Acute Alcoholic Hepatitis
Conditions
Keywords
Hepatitis, alcoholic, pentoxifylline, zinc, anakinra, glucocorticoids, MELD score, Intestinal mucosa
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.
Interventions
DRUGAnakinra
Anakinra, interleukin-1 receptor antagonist; 100 mg/0.67 mL solution for subcutaneous injection.
DRUGPentoxifylline
Pentoxifylline, generic
DRUGZinc Sulfate
Zinc Sulfate, nutritional supplement
DRUGMethylprednisolone
Methylprednisolone, corticosteroid
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
The Cleveland Clinic
University of Massachusetts, Worcester
University of Louisville
Mack Mitchell
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 180 Days Mortality | Time to event up to 6 months | Death at 180 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MELD Score at 28 Days | 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 | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 53 |
| Methylprednisolone methylprednisolone 32 mg orally daily for 28 days
Methylprednisolone: Methylprednisolone, corticosteroid | 50 |
| 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. | 1 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Anakinra & Pentoxifylline & Zinc Sulfate | Methylprednisolone | Observational | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 50 Participants | 0 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 9 Participants | 0 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 38 Participants | 1 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 47 Participants | 1 Participants | 95 Participants |
| Sex: Female, Male Female | 18 Participants | 22 Participants | 1 Participants | 41 Participants |
| Sex: Female, Male Male | 35 Participants | 28 Participants | 0 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 17 / 53 | 22 / 50 | 0 / 0 |
| other Total, other adverse events | 20 / 53 | 4 / 50 | 0 / 0 |
| serious Total, serious adverse events | 33 / 53 | 30 / 50 | 0 / 0 |
Outcome results
Primary
180 Days Mortality
Death at 180 days
Time frame: Time to event up to 6 months
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra & Pentoxifylline & Zinc Sulfate | 180 Days Mortality | 17 Participants |
| Methylprednisolone | 180 Days Mortality | 22 Participants |
| Observational | 180 Days Mortality | 0 Participants |
p-value: 0.3Log Rank
Secondary
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.
Time frame: 180 Days
Population: This outcome could not be calculated for the observational subject who was lost to follow up.~Analysis were limited to the subjects that were alive for this time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anakinra & Pentoxifylline & Zinc Sulfate | MELD Score at 180 Days | 15.81 score on a scale | Standard Deviation 10.1 |
| Methylprednisolone | MELD Score at 180 Days | 11.85 score on a scale | Standard Deviation 4.47 |
p-value: 0.17t-test, 2 sided
Secondary
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.
Time frame: 28 days
Population: This outcome could not be calculated for the observational subject who was lost to follow up.~Analysis were limited to the subjects that were alive for this time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anakinra & Pentoxifylline & Zinc Sulfate | MELD Score at 28 Days | 22.57 score on a scale | Standard Deviation 6.31 |
| Methylprednisolone | MELD Score at 28 Days | 20.95 score on a scale | Standard Deviation 6.44 |
Comparison: the observational subject was lost to follow-upp-value: 0.42t-test, 2 sided
Secondary
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.
Time frame: 90 Days
Population: This outcome could not be calculated for the observational subject who was lost to follow up.~Analysis were limited to the subjects that were alive for this time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anakinra & Pentoxifylline & Zinc Sulfate | MELD Score at 90 Days | 15.50 score on a scale | Standard Deviation 6.11 |
| Methylprednisolone | MELD Score at 90 Days | 16.38 score on a scale | Standard Deviation 9.58 |
p-value: 0.75t-test, 2 sided