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Acute Alcoholic HepatitisPhase 2/3NCT01809132

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

A Phase 2/3 study testing Anakinra, Pentoxifylline and Zinc Sulfate in people with Acute Alcoholic Hepatitis, run by Mack Mitchell at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 21 to 70 years
Conditions the study is for
Acute Alcoholic Hepatitis
What is being tested?
Anakinra, Pentoxifylline and Zinc Sulfate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
104 participants
Where
4 sitesUnited States
Study dates
Sep 2013to Oct 2018
Phase
Phase 2/3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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.

Who cannot join

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

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75390-9030

  • University of Louisville

    Louisville, Kentucky, 40202

  • University of Massachusetts Medical School

    Worcester, Massachusetts, 01655

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
Anakinra, Pentoxifylline, Zinc Sulfate, Methylprednisolone
Keywords
Hepatitis, alcoholic, pentoxifylline, zinc, anakinra, glucocorticoids, MELD score, Intestinal mucosa
Medical subject headings
Hepatitis, Alcoholic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AnakinraDrug

    Also called Kineret

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

  • PentoxifyllineDrug

    Also called Pentoxifylline, generic

    Pentoxifylline, generic

  • Zinc SulfateDrug

    Also called Zinc Sulfate, generic

    Zinc Sulfate, nutritional supplement

  • MethylprednisoloneDrug

    Also called Methylprednisolone, generic

    Methylprednisolone, corticosteroid

Study groups in NCT01809132
Study groupRoleWhat they receive
Anakinra & Pentoxifylline & Zinc SulfateExperimentalanakinra 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
Receives: Drug: Anakinra; Drug: Pentoxifylline; Drug: Zinc Sulfate
MethylprednisoloneActive comparatormethylprednisolone 32 mg orally daily for 28 days
Receives: Drug: Methylprednisolone
ObservationalNo interventionIndividuals 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 being measured

The primary outcome is the main question the study is designed to answer.

  1. 180 Days Mortality

    Death at 180 days

    Measured: Time to event up to 6 months

Secondary outcomes (3)

  1. MELD Score at 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.

    Measured: 28 days

  2. MELD Score at 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.

    Measured: 90 Days

  3. MELD Score at 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.

    Measured: 180 Days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Mar 2013 (estimated)
  2. Study startSep 2013
  3. Primary completionOct 2018
  4. Study completionOct 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
104 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01809132
Sponsor's protocol ID
U01AA021893-01
Other IDs
U01AA021893-01
Status last verified
Oct 2021
First submitted
8 Mar 2013
Last updated
1 Nov 2021
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 37011138

  • 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.

    PubMed 35340032

  • 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.

    PubMed 35084335

  • 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.

    PubMed 31811953

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Anakinra, Pentoxifylline and Zinc Sulfate in people with Acute Alcoholic Hepatitis, run by Mack Mitchell at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

180 Days Mortality (time frame: Time to event up to 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01809132, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2021.

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