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

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Primary Purpose

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Anakinra

Pentoxifylline

Zinc Sulfate

Methylprednisolone

About this trial

This is an interventional treatment trial for Acute Alcoholic Hepatitis focused on measuring Hepatitis, alcoholic, pentoxifylline, zinc, anakinra, glucocorticoids, MELD score, Intestinal mucosa

Eligibility Criteria

21 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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.
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.

Sites / Locations

University of Louisville
University of Massachusetts Medical School
Cleveland Clinic
University of Texas Southwestern Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

No Intervention

Arm Label

Anakinra & Pentoxifylline & Zinc Sulfate

Methylprednisolone

Observational

Arm Description

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

methylprednisolone 32 mg orally daily for 28 days

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.

Outcomes

Primary Outcome Measures

180 Days Mortality

Death at 180 days

Secondary Outcome Measures

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.

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.

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.

Full Information

NCT ID

NCT01809132

First Posted

March 8, 2013

Last Updated

October 19, 2021

Sponsor

Mack Mitchell

Collaborators

National Institute on Alcohol Abuse and Alcoholism (NIAAA), The Cleveland Clinic, University of Massachusetts, Worcester, University of Louisville

1. Study Identification

Unique Protocol Identification Number

NCT01809132

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Completed

Study Start Date

September 2013 (undefined)

Primary Completion Date

October 2018 (Actual)

Study Completion Date

October 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Mack Mitchell

Collaborators

National Institute on Alcohol Abuse and Alcoholism (NIAAA), The Cleveland Clinic, University of Massachusetts, Worcester, University of Louisville

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Alcoholic Hepatitis

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

104 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Anakinra & Pentoxifylline & Zinc Sulfate

Arm Type

Experimental

Arm Description

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

Arm Title

Methylprednisolone

Arm Type

Active Comparator

Arm Description

methylprednisolone 32 mg orally daily for 28 days

Arm Title

Observational

Arm Type

No Intervention

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Anakinra

Other Intervention Name(s)

Kineret

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Pentoxifylline

Other Intervention Name(s)

Pentoxifylline, generic

Intervention Description

Pentoxifylline, generic

Intervention Type

Drug

Intervention Name(s)

Zinc Sulfate

Other Intervention Name(s)

Zinc Sulfate, generic

Intervention Description

Zinc Sulfate, nutritional supplement

Intervention Type

Drug

Intervention Name(s)

Methylprednisolone

Other Intervention Name(s)

Methylprednisolone, generic

Intervention Description

Methylprednisolone, corticosteroid

Primary Outcome Measure Information:

Title

180 Days Mortality

Description

Death at 180 days

Time Frame

Time to event up to 6 months

Secondary Outcome Measure Information:

Title

MELD Score at 28 Days

Description

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.

Time Frame

28 days

Title

MELD Score at 90 Days

Description

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.

Time Frame

90 Days

Title

MELD Score at 180 Days

Description

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.

Time Frame

180 Days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mack C Mitchell, MD

Organizational Affiliation

University of Texas Southwestern Medical Center

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Arthur J McCullough, MD

Organizational Affiliation

The Cleveland Clinic

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Craig J McClain, MD

Organizational Affiliation

University of Louisville

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Gyongi Szabo, MD

Organizational Affiliation

University of Massachusetts, Worcester

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Louisville

City

Louisville

State/Province

Kentucky

ZIP/Postal Code

40202

Country

United States

Facility Name

University of Massachusetts Medical School

City

Worcester

State/Province

Massachusetts

ZIP/Postal Code

01655

Country

United States

Facility Name

Cleveland Clinic

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

University of Texas Southwestern Medical Center

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390-9030

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

35340032

Citation

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.

Results Reference

derived

PubMed Identifier

35084335

Citation

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.

Results Reference

derived

PubMed Identifier

31811953

Citation

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.

Results Reference

derived

Acute Alcoholic Hepatitis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial