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

Condition(s) targeted: Acute Alcoholic Hepatitis

Intervention: Anakinra (Drug); Pentoxifylline (Drug); Zinc Sulfate (Drug); Methylprednisolone (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Mack Mitchell

Official(s) and/or principal investigator(s):
Mack C Mitchell, MD, Principal Investigator, Affiliation: University of Texas Southwestern Medical Center
Arthur J McCullough, MD, Principal Investigator, Affiliation: The Cleveland Clinic
Craig J McClain, MD, Principal Investigator, Affiliation: University of Louisville
Gyongi Szabo, MD, Principal Investigator, Affiliation: University of Massachusetts, Worcester

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.

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Death

Secondary outcome: MELD score

Detailed description: 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.

Minimum age: 21 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Ability to provide informed consent by subject or appropriate family member 2. Age between 21-70 years 3. Recent alcohol consumption > 50 g/d for > 6 months, continuing within two months before enrollment 4. At least 2 of the following symptoms of acute alcoholic hepatitis: Anorexia, nausea, right upper quadrant pain, jaundice, leukocytosis, hepatomegaly AND 5. Elevation of AST > 80 U/L within 3 days of baseline, but < 500 U/L; AST > ALT and ALT < 200 U/L; total bilirubin > 3 mg/dL. 6. 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 > 80 is waived. The liver biopsy must be done within 60 days of study enrollment. 7. Model for End-Stage Liver Disease (MELD) ≥ 20 and Maddrey DF ≥ 32. 8. 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: 1. Hypotension with BP < 80/50 after volume repletion 2. Pregnancy; incarceration; inability to provide consent or lack of appropriate family member 3. 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 4. Acute gastrointestinal bleeding requiring >2 units blood transfusion within the previous 4 days 5. 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 6. 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. 7. Evidence of acute pancreatitis: CT evidence or amylase or lipase > 5 X upper limit of normal (ULN). 8. 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 9. Acute or chronic kidney injury with serum creatinine > 3. 0 mg/dl.

University of Louisville, Louisville, Kentucky 40202, United States; Recruiting
Craig J McClain, MD, Phone: 502-852-6991
Craig J McClain, MD, Principal Investigator

University of Massachusetts Medical School, Worcester, Massachusetts 01655, United States; Recruiting
Gyongi Szabo, MD, Phone: 508-856-5275
Gyongi Szabo, MD, Principal Investigator

Cleveland Clinic, Cleveland, Ohio 44195, United States; Recruiting
Arthur J McCullough, MD, Phone: 216-444-2766
Arthur J McCullough, MD, Principal Investigator

University of Texas Southwestern Medical Center, Dallas, Texas 75390-9030, United States; Recruiting
Mack C Mitchell, MD, Phone: 214-648-5036
Mack C Mitchell, MD, Principal Investigator

Starting date: September 2013
Last updated: June 23, 2015