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

October 19, 2021 updated by: Mack Mitchell

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

104

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • University of Louisville
    • Massachusetts
      • Worcester, Massachusetts, United States, 01655
        • University of Massachusetts Medical School
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic
    • Texas
      • Dallas, Texas, United States, 75390-9030
        • University of Texas Southwestern Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

17 years to 66 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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. d. At least 2 of the following symptoms of acute alcoholic hepatitis: Anorexia, nausea, RUQ pain
  5. 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.

  6. 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.
  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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • Kineret
Drug: Pentoxifylline
Pentoxifylline, generic
Other Names:
  • Pentoxifylline, generic
Drug: Zinc Sulfate
Zinc Sulfate, nutritional supplement
Other Names:
  • Zinc Sulfate, generic
Active Comparator: Methylprednisolone
methylprednisolone 32 mg orally daily for 28 days
Drug: Methylprednisolone
Methylprednisolone, corticosteroid
Other Names:
  • 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
180 Days Mortality
Time Frame: Time to event up to 6 months
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
Time Frame: 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
Time Frame: 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
Time Frame: 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mack Mitchell

Collaborators

National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2013

Primary Completion (Actual)

October 1, 2018

Study Completion (Actual)

October 1, 2018

Study Registration Dates

First Submitted

March 8, 2013

First Submitted That Met QC Criteria

March 8, 2013

First Posted (Estimate)

March 12, 2013

Study Record Updates

Last Update Posted (Actual)

November 1, 2021

Last Update Submitted That Met QC Criteria

October 19, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • U01AA021893-01 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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