AlcHepNet: Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis
Study Details
Study Description
Brief Summary
This multicenter, randomized, double blinded, placebo-controlled clinical trial is focused on novel treatments for severe alcoholic hepatitis (AH), a life-threatening stage of alcoholic liver injury that has a short-term mortality rate much higher than that of other liver diseases.
The primary objective of the study is to determine the clinical efficacy and safety of Anakinra (plus zinc) compared to the current standard medical treatment consisting of prednisone in participants with clinically severe AH. Key secondary objectives broadly are as follows: (a) to evaluate the use of biomarkers to assess disease severity and treatment response; and (b) to develop novel endpoints to overcome the limitations of current assessment strategies for severe AH.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Prednisone Standard of care plus prednisone 40 mg orally once daily on Days 1-30 and matching placebos for Anakinra (1 syringe s.c. once daily on Days 1-14), and zinc (matched pill once daily on Days 1-90). |
Drug: Prednisone
Prednisone is indicated for numerous conditions including inflammatory disease. Corticosteroids, such as prednisolone, are considered standard of care in alcoholic liver disease.
Drug: Placebos
Matching placebo
|
| Active Comparator: Anakinra and Zinc Standard of care plus Anakinra (100 mg s.c.) once daily on Days 1-14 zinc sulfate 220 mg once daily on Days 1-90, and placebo for prednisone (matched pill once daily on Days 1-30). |
Drug: Anakinra and Zinc
Anakinra is indicated for reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis. It has been previously studied in AH. Zinc is a nutritional supplement. Zinc supplementation reverses the clinical signs of zinc deficiency in participants with alcoholic liver disease.
Drug: Placebos
Matching placebo
|
Outcome Measures
Primary Outcome Measures
- Survival at 90 days [90 days]
The primary analysis will be comparisons of 90-day mortality of Prednisone and Anakinra plus zinc vs Prednisone.
Secondary Outcome Measures
- Changes is Lille score [7, 30, and 90 days]
Score will be calculated using the following website: https://www.mdcalc.com/lille-model-alcoholic-hepatitis (exp(-R))/(1 + exp(-R)) where the variables are as follows: R = 3.19 - 0.101*(age, years) + 0.147*(albumin day 0, g/L) + 0.0165* (evolution in bilirubin level, µmol/L) - 0.206*(renal insufficiency) - 0.0065*(bilirubin day 0, µmol/L) - 0.0096*(PT, sec) Renal insufficiency = 1 (if Cr >1.3 mg/dL (115 µmol/L)) or 0 (if ≤1.3 mg/dL (115 µmol/L))
- Changes in MELD score [7, 30, and 90 days]
The Model for End-Stage Liver Disease (MELD) is a numerical scale, ranging from 6 (less ill) to 40 (gravely ill), used for liver transplant candidates age 12 and older. It gives each person a 'score' (number) based on how urgently he or she needs a liver transplant within the next three months.
- Progression of the development of AKI (acute kidney injury) [7, 30, and 90 days]
Increase in creatinine of 50% above baseline over a period of 7 days Increase in creatinine of 0.3 mg/dl within a period of 48 hrs Onset of renal failure requiring dialysis
- Progression of the development of multi-organ failure [7, 30, and 90 days]
Defined as failure ≥2 organs
- Progression of the development of SIRS (Systemic Inflammatory Response Syndrome) [7, 30, and 90 days]
Defined as two or more abnormalities in temperature, increased heart rate, respiration, or white blood cell count with increase in SOFA score ≥2 points
- Number of Transfers to ICU [7, 30, and 90 days]
Recording the change of hospital word from regular floor to ICU floor as a marker for worsening illness and care escalation
- Rate of changes in liver function [7, 30, and 90 days]
New onset of ascites if not present on admission to study New onset of variceal hemorrhage New onset of hepatic encephalopathy (HE).
- Measure of changes in sequential organ failure Assessment (SOFA) scores and proportions requiring hemodynamic support for MAP < 65 mm Hg and lactate > 2 mmol/l, renal replacement therapy or mechanical ventilation. [180 days]
The SOFA score will be modified and re-evaluated without platelet counts given that these are usually low in AH.
- Measuring the types of infections [180 days]
Pneumonia defined as new infiltrate by CXR or Chest CT scan not explained by "fluid overload" Positive blood cultures for bacteria or fungus, not suspected as contaminant Positive urine fungal culture > 50,000 colonies/ml Positive urine bacterial culture > 100,000 colonies/ml (mixed flora is excluded) Soft tissue or bone infections including cellulitis or abscess documented by exam or scan CNS infection defined as positive culture of CSF or > 5 WBC/ml Ascitic fluid white cell count >500/ml or neutrophils>250/ml. with or without positive bacterial or fungal cultures
- Rate of the progression of sepsis [180 days]
Life-threatening organ dysfunction caused by a dysregulated host response to infection An increase in SOFA score of 2 points of more Note: most participants with severe AH have 4 points based on bilirubin only
- Rate of the progression of renal dysfunction [180 days]
Defined by a creatinine > 2 mg/dl
- Need for care escalation [180 days]
Proportion of participants requiring transfer to ICU for care, intubation for airway control, need for ventilator support or RRT.
