Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis

Alcoholic Hepatitis Clinical Trial

— AlcHepNet  

Official title:

A Multicenter, Randomized, Double Blinded, Placebo-controlled Clinical Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis by the AlcHepNet Consortium

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04072822
• Other study ID #: AlcHepNet-02
• Status: Completed
• Phase: Phase 2
• Start date: July 10, 2020
• Est. completion date: August 12, 2022

Study information

• Verified date: July 2023
• Source: Indiana University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 147
• Est. completion date: August 12, 2022
• Est. primary completion date: May 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion Criteria

1. AH, as defined by the NIAAA pan-consortia for AH:

1. Onset of jaundice (defined as serum total bilirubin >3 mg/dL) within the prior 8 weeks to screening visit

2. 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

3. AST > 50 IU/l

4. AST:ALT > 1.5 and both values < 400 IU/l

5. and/or histological evidence of AH*

2. MELD 20-35 on day of randomization.

3. 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

Exclusion Criteria

1. MELD SCORE <20 or > 35

2. Active sepsis (positive blood or ascitic cultures) with Systemic Inflammatory Response Syndrome (SIRS) or hemodynamic compromise requiring intravenous pressors to maintain tissue perfusion

3. Pneumonia as evidenced by radiological exam

4. Multi-organ failure

5. Renal failure defined by GFR <35 mL/min by CKD-EPI.

6. Clinically active C. diff infection

7. History of imaging of the liver (ultrasound, computerized tomography or magnetic resonance) showing other causes of jaundice

8. 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.

9. History of HIV infection (positive HIV RNA or on treatment for HIV infection)

10. History or presence of cancer (including hepatocellular carcinoma) other than non- melanoma skin cancer

11. History of other significant medical problems such as autoimmune diseases, severe asthma, psoriasis, Inflammatory Bowel Disease (IBD), etc. that might require immunosuppressive treatments

12. Pregnancy or breastfeeding

13. Prior exposure to experimental therapies in last 3 months

14. Prior exposure to systemic corticosteroid (glucocorticoid) or immunosuppressive therapy for more than 4 days within previous 30 days

15. Need for inotropic pressor support to maintain perfusion to critical organs within prior 48 hours before randomization and initiation of experimental treatment

16. Clinically significant pancreatitis- abdominal pain, elevated lipase (> 3 X ULN) and at least edema of pancreas with fat-stranding on CT scan

17. Total WBC count > 30,000/mm3

18. Known allergy or intolerance to therapeutic agents to be tested

19. Inability to voluntarily obtain informed consent from participant or guardian

20. Perceived inability to follow study procedures and comply with protocol

21. Platelet count < 40,000 k/cumm.

22. Positive PCR test for COVID -19 within 7 days prior to the baseline day 0 visit

23. Active gastrointestinal bleeding defined as hematemesis or melena with a decrease 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.

Related Conditions & MeSH terms

• Alcoholic Hepatitis
• Hepatitis
• Hepatitis A
• Hepatitis, Alcoholic

Intervention

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.
• Prednisone
Prednisone is indicated for numerous conditions including inflammatory disease. Corticosteroids, such as prednisolone, are considered standard of care in alcoholic liver disease.
• Placebos
Matching placebo

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	University of Texas Southwestern Medical School	Dallas	Texas
United States	Indiana Universtiy	Indianapolis	Indiana
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Louisville	Louisville	Kentucky
United States	Mayo Clinic	Phoenix	Arizona
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Indiana University	National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival at 90 Days	The primary analysis will be comparisons of 90-day mortality of Prednisone and Anakinra plus zinc vs Prednisone.	90 days
Secondary	To Measure the Changes in Lille Score	Change in Lille score is represented as the percentage of participants who achieved a Lille score < 0.45 on day 7.; The Lille score will be calculated using the following website: https://www.mdcalc.com/lille-model-alcoholic-hepatitis Lille score = (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*(prothrombin time, sec) Renal insufficiency = 1 (if creatinine >1.3 mg/dL (115 µmol/L)) or 0 (if =1.3 mg/dL (115 µmol/L)) The Lille score was developed to provide early recognition of patients with severe alcoholic hepatitis not responding to corticosteroids. Lower scores indicate more improvement in response to corticosteroids. A Lille score > 0.45 predicts worse 6-month survival. A Lille score < 0.45 predicts better 6-month survival.	Day 7
Secondary	Changes in MELD Score	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.	7, 30, and 90 days
Secondary	Number of Participants With AKI (Acute Kidney Injury)	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	7, 30, and 90 days
Secondary	Development of Multi-organ Failure	Defined as failure =2 organs	7, 30, and 90 days
Secondary	Development of SIRS (Systemic Inflammatory Response Syndrome)	Defined as two or more abnormalities in temperature, increased heart rate, respiration, or white blood cell count with increase in SOFA score =2 points	7, 30, and 90 days
Secondary	Number of Transfers to ICU	Recording the change of hospital word from regular floor to ICU floor as a marker for worsening illness and care escalation	7, 30, and 90 days
Secondary	Changes in Liver Function	Changes in liver function were evaluated by changes in the Child Pugh Score at days 7, 30, and 90. The Child Pugh Score is a scoring system used to assess the severity of chronic liver disease. Scores range from 5 to 15, with higher scores indicating more severe disease. Points are assigned as follows: Hepatic encephalopathy: None = 1 point, Grade 1 and 2 = 2 points, Grade 3 and 4 = 3 points Ascites: None = 1 point, mild = 2 points, moderate to severe = 3 points Total Bilirubin: under 2 mg/dl = 1 point, 2 to 3 mg/dl = 2 points, over 3 mg/dl = 3 points Albumin: greater than 3.5g/dl = 1 point, 2.8 to 3.5g/dl = 2 points, less than 2.8g/dl = 3 points International normalised ratio (INR): under 1.7 = 1 point, 1.7 to 2.3 = 2 points, above 2.3 = 3 points; Assigned points for each category are summed to calculate the Child Pugh Score.	7, 30, and 90 days
Secondary	Number of Participants With 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.	The SOFA score will be calculated at the following website https://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score; Scores can be from 0 - >14 (favorable to less favorable)	180 days
Secondary	Number of Participants With Infections		180 days
Secondary	Number of Participants With Progression of Sepsis	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	180 days
Secondary	Percentage of Participants With Renal Dysfunction	Defined by a creatinine > 2 mg/dl	180 days
Secondary	Number of Participants Requiring Transfer to ICU for Care, Intubation for Airway Control, Need for Ventilator Support or RRT.		180 days
Secondary	Indicators of Gut Permeability		180 days
Secondary	Survival		30 days and 180 days
Secondary	Transplant Free Survival Rate		90 Days

External Links

•   AlcHepNet Website