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

NCT01809132 | Completed Phase 2 Results DMC

• 1 other identifier: U01AA021893-01
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Acute Alcoholic Hepatitis

Keywords

Hepatitis, alcoholic; pentoxifylline; zinc; anakinra; glucocorticoids; MELD score; Intestinal mucosa

Outcome Measures

Primary Outcomes (1)

• 180 Days Mortality

  Death at 180 days

  Time to event up to 6 months

Secondary Outcomes (3)

• MELD Score at 28 Days

  28 days

• MELD Score at 90 Days

  90 Days

• MELD Score at 180 Days

  180 Days

Study Arms (3)

Anakinra & Pentoxifylline & Zinc Sulfate

EXPERIMENTAL

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; Drug: Pentoxifylline; Drug: Zinc Sulfate

Methylprednisolone

ACTIVE COMPARATOR

methylprednisolone 32 mg orally daily for 28 days

Drug: Methylprednisolone

Observational

NO INTERVENTION

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.

Interventions

Anakinra DRUG

Anakinra, interleukin-1 receptor antagonist; 100 mg/0.67 mL solution for subcutaneous injection.

Also known as: Kineret

Anakinra & Pentoxifylline & Zinc Sulfate

Pentoxifylline DRUG

Pentoxifylline, generic

Also known as: Pentoxifylline, generic

Anakinra & Pentoxifylline & Zinc Sulfate

Zinc Sulfate DRUG

Zinc Sulfate, nutritional supplement

Also known as: Zinc Sulfate, generic

Anakinra & Pentoxifylline & Zinc Sulfate

Methylprednisolone DRUG

Methylprednisolone, corticosteroid

Also known as: Methylprednisolone, generic

Methylprednisolone

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Hypotension with BP \< 80/50 after volume repletion
• Pregnancy; incarceration; inability to provide consent or lack of appropriate family member
• 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.

Sponsors & Collaborators

• Mack Mitchell: lead
• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator
• The Cleveland Clinic: collaborator
• University of Massachusetts, Worcester: collaborator
• University of Louisville: collaborator

Study Sites (4)

University of Louisville

Louisville, Kentucky, 40202, United States

Location

University of Massachusetts Medical School

Worcester, Massachusetts, 01655, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390-9030, United States

Location

Related Publications (4)

• Hassanein T, McClain CJ, Vatsalya V, Stein LL, Flamm SL, Martin P, Cave MC, Mitchell M Jr, Barton B, Nagy L, Szabo G, McCullough A, Dasarathy S, Shah J, Blevins C, Scott D, Krebs W, Brown JE, Lin W. Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis. Am J Gastroenterol. 2024 Jan 1;119(1):107-115. doi: 10.14309/ajg.0000000000002275. Epub 2023 Apr 3.

  PMID: 37011138 DERIVED

• Szabo G, Mitchell M, McClain CJ, Dasarathy S, Barton B, McCullough AJ, Nagy LE, Kroll-Desrosiers A, Tornai D, Min HA, Radaeva S, Holbein MEB, Casey L, Cuthbert J. IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis. Hepatology. 2022 Oct;76(4):1058-1068. doi: 10.1002/hep.32478. Epub 2022 Jun 2.

  PMID: 35340032 DERIVED

• Helsley RN, Miyata T, Kadam A, Varadharajan V, Sangwan N, Huang EC, Banerjee R, Brown AL, Fung KK, Massey WJ, Neumann C, Orabi D, Osborn LJ, Schugar RC, McMullen MR, Bellar A, Poulsen KL, Kim A, Pathak V, Mrdjen M, Anderson JT, Willard B, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Garcia-Garcia JC, Rotroff DM, Allende DS, Wang Z, Hazen SL, Nagy LE, Brown JM. Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice. Elife. 2022 Jan 27;11:e76554. doi: 10.7554/eLife.76554.

  PMID: 35084335 DERIVED

• Vatsalya V, Cave MC, Kong M, Gobejishvili L, Falkner KC, Craycroft J, Mitchell M, Szabo G, McCullough A, Dasarathy S, Radaeva S, Barton B, McClain CJ. Keratin 18 Is a Diagnostic and Prognostic Factor for Acute Alcoholic Hepatitis. Clin Gastroenterol Hepatol. 2020 Aug;18(9):2046-2054. doi: 10.1016/j.cgh.2019.11.050. Epub 2019 Dec 4.

  PMID: 31811953 DERIVED

MeSH Terms

Conditions

Hepatitis, Alcoholic

Interventions

Interleukin 1 Receptor Antagonist Protein; Pentoxifylline; Drugs, Generic; Zinc Sulfate; Methylprednisolone

Condition Hierarchy (Ancestors)

Hepatitis; Liver Diseases; Digestive System Diseases; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Theobromine; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pharmaceutical Preparations; Sulfates; Sulfuric Acids; Sulfur Acids; Sulfur Compounds; Inorganic Chemicals; Zinc Compounds; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Mack C. Mitchell
• Organization: UTexas Southwestern Medical Center

mack.mitchell@utsouthwestern.edu

2146485036

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine, Division of Digestive and Liver Diseases

Study Record Dates

• First Submitted: March 8, 2013
• First Posted: March 12, 2013
• Study Start: September 1, 2013
• Primary Completion: October 1, 2018
• Study Completion: October 1, 2018
• Last Updated: November 1, 2021
• Results First Posted: December 10, 2020

Record last verified: 2021-10

Locations

US (4)