff infection 7. History of imaging of the liver (ultrasound, computerized tomography or magnetic resonance) showing other causes of jaundice 8. History of other liver diseases including hepatitis B (positive HBsAg or HBV DNA), hepatitis C (positive HCV RNA), autoimmune hepatitis, Wilson disease, genetic \\hemochromatosis, alpha1-antitrypsin deficiency or strong suspicion of Drug Induced Liver Injury (DILI). Previously treated hepatitis C that was cured (sustained virological response with negative RNA ≥24 weeks following treatment) is not an exclusion. 9. History of HIV infection (positive HIV RNA or on treatment for HIV infection) 10. History or presence of cancer (including hepatocellular carcinoma) other than non- melanoma skin cancer 11. History of other significant medical problems such as autoimmune diseases, severe asthma, psoriasis, Inflammatory Bowel Disease (IBD), etc. that might require immunosuppressive treatments 12. Pregnancy or breastfeeding 13. Prior exposure to experimental therapies in last 3 months 14. Prior exposure to systemic corticosteroid (glucocorticoid) or immunosuppressive therapy for more than 4 days within previous 30 days 15. Need for inotropic pressor support to maintain perfusion to critical organs within prior 48 hours before randomization and initiation of experimental treatment 16. Clinically significant pancreatitis- abdominal pain, elevated lipase (\> 3 X ULN) and at least edema of pancreas with fat-stranding on CT scan 17. Total WBC count \> 30,000/mm3 18. Known allergy or intolerance to therapeutic agents to be tested 19. Inability to voluntarily obtain informed consent from participant or guardian 20. Perceived inability to follow study procedures and comply with protocol 21. Platelet count \< 40,000 k/cumm. 22. Positive PCR test for COVID -19 within 7 days prior to the baseline day 0 visit 23. Active gastrointestinal bleeding defined as hematemesis or melena with a decrease in hemoglobin more than 2 g/dl in 24 hrs. Due to gastrointestinal bleeding, or with a decrease in mean arterial BP to \< 65 mmHg. * Positive test is exclusionary only during screening period. If a patient tests positive any time after baseline randomization, a positive PCR test for COVID-19 will be considered as a SAE.

Locations (10)

Mayo Clinic

Phoenix, Arizona, United States

Mayo Clinic

Jacksonville, Florida, United States

Indiana Universtiy

Indianapolis, Indiana, United States

University of Louisville

Louisville, Kentucky, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Texas Southwestern Medical School

Dallas, Texas, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Outcomes

Primary Outcomes

Survival at 90 Days

The primary analysis will be comparisons of 90-day mortality of Prednisone and Anakinra plus zinc vs Prednisone.

Time frame: 90 days

Secondary Outcomes

To Measure the Changes in Lille Score

Change in Lille score is represented as the percentage of participants who achieved a Lille score \< 0.45 on day 7. The Lille score will be calculated using the following website: https://www.mdcalc.com/lille-model-alcoholic-hepatitis Lille score = (exp(-R))/(1 + exp(-R)) where the variables are as follows: R = 3.19 - 0.101\*(age, years) + 0.147\*(albumin day 0, g/L) + 0.0165\* (evolution in bilirubin level, µmol/L) - 0.206\*(renal insufficiency) - 0.0065\*(bilirubin day 0, µmol/L) - 0.0096\*(prothrombin time, sec) Renal insufficiency = 1 (if creatinine \>1.3 mg/dL (115 µmol/L)) or 0 (if ≤1.3 mg/dL (115 µmol/L)) The Lille score was developed to provide early recognition of patients with severe alcoholic hepatitis not responding to corticosteroids. Lower scores indicate more improvement in response to corticosteroids. A Lille score \> 0.45 predicts worse 6-month survival. A Lille score \< 0.45 predicts better 6-month survival.

Time frame: Day 7

Changes in MELD Score

The Model for End-Stage Liver Disease (MELD) is a numerical scale, ranging from 6 (less ill) to 40 (gravely ill), used for liver transplant candidates age 12 and older. It gives each person a 'score' (number) based on how urgently he or she needs a liver transplant within the next three months.