Clinical trial NCT05014087: Digoxin In Treatment of Alcohol Associated Hepatitis
Official title: Digoxin In Treatment of Alcohol Associated Hepatitis (DIGIT-AlcHep)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Alcoholic Hepatitis
Chemical and Drug Induced Liver Injury
Alcohol-Induced Disorders
Steatohepatitis Caused by Ingestible Alcohol
Keywords: Acute alcoholic hepatitis
Liver injury
Liver inflammation
Liver disease
Digoxin
Lead sponsor: Yale University
Sponsor class: OTHER
First posted: 2021-08-20
Enrollment: 60
Sex: ALL
Minimum age (years): 21
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, single center, open label, randomized 1:1 controlled trial.
Primary purpose: TREATMENT

Brief summary: Prospective, single center, open label, randomized controlled trial to explore whether digoxin treatment affects cytokine levels as biomarkers of inflammation in patients with acute alcohol associated hepatitis, digoxin administration and dose adjustment.

The study intervention will be intravenous digoxin (renal-based dosing for maximum of 28 days) versus no digoxin in an open-label 1:1 randomized allocation of patients with severe acute alcohol associated hepatitis.

Detailed description: Severe alcohol associated hepatitis is a condition of acute on chronic immune liver dysfunction that is associated with high mortality, necessitating a search for drugs that may prove safe and efficacious in treating this disease. Pre-clinical studies suggest that digoxin, which is currently used for treating cardiac conditions, is also effective in improving alcohol-associated liver injury. To date, there have been no clinical studies of digoxin use in patients with alcohol associated hepatitis.

The primary objective of this randomized control study of digoxin versus no digoxin in patients with severe alcohol associated hepatitis is to explore whether digoxin treatment affects cytokine levels as biomarkers of inflammation in patients hospitalized with severe alcohol associated hepatitis.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of alcohol associated hepatitis based on clinical criteria or histologic evidence

1. Clinical criteria:

   * Onset of jaundice (bilirubin \>3 mg/dL) within the prior 8 weeks
   * Regular alcohol use \> 6 months, with intake of \> 40 g/day (\>280 g/week) for women; and \> 60 g/day (\>420 g/week) for men
   * AST \> 50 IU/l
   * AST: ALT \> 1.5 and both values \< 400 IU/l
2. Histological evidence of alcohol associated hepatitis\*

   2. MDF \>32 or MELD ≥ 20 to ≤ 35 on Day 0 of the trial

   3. Age between 21 and 70 years, inclusive

   \* In patients with possible alcohol associated hepatitis with confounding factors such as possible ischemic hepatitis, possible DILI, uncertain history of alcohol use, or atypical/abnormal laboratory tests (e.g., AST \< 50 IU/IU/L or \> 400 IU/IU/L, AST/ALT ratio \< 1.5), antinuclearantibody \> 1:160 or SMA \> 1:80, standard of care liver biopsy may be performed as per discretion of the primary attending physician to confirm alcohol associated hepatitis and exclude competing etiologies. The decision to perform liver biopsy will be made by the primary team and will occur regardless of the study. As per current SOC, a liver biopsy may be obtained to confirm suspected alcohol-associated hepatitis and to rule out other potential etiologies of liver disease.

   If a liver biopsy is performed for clinically indicated reasons, we will store liver tissue that is left over after the portion needed for the primary indication has been identified.

   Exclusion Criteria:
   1. - Currently pregnant or breastfeeding
   2. - Inability of patient, legally authorized representative or next-of-kin to provide informed consent
   3. - Allergy or intolerance to digoxin
   4. - Clinically active C. diff infection
   5. - Positive test for COVID-19 within 14 days prior to the screening visit
   6. - Acute hepatitis E, Cytomegalovirus, Epstein Barr Virus, Herpes Simplex Virus

   7- History of other liver diseases including hepatitis B (positive HBsAg or HBV DNA), hepatitis 8-C (positive HCV RNA), autoimmune hepatitis, Wilson disease, genetic hemochromatosis, alpha1-antitrypsin deficiency.

