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

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ClinicalTrials.gov Identifier: NCT04072822
Recruitment Status : Recruiting
First Posted : August 28, 2019
Last Update Posted : October 1, 2020
Sponsor:
Collaborator:
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Information provided by (Responsible Party):
Samer Gawrieh, Indiana University

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.


Condition or disease Intervention/treatment Phase
Alcoholic Hepatitis Drug: Anakinra and Zinc Drug: Prednisone Drug: Placebos Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 258 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 10, 2020
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine


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: 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.

Drug: Placebos
Matching placebo




Primary Outcome Measures :
  1. Survival at 90 days [ Time Frame: 90 days ]
    The primary analysis will be comparisons of 90-day mortality of Prednisone and Anakinra plus zinc vs Prednisone.


Secondary Outcome Measures :
  1. Changes is Lille score [ Time Frame: 7, 30, and 90 days ]

    Score will be calculated using the following website: https://www.mdcalc.com/lille-model-alcoholic-hepatitis

    (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*(PT, sec)

    Renal insufficiency = 1 (if Cr >1.3 mg/dL (115 µmol/L)) or 0 (if ≤1.3 mg/dL (115 µmol/L))


  2. Changes in MELD score [ Time Frame: 7, 30, and 90 days ]
    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.

  3. Progression of the development of AKI (acute kidney injury) [ Time Frame: 7, 30, and 90 days ]
    • 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

  4. Progression of the development of multi-organ failure [ Time Frame: 7, 30, and 90 days ]
    Defined as failure ≥2 organs

  5. Progression of the development of SIRS (Systemic Inflammatory Response Syndrome) [ Time Frame: 7, 30, and 90 days ]
    Defined as two or more abnormalities in temperature, increased heart rate, respiration, or white blood cell count with increase in SOFA score ≥2 points

  6. Number of Transfers to ICU [ Time Frame: 7, 30, and 90 days ]
    Recording the change of hospital word from regular floor to ICU floor as a marker for worsening illness and care escalation

  7. Rate of changes in liver function [ Time Frame: 7, 30, and 90 days ]
    • New onset of ascites if not present on admission to study
    • New onset of variceal hemorrhage
    • New onset of hepatic encephalopathy (HE).

  8. Measure of 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. [ Time Frame: 180 days ]
    The SOFA score will be modified and re-evaluated without platelet counts given that these are usually low in AH.

  9. Measuring the types of infections [ Time Frame: 180 days ]
    • Pneumonia defined as new infiltrate by CXR or Chest CT scan not explained by "fluid overload"
    • Positive blood cultures for bacteria or fungus, not suspected as contaminant
    • Positive urine fungal culture > 50,000 colonies/ml
    • Positive urine bacterial culture > 100,000 colonies/ml (mixed flora is excluded)
    • Soft tissue or bone infections including cellulitis or abscess documented by exam or scan
    • CNS infection defined as positive culture of CSF or > 5 WBC/ml
    • Ascitic fluid white cell count >500/ml or neutrophils>250/ml. with or without positive bacterial or fungal cultures

  10. Rate of the progression of sepsis [ Time Frame: 180 days ]
    • 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

  11. Rate of the progression of renal dysfunction [ Time Frame: 180 days ]
    Defined by a creatinine > 2 mg/dl

  12. Need for care escalation [ Time Frame: 180 days ]
    Proportion of participants requiring transfer to ICU for care, intubation for airway control, need for ventilator support or RRT.

  13. Indicators of gut permeability [ Time Frame: 180 days ]
  14. Survival [ Time Frame: 30 days and 180 days ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 <50 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04072822


Contacts
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Contact: Savannah Yarnelle 3172786424 samussel@iu.edu

Locations
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United States, Arizona
Mayo Clinic Recruiting
Phoenix, Arizona, United States, 85054
Contact: Jill Weidknecht, RN, MBA/HCM    480-342-3007    weidknecht.jill@mayo.edu   
Principal Investigator: Hugo Vargas, MD         
United States, Florida
Mayo Clinic Recruiting
Jacksonville, Florida, United States, 32224
Contact: Robert Brannock    904-953-4133    Brannock.Robert@mayo.edu   
Principal Investigator: Liu Yang, MBBS         
United States, Indiana
Indiana Universtiy Recruiting
Indianapolis, Indiana, United States, 46202-2879
Contact: Jennifer Lehman, RN    317-278-1872    jgeck@iu.edu   
Principal Investigator: Naga Chalasani, MD         
United States, Kentucky
University of Louisville Recruiting
Louisville, Kentucky, United States, 40292
Contact: Vatsalya Vatsalya    502-852-8928    vatsalya.vatsalya@louisville.org   
Sub-Investigator: Steve Mahanes         
Principal Investigator: Craig McClain, MD         
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 01003
Contact: Jeanie Lee, CCRP    617-235-2886    jlee75@bidmc.harvard.edu   
Principal Investigator: Gyongi Szabo, MD         
University Of Massachusetts Recruiting
Worcester, Massachusetts, United States, 01605
Contact: Monique Rinner, RN, MBA    774-442-1982    monique.rinner@umassmemorial.org   
Principal Investigator: Deepika Devuni, MD         
United States, New York
Mayo Clinic Recruiting
Rochester, New York, United States, 55901
Contact: Amy Olofson, BSN    507-284-4531    olofson.amy@mayo.edu   
Contact: Janelle Worthington    5072848271    Worthington.Janelle@mayo.edu   
Principal Investigator: Vijay Shah, MD         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Annette Bellar    216-445-6268    bellara@ccf.org   
Principal Investigator: Srinivasan Dasarathy, MD         
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15260
Contact: Janet McLaughlin    412-383-0479    jam415@pitt.edu   
Principal Investigator: Ramon Bataller, MD         
United States, Texas
University of Texas Southwestern Medical School Recruiting
Dallas, Texas, United States, 75390
Contact: Mack Mitchell, MD         
Principal Investigator: Mack Mitchell, MD         
United States, Virginia
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23284
Contact: Stephanie Taylor, MSN, RN    804-828-9311    stephanie.taylor@vcuhealth.org   
Contact: Shawn Fenner    804-828-9154    shawn.fenner@vcuhealth.org   
Principal Investigator: Arun Sanyal, MD         
Sponsors and Collaborators
Indiana University
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Additional Information:
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Responsible Party: Samer Gawrieh, Co-Director, Alcoholic Hepatitis Network Data Coordinating Center and Associate Professor of Medicine Division of Gastroenterology and Hepatology, Indiana University
ClinicalTrials.gov Identifier: NCT04072822    
Other Study ID Numbers: AlcHepNet-02
First Posted: August 28, 2019    Key Record Dates
Last Update Posted: October 1, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis
Hepatitis, Alcoholic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Liver Diseases, Alcoholic
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Prednisone
Interleukin 1 Receptor Antagonist Protein
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antirheumatic Agents