Efficacy Study of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis

Study Overview
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Brief Summary
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This study will compare two different treatments of acute alcoholic hepatitis. The current standard of care is treatment with corticosteroids (methylprednisolone). This will be compared to treatment with anakinra, pentoxifylline, plus zinc sulfate. The participants will be treated and followed for 6 months and the two treatment groups will be compared for differences in death rates and laboratory tests that measure liver and gut function.

Detailed Description
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This study will test the hypothesis that the syndrome of acute alcoholic hepatitis results from severe inflammation and dysregulated cytokines. Steroid monotherapy is not effective in all patients and this study will utilize compounds that have the potential to improve gut barrier function, to reduce the associated inflammation, and to prevent the development of hepatorenal syndrome and other organ failure. Patients will be randomized to receive 28 days of methylprednisolone 32 mg daily OR therapy that includes a combination of anakinra (interleukin-1 receptor antagonist) 100mg by subcutaneous injection daily for 14 days plus pentoxifylline 400 mg orally three times daily for one month plus zinc supplements (220 mg of zinc sulfate) given orally for 6 months. This combination strategy will address the acute inflammatory component of the disease (anakinra) and protect against development of hepatorenal syndrome (pentoxifylline), one of the most frequent causes of death in severe acute alcoholic hepatitis, and improve gut mucosal integrity (zinc supplements). The primary outcome will be 6 month mortality rate. Secondary outcomes will be measured at 30, 90 and 180 days. Individuals who are not participating in the interventional arm of the trial will be receive standard care and be observed for 6 months. They will be enrolled to have baseline and interval health information and laboratory results collected.

Official Title
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Double-blind Randomized Controlled Trial of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis

Conditions
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Acute Alcoholic Hepatitis

Intervention / Treatment
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* Drug: Anakinra
* Drug: Pentoxifylline
* Drug: Zinc Sulfate
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide informed consent by subject or appropriate family member Age between 21-70 years Recent alcohol consumption > 50 g/d for > 6 months, continuing within two months before enrollment d. At least 2 of the following symptoms of acute alcoholic hepatitis: Anorexia, nausea, RUQ pain Liver biopsy showing alcoholic hepatitis (steatohepatitis) OR ultrasound of liver showing increased echogenicity OR CT scan showing decreased attenuation of liver compared to spleen OR MRI showing fatty liver (decreased signaling intensity on T1 weighted images) If liver biopsy confirms diagnosis of alcoholic hepatitis then requirement for AST elevation > 50 is waived. The liver biopsy must be done within 60 days of study enrollment. AST levels: AST> Or equal to 50 IU/mL but less than 500 IU/mL AST> ALT, ratio AST/ALT> 1.5; ALT < 200 IU/mL or biopsy proven alcoholic hepatitis. Model for End-Stage Liver Disease (MELD) ≥ 20 and Maddrey DF ≥ 32. Willingness to utilize two reliable forms of contraception (both males and females of childbearing potential) from screening through the first 6 weeks of the study. Exclusion Criteria: Hypotension with BP < 80/50 after volume repletion Pregnancy; incarceration; inability to provide consent or lack of appropriate family member Signs of uncontrolled systemic infection: Fever > 38°C and positive blood or ascites cultures and on appropriate antibiotic therapy for ≥ 3 days within 3 days of inclusion Acute gastrointestinal bleeding requiring >2 units blood transfusion within the previous 4 days Undue risk from immunosuppression: Positive HBsAg; a positive skin PPD skin test, a positive quantiferon, or history of treatment for tuberculosis; history of any malignancy except skin cancer but including hepatocellular carcinoma within the last five years; HIV infection Recent previous treatment with corticosteroids or other immunosuppressive medications including specific anti-TNF therapy (not including pentoxifylline), calcineurin inhibitors within the previous 3 months. Treatment with corticosteroids for ≤3 days prior to baseline is acceptable. Evidence of acute pancreatitis: CT evidence or amylase or lipase > 5 X upper limit of normal (ULN). Serious cardiac, respiratory or neurologic disease or evidence of other liver diseases such as autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, hemochromatosis, secondary iron overload due to chronic hemolysis, alpha-1-antitrypsin deficiency Acute or chronic kidney injury with serum creatinine > 3.0 mg/dl.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anakinra & Pentoxifylline & Zinc Sulfate<br>anakinra 100mg subcutaneous injection daily for 14 days pentoxifylline 400 mg orally three times daily for 28 day zinc sulfate 220 mg orally for 180 days | Drug: Anakinra<br>* Anakinra, interleukin-1 receptor antagonist; 100 mg/0.67 mL solution for subcutaneous injection.<br>* Other names: Kineret;Drug: Pentoxifylline<br>* Pentoxifylline, generic<br>* Other names: Pentoxifylline, generic;Drug: Zinc Sulfate<br>* Zinc Sulfate, nutritional supplement<br>* Other names: Zinc Sulfate, generic;|
| Active Comparator: Methylprednisolone<br>methylprednisolone 32 mg orally daily for 28 days | Drug: Methylprednisolone<br>* Methylprednisolone, corticosteroid<br>* Other names: Methylprednisolone, generic;|
| No Intervention: Observational<br>Individuals who choose not to participate in the interventional arm of the trial will be receive standard care and be observed for 6 months. They will be enrolled to have baseline and interval health information and laboratory results collected. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 180 Days Mortality | Death at 180 days | Time to event up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MELD Score at 28 Days | Model of End Stage Liver Disease Score calculated from serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR). MELD score ranges from 6-40. A higher score indicates a lesser outcome. The Model for End Stage Liver Disease scoring system is based on the INR, total serum bilirubin and serum creatinine. The measure reflects 90 day prognosis of alcohol associated liver disease from the time of measurement and therefore can only be assessed on subjects who are alive at the specified time point since lab values from that time point are required for the measure. | 28 days | 
| MELD Score at 90 Days | Model of End Stage Liver Disease Score calculated from serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR). MELD score ranges from 6-40. A higher score indicates a lesser outcome. The Model for End Stage Liver Disease scoring system is based on the INR, total serum bilirubin and serum creatinine. The measure reflects 90 day prognosis of alcohol associated liver disease from the time of measurement and therefore can only be assessed on subjects who are alive at the specified time point since lab values from that time point are required for the measure. | 90 Days | 
| MELD Score at 180 Days | Model of End Stage Liver Disease Score calculated from serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR). MELD score ranges from 6-40. A higher score indicates a lesser outcome. The Model for End Stage Liver Disease scoring system is based on the INR, total serum bilirubin and serum creatinine. The measure reflects 90 day prognosis of alcohol associated liver disease from the time of measurement and therefore can only be assessed on subjects who are alive at the specified time point since lab values from that time point are required for the measure. | 180 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis, alcoholic, pentoxifylline, zinc, anakinra, glucocorticoids, MELD score, Intestinal mucosa