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

 1. AH, as defined by the NIAAA pan-consortia for AH6:

 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 17

 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 adecrease 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.