   8-Diagnosis of Drug Induced Liver Injury (DILI), or other etiologies seen on liver imaging.

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

   10 - Current diagnosis of cancer

   11- Renal failure defined by GFR \<30 mL/min

   12 - Refractory ascites, defined as having more than 4 paracenteses in the preceding 8 weeks despite diuretic therapy

   13 - Prior exposure to experimental therapies or other clinical trial in last 3 months

   14 - Current acute or chronic pancreatitis

   15 - Active gastrointestinal bleeding unless resolved for \>48 hours

   16 - Experiencing withdrawal seizures or considered at high risk for alcohol withdrawal seizures or delirium tremens

   17 - Heart rate less than 60 bpm at screening visit or at baseline

   18 - Current diagnosis of atrial fibrillation

   19 - Cardiomyopathy

   20 - Heart failure

   21 - Severe aortic valve disease

   22 - Presence of Accessory arterio-ventricular pathway (eg Wolf-Parkinson-White syndrome)

   23 - Complete heart block or second degree arterio-ventricular block without pacemaker or implantable cardiac device

   24 - Any of the following within the previous 6 months: myocardial infarction, percutaneous intervention, pacemaker/implantable cardiac device implantation, cardiac surgery or stroke

   25 - Current use of the following medications:
   * Antiarrhythmic (amiodarone, dofetilide, sotalol, dronedarone)
   * Parathyroid hormone analog (teriparatide)
   * Thyroid supplement (thyroid, levothyroxine sodium)
   * Sympathomimetics or ionotropic drugs (epinephrine, norepinephrine, dopamine, dobutamine, milrinone)
   * Neuromuscular blocking agents (succinylcholine)
   * Calcium supplement
   * Ivabradine
   * Disulfiram

Primary outcomes:
measure: Change in biomarkers of inflammation
timeFrame: day 3
Secondary outcomes:
measure: Practicality of daily digoxin measurements
timeFrame: Up to 28 days
measure: Feasibility of digoxin dosing in a timely manner.
timeFrame: Up to 28 days
measure: Feasibility of digoxin dose adjustments in renal insufficiency.
timeFrame: Up to 28 days
measure: Mortality at 7, 14, 28, 90 days. All cause mortality of patients enrolled in the trial.
timeFrame: Up to 90 days
measure: Development of ECG abnormalities
timeFrame: Up to 28 days
measure: Recruitment
timeFrame: up to 90 days
Other outcomes:
measure: Organ dysfunction (Liver - Lille Score)
timeFrame: Up to 28 days
measure: Organ dysfunction (Liver) with Model for End-stage Liver Disease (MELD)
timeFrame: Up to 28 days
measure: Organ dysfunction (Liver Enzyme: Bilirubin)
timeFrame: Up to 28 days
measure: Organ dysfunction (Liver Enzyme: Alkaline Phosphatase [ALP])
timeFrame: Up to 28 days
measure: Organ dysfunction (Liver Enzyme: Aspartate Aminotransferase [AST])
timeFrame: Up to 28 days
measure: Organ dysfunction (Liver Enzyme: Alanine Aminotransferase [ALT])
timeFrame: Up to 28 days
measure: Organ Dysfunction (Multi-Organ) with Sequential Organ Failure Assessment (SOFA)
timeFrame: Up to 28 days
measure: Organ Dysfunction (Multi-Organ) with the Multi-Organ Dysfunction Score (MODS)
timeFrame: Up to 28 days
measure: Development of new or recurrent renal failure.
timeFrame: Up to 28 days
measure: Racial and ethnic diversity in subject recruitment and retention.
timeFrame: Up to 90 days
Locations:
city: New Haven
country: United States
facility: Yale New Haven Hospital, Yale School of Medicine
state: Connecticut
Study officials:
affiliation: Yale University
name: Bubu Banini, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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