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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Texas Southwestern Medical Center
Sponsor:
Collaborators:
The Cleveland Clinic
University of Massachusetts, Worcester
University of Louisville
Information provided by (Responsible Party):
Mack Mitchell, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT01809132
First received: March 8, 2013
Last updated: May 19, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Acute Alcoholic Hepatitis
Drug: Anakinra
Drug: Pentoxifylline
Drug: Zinc Sulfate
Drug: Methylprednisolone
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Double-blind Randomized Controlled Trial of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Death [ Time Frame: Time to event up to 6 months ] [ Designated as safety issue: Yes ]
    Mortality


Secondary Outcome Measures:
  • MELD score [ Time Frame: 30, 90, and 180 days ] [ Designated as safety issue: Yes ]
    Model of End Stage Liver Disease Score calculated from serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR)


Other Outcome Measures:
  • Laboratory assay for biomarkers of inflammation [ Time Frame: 2,7, 30, 90, and 180 days ] [ Designated as safety issue: No ]
    Serum endotoxin, IL-1, TNF-alpha


Estimated Enrollment: 130
Study Start Date: September 2013
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Anakinra & Pentoxifylline & Zinc Sulfate
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
Anakinra, interleukin-1 receptor antagonist; 100 mg/0.67 mL solution for subcutaneous injection.
Other Name: Kineret
Drug: Pentoxifylline
Pentoxifylline, generic
Other Name: Pentoxifylline, generic
Drug: Zinc Sulfate
Zinc Sulfate, nutritional supplement
Other Name: Zinc Sulfate, generic
Active Comparator: Methylprednisolone
methylprednisolone 32 mg orally daily for 28 days
Drug: Methylprednisolone
Methylprednisolone, corticosteroid
Other Name: Methylprednisolone, generic
No Intervention: Observational
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.

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.

  Eligibility

Ages Eligible for Study:   21 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 or signs of acute alcoholic hepatitis: Anorexia, nausea, RUQ pain, jaundice, leukocytes, hepatomegaly, AND Elevation of AST > 80 U/L, but < 500 U/L; AST > ALT and ALT < 200 U/L; total bilirubin > 3 mg/dL AND
  5. Liver biopsy showing alcoholic hepatitis (steatohepatitis) OR ultrasound of liver showing increased echogenicity OR CT scan showing cirrhosis or decreased attenuation of liver compared to spleen OR MRI showing fatty liver (decreased signaling intensity on T1 weighted images)
  6. Model for End-Stage Liver Disease (MELD) ≥ 20 and Maddrey ≥ 32
  7. Willingness to utilize two reliable forms of contraception (both males and females of childbearing potential) from screening through the first six 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 on appropriate antibiotic therapy for > 3 days within 3 days of inclusion
  4. Acute gastrointestinal bleeding requiring > 2 units of 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; known HIV infection
  6. Previous treatment with corticosteroids or other immunosuppressive medications including specific anti-TNF therapy (not including pentoxifylline), calcineurin inhibitors within the previous 3 months
  7. Evidence of acute pancreatitis: CT evidence or amylase or lipase > 4 X ULN
  8. Serious cardiac, respiratory or neurologic disease or evidence of 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01809132

Locations
United States, Kentucky
University of Louisville Recruiting
Louisville, Kentucky, United States, 40202
Contact: Craig J McClain, MD    502-852-6991      
Principal Investigator: Craig J McClain, MD         
United States, Massachusetts
University of Massachusetts Medical School Recruiting
Worcester, Massachusetts, United States, 01655
Contact: Gyongi Szabo, MD    508-856-5275      
Principal Investigator: Gyongi Szabo, MD         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Arthur J McCullough, MD    216-444-2766      
Principal Investigator: Arthur J McCullough, MD         
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390-9030
Contact: Mack C Mitchell, MD    214-648-5036      
Principal Investigator: Mack C Mitchell, MD         
Sponsors and Collaborators
Mack Mitchell
The Cleveland Clinic
University of Massachusetts, Worcester
University of Louisville
Investigators
Principal Investigator: Mack C Mitchell, MD University of Texas Southwestern Medical Center
Principal Investigator: Arthur J McCullough, MD The Cleveland Clinic
Principal Investigator: Craig J McClain, MD University of Louisville
Principal Investigator: Gyongi Szabo, MD University of Massachusetts, Worcester
  More Information

No publications provided

Responsible Party: Mack Mitchell, Professor of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01809132     History of Changes
Other Study ID Numbers: U01-AA021893-01, U01AA021893-01
Study First Received: March 8, 2013
Last Updated: May 19, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Texas Southwestern Medical Center:
Hepatitis, alcoholic
pentoxifylline
zinc
anakinra
glucocorticoids
MELD score
Intestinal mucosa

Additional relevant MeSH terms:
Hepatitis, Alcoholic
Hepatitis
Hepatitis A
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
Zinc
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Pentoxifylline
Zinc Sulfate
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014