Efficacy Study of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis
NCT ID: NCT01809132
Last Updated: 2021-11-01
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2/PHASE3
104 participants
INTERVENTIONAL
2013-09-30
2018-10-31
Brief Summary
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Detailed Description
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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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
Anakinra
Anakinra, interleukin-1 receptor antagonist; 100 mg/0.67 mL solution for subcutaneous injection.
Pentoxifylline
Pentoxifylline, generic
Zinc Sulfate
Zinc Sulfate, nutritional supplement
Methylprednisolone
methylprednisolone 32 mg orally daily for 28 days
Methylprednisolone
Methylprednisolone, corticosteroid
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.
No interventions assigned to this group
Interventions
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Anakinra
Anakinra, interleukin-1 receptor antagonist; 100 mg/0.67 mL solution for subcutaneous injection.
Pentoxifylline
Pentoxifylline, generic
Zinc Sulfate
Zinc Sulfate, nutritional supplement
Methylprednisolone
Methylprednisolone, corticosteroid
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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.
21 Years
70 Years
ALL
No
Sponsors
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National Institute on Alcohol Abuse and Alcoholism (NIAAA)
NIH
The Cleveland Clinic
OTHER
University of Massachusetts, Worcester
OTHER
University of Louisville
OTHER
Mack Mitchell
OTHER
Responsible Party
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Mack Mitchell
Professor of Medicine, Division of Digestive and Liver Diseases
Principal Investigators
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Mack C Mitchell, MD
Role: PRINCIPAL_INVESTIGATOR
University of Texas Southwestern Medical Center
Arthur J McCullough, MD
Role: PRINCIPAL_INVESTIGATOR
The Cleveland Clinic
Craig J McClain, MD
Role: PRINCIPAL_INVESTIGATOR
University of Louisville
Gyongi Szabo, MD
Role: PRINCIPAL_INVESTIGATOR
University of Massachusetts, Worcester
Locations
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University of Louisville
Louisville, Kentucky, United States
University of Massachusetts Medical School
Worcester, Massachusetts, United States
Cleveland Clinic
Cleveland, Ohio, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Countries
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References
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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.
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.
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.
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.
Provided Documents
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