Clinical trial NCT04072822: Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcoholic Hepatitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alcoholic Hepatitis
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2019-08-28
Enrollment: 147
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Survival at 90 Days
timeFrame: 90 days
Secondary outcomes:
measure: To Measure the Changes in Lille Score
timeFrame: Day 7
measure: Changes in MELD Score
timeFrame: 7, 30, and 90 days
measure: Number of Participants With AKI (Acute Kidney Injury)
timeFrame: 7, 30, and 90 days
measure: Development of Multi-organ Failure
timeFrame: 7, 30, and 90 days
measure: Development of SIRS (Systemic Inflammatory Response Syndrome)
timeFrame: 7, 30, and 90 days
measure: Number of Transfers to ICU
timeFrame: 7, 30, and 90 days
measure: Changes in Liver Function
timeFrame: 7, 30, and 90 days
measure: 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.
timeFrame: 180 days
measure: Number of Participants With Infections
timeFrame: 180 days
measure: Number of Participants With Progression of Sepsis
timeFrame: 180 days
measure: Percentage of Participants With Renal Dysfunction
timeFrame: 180 days
measure: Number of Participants Requiring Transfer to ICU for Care, Intubation for Airway Control, Need for Ventilator Support or RRT.
timeFrame: 180 days
measure: Indicators of Gut Permeability
timeFrame: 180 days
measure: Survival
timeFrame: 30 days and 180 days
measure: Transplant Free Survival Rate
timeFrame: 90 Days
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Indianapolis
country: United States
facility: Indiana Universtiy
state: Indiana
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical School
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
References: