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

Phase 2

Completed

Conditions: Alcoholic Hepatitis

Interventions: Drug: Anakinra and Zinc
Drug: Prednisone
Drug: Placebos

Registration Number: NCT04072822

Lead Sponsor: Indiana University

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 147

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Anakinra and Zinc	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).
Anakinra and Zinc	Placebos	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).
Prednisone	Placebos	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).
Prednisone	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).

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Number of Participants With 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
Development of Multi-organ Failure	7, 30, and 90 days	Defined as failure ≥2 organs
Number of Participants Requiring Transfer to ICU for Care, Intubation for Airway Control, Need for Ventilator Support or RRT.	180 days
Indicators of Gut Permeability	180 days
Transplant Free Survival Rate	90 Days
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.	180 days	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)
Number of Participants With Infections	180 days
Number of Participants With 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
Changes in Liver Function	7, 30, and 90 days	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.
Percentage of Participants With Renal Dysfunction	180 days	Defined by a creatinine \> 2 mg/dl
To Measure the Changes in Lille Score	Day 7	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.
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
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.
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
Survival	30 days and 180 days

Trial Locations

Locations (8): University of Louisville
🇺🇸
Louisville, Kentucky, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Texas Southwestern Medical School
🇺🇸
Dallas, Texas, United States
Indiana Universtiy
🇺🇸
Indianapolis, Indiana, United States