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

NCT04072822 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: AlcHepNet-02
• Study Type: interventional
• Target: 147
• Locations: 1 country
• Sites: 10

Brief 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.

Conditions

Alcoholic Hepatitis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• To Measure the Changes in Lille Score

  Day 7

• Changes in MELD Score

  7, 30, and 90 days

• Number of Participants With AKI (Acute Kidney Injury)

  7, 30, and 90 days

• Development of Multi-organ Failure

  7, 30, and 90 days

• Development of SIRS (Systemic Inflammatory Response Syndrome)

  7, 30, and 90 days

Study Arms (2)

Prednisone

ACTIVE COMPARATOR

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; Drug: Placebos

Anakinra and Zinc

ACTIVE COMPARATOR

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: Anakinra and Zinc; Drug: Placebos

Interventions

Anakinra and Zinc DRUG

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.

Anakinra and Zinc

Prednisone DRUG

Prednisone is indicated for numerous conditions including inflammatory disease. Corticosteroids, such as prednisolone, are considered standard of care in alcoholic liver disease.

Prednisone

Placebos DRUG

Matching placebo

Anakinra and Zinc; Prednisone

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• AH, as defined by the NIAAA pan-consortia for AH:
• Onset of jaundice (defined as serum total bilirubin \>3 mg/dL) within the prior 8 weeks to screening visit
• 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
• AST \> 50 IU/l
• AST:ALT \> 1.5 and both values \< 400 IU/l
• and/or histological evidence of AH\*
• MELD 20-35 on day of randomization.
• 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

You may not qualify if:

• MELD SCORE \<20 or \> 35
• Active sepsis (positive blood or ascitic cultures) with Systemic Inflammatory Response Syndrome (SIRS) or hemodynamic compromise requiring intravenous pressors to maintain tissue perfusion
• Pneumonia as evidenced by radiological exam
• Multi-organ failure
• Renal failure defined by GFR \<35 mL/min by CKD-EPI.
• Clinically active C. diff infection
• History of imaging of the liver (ultrasound, computerized tomography or magnetic resonance) showing other causes of jaundice
• History of HIV infection (positive HIV RNA or on treatment for HIV infection)
• History or presence of cancer (including hepatocellular carcinoma) other than non- melanoma skin cancer
• History of other significant medical problems such as autoimmune diseases, severe asthma, psoriasis, Inflammatory Bowel Disease (IBD), etc. that might require immunosuppressive treatments
• Pregnancy or breastfeeding
• Prior exposure to experimental therapies in last 3 months
• Prior exposure to systemic corticosteroid (glucocorticoid) or immunosuppressive therapy for more than 4 days within previous 30 days
• Need for inotropic pressor support to maintain perfusion to critical organs within prior 48 hours before randomization and initiation of experimental treatment
• Clinically significant pancreatitis- abdominal pain, elevated lipase (\> 3 X ULN) and at least edema of pancreas with fat-stranding on CT scan

Sponsors & Collaborators

• Indiana University: lead
• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator

Study Sites (10)

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

Indiana Universtiy

Indianapolis, Indiana, 46202-2879, United States

Location

University of Louisville

Louisville, Kentucky, 40292, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 01003, United States

Location

Mayo Clinic

Rochester, Minnesota, 55902, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15260, United States

Location

University of Texas Southwestern Medical School

Dallas, Texas, 75390, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23284, United States

Location

Related Publications (2)

• Gawrieh S, Dasarathy S, Tu W, Kamath PS, Chalasani NP, McClain CJ, Bataller R, Szabo G, Tang Q, Radaeva S, Barton B, Nagy LE, Shah VH, Sanyal AJ, Mitchell MC; AlcHepNet Investigators. Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis. J Hepatol. 2024 May;80(5):684-693. doi: 10.1016/j.jhep.2024.01.031. Epub 2024 Feb 10.

  PMID: 38342441 DERIVED

• Dasarathy S, Tu W, Bellar A, Welch N, Kettler C, Tang Q, Liangpunsakul S, Gawrieh S, Radaeva S, Mitchell M; AlcHepNet. Development and evaluation of objective trial performance metrics for multisite clinical studies: Experience from the AlcHep Network. Contemp Clin Trials. 2024 Mar;138:107437. doi: 10.1016/j.cct.2024.107437. Epub 2024 Jan 11.

  PMID: 38215876 DERIVED

Related Links

• AlcHepNet Website

MeSH Terms

Conditions

Hepatitis, Alcoholic

Interventions

Interleukin 1 Receptor Antagonist Protein; Zinc; Prednisone

Condition Hierarchy (Ancestors)

Hepatitis; Liver Diseases; Digestive System Diseases; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Samer Gawrieh, MD
• Organization: Indiana University School of Medicine

sgawrieh@iu.edu

(317) 278-9326

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical-Director, Alcoholic Hepatitis Network Data Coordinating Center and Associate Professor of Clinical Medicine Division of Gastroenterology and Hepatology

Study Record Dates

• First Submitted: August 9, 2019
• First Posted: August 28, 2019
• Study Start: July 10, 2020
• Primary Completion: May 24, 2022
• Study Completion: August 12, 2022
• Last Updated: February 10, 2025
• Results First Posted: July 28, 2023

Record last verified: 2025-02

Locations

US (10)