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

A Multicenter, Randomized, Double Blinded, Placebo-controlled Clinical Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis by the AlcHepNet Consortium

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 Overview

• Status: Completed
• Conditions: Alcoholic Hepatitis
• Intervention / Treatment: Drug: Prednisone; Drug: Placebos; Drug: Anakinra and Zinc

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Indiana
    • Indianapolis, Indiana, United States, 46202-2879
      • Indiana Universtiy
  • Kentucky
    • Louisville, Kentucky, United States, 40292
      • University of Louisville
  • Massachusetts
    • Boston, Massachusetts, United States, 01003
      • Beth Israel Deaconess Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical School
  • Virginia
    • Richmond, Virginia, United States, 23284
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prednisone; Standard of care plus prednisone 40 mg orally once daily on Days 1-30 and matching placebos for Anakinra (1 syringe s.c. once daily on Days 1-14), and zinc (matched pill once daily on Days 1-90).	Drug: Prednisone; Prednisone is indicated for numerous conditions including inflammatory disease. Corticosteroids, such as prednisolone, are considered standard of care in alcoholic liver disease.; Drug: Placebos; Matching placebo
Active Comparator: Anakinra and Zinc; Standard of care plus Anakinra (100 mg s.c.) once daily on Days 1-14 zinc sulfate 220 mg once daily on Days 1-90, and placebo for prednisone (matched pill once daily on Days 1-30).	Drug: Placebos; Matching placebo; Drug: Anakinra and Zinc; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival at 90 Days	The primary analysis will be comparisons of 90-day mortality of Prednisone and Anakinra plus zinc vs Prednisone.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Transfers to ICU	Recording the change of hospital word from regular floor to ICU floor as a marker for worsening illness and care escalation	7, 30, and 90 days
Survival		30 days and 180 days
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.	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.	7, 30, and 90 days
Number of Participants With AKI (Acute Kidney Injury)	Increase in creatinine of 50% above baseline over a period of 7 days; Increase in creatinine of 0.3 mg/dl within a period of 48 hrs; Onset of renal failure requiring dialysis	7, 30, and 90 days
Development of Multi-organ Failure	Defined as failure ≥2 organs	7, 30, and 90 days
Development of SIRS (Systemic Inflammatory Response Syndrome)	Defined as two or more abnormalities in temperature, increased heart rate, respiration, or white blood cell count with increase in SOFA score ≥2 points	7, 30, and 90 days
Changes in Liver Function	Changes in liver function were evaluated by changes in the Child Pugh Score at days 7, 30, and 90. The Child Pugh Score is a scoring system used to assess the severity of chronic liver disease. Scores range from 5 to 15, with higher scores indicating more severe disease. Points are assigned as follows: Hepatic encephalopathy: None = 1 point, Grade 1 and 2 = 2 points, Grade 3 and 4 = 3 points Ascites: None = 1 point, mild = 2 points, moderate to severe = 3 points Total Bilirubin: under 2 mg/dl = 1 point, 2 to 3 mg/dl = 2 points, over 3 mg/dl = 3 points Albumin: greater than 3.5g/dl = 1 point, 2.8 to 3.5g/dl = 2 points, less than 2.8g/dl = 3 points International normalised ratio (INR): under 1.7 = 1 point, 1.7 to 2.3 = 2 points, above 2.3 = 3 points Assigned points for each category are summed to calculate the Child Pugh Score.	7, 30, and 90 days
Number of Participants With Changes in Sequential Organ Failure Assessment (SOFA) Scores and Proportions Requiring Hemodynamic Support for MAP < 65 mm Hg and Lactate > 2 mmol/l, Renal Replacement Therapy or Mechanical Ventilation.	The SOFA score will be calculated at the following website https://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score Scores can be from 0 - >14 (favorable to less favorable)	180 days
Number of Participants With Infections		180 days
Number of Participants With Progression of Sepsis	Life-threatening organ dysfunction caused by a dysregulated host response to infection; An increase in SOFA score of 2 points of more; Note: most participants with severe AH have 4 points based on bilirubin only	180 days
Percentage of Participants With Renal Dysfunction	Defined by a creatinine > 2 mg/dl	180 days
Number of Participants Requiring Transfer to ICU for Care, Intubation for Airway Control, Need for Ventilator Support or RRT.		180 days
Indicators of Gut Permeability		180 days
Transplant Free Survival Rate		90 Days

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Publications and helpful links

Helpful Links

• AlcHepNet Website

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2020
• Primary Completion (Actual): May 24, 2022
• Study Completion (Actual): August 12, 2022

Study Registration Dates

• First Submitted: August 9, 2019
• First Submitted That Met QC Criteria: August 26, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 6, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; RNA Virus Infections; Virus Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis A; Hepatitis; Hepatitis, Alcoholic; Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antirheumatic Agents; Prednisone; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: AlcHepNet-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No