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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

147 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-07-10

Study Completion Date

2022-08-12

Brief Summary

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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.

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Detailed Description

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Conditions

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Alcoholic Hepatitis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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).

Group Type ACTIVE_COMPARATOR

Prednisone

Intervention Type DRUG

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

Placebos

Intervention Type DRUG

Matching placebo

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).

Group Type ACTIVE_COMPARATOR

Anakinra and Zinc

Intervention Type 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.

Placebos

Intervention Type DRUG

Matching placebo

Interventions

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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.

Intervention Type DRUG

Prednisone

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

Intervention Type DRUG

Placebos

Matching placebo

Intervention Type DRUG

Eligibility Criteria

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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.

Minimum Eligible Age

21 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Samer Gawrieh

Clinical-Director, Alcoholic Hepatitis Network Data Coordinating Center and Associate Professor of Clinical Medicine Division of Gastroenterology and Hepatology

Responsibility Role PRINCIPAL_INVESTIGATOR