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

Study Overview
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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.

Official Title
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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

Conditions
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Alcoholic Hepatitis

Intervention / Treatment
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* Drug: Anakinra and Zinc
* Drug: Prednisone
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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 Exclusion Criteria 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 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. 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 Total WBC count > 30,000/mm3 Known allergy or intolerance to therapeutic agents to be tested Inability to voluntarily obtain informed consent from participant or guardian Perceived inability to follow study procedures and comply with protocol Platelet count < 40,000 k/cumm. Positive PCR test for COVID -19 within 7 days prior to the baseline day 0 visit 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.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prednisone<br>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<br>* Prednisone is indicated for numerous conditions including inflammatory disease. Corticosteroids, such as prednisolone, are considered standard of care in alcoholic liver disease.<br>Drug: Placebos<br>* Matching placebo<br>|
| Active Comparator: Anakinra and Zinc<br>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<br>* 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.<br>Drug: Placebos<br>* Matching placebo<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Survival |  | 30 days and 180 days | 
| Transplant Free Survival Rate |  | 90 Days |