- Indicators of gut permeability [180 days]
- Survival [30 days and 180 days]
Eligibility Criteria
Criteria
Inclusion Criteria
-
AH, as defined by the NIAAA pan-consortia for AH6:
-
Onset of jaundice (defined as serum total bilirubin >3 mg/dL) within the prior 8 weeks to screening visit
-
Regular consumption of alcohol with an intake of > 40 gm daily or >280gm weekly on average for women and > 60 gm daily or >420gm weekly on average for men for 6 months or more, with less than 8 weeks of abstinence before onset of jaundice
-
AST > 50 IU/l
-
AST:ALT > 1.5 and both values < 400 IU/l
-
and/or histological evidence of AH*
-
MELD 20-35 on day of randomization.
-
Ages >21
- In patients with possible AH or AH with confounding factors such as possible ischemic hepatitis, possible DILI, uncertain history of alcohol use (e.g., patient denies excessive alcohol use), and atypical/abnormal laboratory tests (e.g., AST < 50 IU/L or > 400 IU/L, AST/ALT ratio < 1.5), antinuclear antibody > 1:160 or SMA > 1:80, a standard of care liver biopsy may be performed during current hospital admission to confirm AH and exclude competing etiologies 17
Exclusion Criteria
-
MELD SCORE <20 or > 35
-
Active sepsis (positive blood or ascitic cultures) with Systemic Inflammatory Response Syndrome (SIRS) or hemodynamic compromise requiring intravenous pressors to maintain tissue perfusion
-
Pneumonia as evidenced by radiological exam
-
Multi-organ failure
-
Renal failure defined by GFR <35 mL/min by CKD-EPI.
-
Clinically active C. diff infection
-
History of imaging of the liver (ultrasound, computerized tomography or magnetic resonance) showing other causes of jaundice
-
History of other liver diseases including hepatitis B (positive HBsAg or HBV DNA), hepatitis C (positive HCV RNA), autoimmune hepatitis, Wilson disease, genetic \hemochromatosis, alpha1-antitrypsin deficiency or strong suspicion of Drug Induced Liver Injury (DILI). Previously treated hepatitis C that was cured (sustained virological response with negative RNA ≥24 weeks following treatment) is not an exclusion.
-
History of HIV infection (positive HIV RNA or on treatment for HIV infection)
-
History or presence of cancer (including hepatocellular carcinoma) other than non- melanoma skin cancer
-
History of other significant medical problems such as autoimmune diseases, severe asthma, psoriasis, Inflammatory Bowel Disease (IBD), etc. that might require immunosuppressive treatments
-
Pregnancy or breastfeeding
-
Prior exposure to experimental therapies in last 3 months
-
Prior exposure to systemic corticosteroid (glucocorticoid) or immunosuppressive therapy for more than 4 days within previous 30 days
-
Need for inotropic pressor support to maintain perfusion to critical organs within prior 48 hours before randomization and initiation of experimental treatment
-
Clinically significant pancreatitis- abdominal pain, elevated lipase (> 3 X ULN) and at least edema of pancreas with fat-stranding on CT scan
-
Total WBC count > 30,000/mm3
-
Known allergy or intolerance to therapeutic agents to be tested
-
Inability to voluntarily obtain informed consent from participant or guardian
-
Perceived inability to follow study procedures and comply with protocol
-
Platelet count < 40,000 k/cumm.
-
Positive PCR test for COVID -19 within 7 days prior to the baseline day 0 visit
-
Active gastrointestinal bleeding defined as hematemesis or melena with adecrease in hemoglobin more than 2 g/dl in 24 hrs. Due to gastrointestinal bleeding, or with a decrease in mean arterial BP to < 65 mmHg.
- Positive test is exclusionary only during screening period. If a patient tests positive any time after baseline randomization, a positive PCR test for COVID-19 will be considered as a SAE.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mayo Clinic | Phoenix | Arizona | United States | 85054 |
| 2 | Mayo Clinic | Jacksonville | Florida | United States | 32224 |
| 3 | Indiana Universtiy | Indianapolis | Indiana | United States | 46202-2879 |
| 4 | University of Louisville | Louisville | Kentucky | United States | 40292 |
| 5 | Beth Israel Deaconess Medical Center | Boston | Massachusetts | United States | 01003 |
| 6 | University Of Massachusetts | Worcester | Massachusetts | United States | 01605 |
| 7 | Mayo Clinic | Rochester | Minnesota | United States | 55902 |
| 8 | Cleveland Clinic | Cleveland | Ohio | United States | 44195 |
| 9 | University of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15260 |
| 10 | University of Texas Southwestern Medical School | Dallas | Texas | United States | 75390 |
| 11 | Virginia Commonwealth University | Richmond | Virginia | United States | 23284 |
Sponsors and Collaborators
- Indiana University
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- AlcHepNet-02