Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis
Condition: Alcoholic Hepatitis
MeSH terms: Hepatitis A; Hepatitis; Hepatitis, Alcoholic
Intervention: Anakinra and Zinc; Prednisone; Placebos
Intervention description: 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.; Prednisone is indicated for numerous conditions including inflammatory disease. Corticosteroids, such as prednisolone, are considered standard of care in alcoholic liver disease.; Matching placebo
Intervention MeSH terms: Prednisone; Interleukin 1 Receptor Antagonist Protein
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 147.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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.