Digoxin In Treatment of Alcohol Associated Hepatitis

Overview

Prospective, single center, open label, randomized controlled trial to determine the feasibility of conducting a future study with respect to patient recruitment, 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.

Full Title of Study: “Digoxin In Treatment of Alcohol Associated Hepatitis (DIGIT-AlcHep)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 2024

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 study of digoxin versus no digoxin in patients with severe alcohol associated hepatitis is to assess the feasibility of conducting a large randomized trial to detect efficacy with respect to patient recruitment, digoxin administration and dose adjustment in patients hospitalized with severe alcohol associated hepatitis.

Interventions

  • Drug: Intravenous digoxin
    • Loading dose: the total loading dose of digoxin will be determined using the Loading nomogram. The FDA-recommended total IV digoxin loading dose range is 8 to 12 mcg/kg. The lowest recommended dose of 8 mcg/kg was used in constructing the digoxin Loading nomogram that will be used in this trial. Maintenance dose: the maintenance dose will be started approximately 24 hours after initiation of digoxin loading. The post-loading digoxin trough will be reviewed prior to starting maintenance dosing. Subjects on P-gp inhibitors or spironolactone, will have an additional digoxin level performed 12-hours after any dose adjustment. Once digoxin levels are stable, 24-hour blood draws will be performed.

Arms, Groups and Cohorts

  • Experimental: Arm A: Digoxin
    • In the digoxin arm, the intervention to be administered will be intravenous digoxin dosed by weight and by renal function using an adaption of the established FDA nomogram. Participants randomized to digoxin will receive an intravenous digoxin loading dose administered in 3 doses over 24 hours starting on Day 1. Digoxin levels will be monitored daily throughout the participant’s hospital stay, to a maximum of 28 days. Digoxin will be discontinued at the time discharge if before 28 days.
  • No Intervention: Arm B: No Digoxin
    • In the no digoxin arm, no study drug or placebo will be administered.

Clinical Trial Outcome Measures

Primary Measures

  • Ability to recruit 4 patients a month.
    • Time Frame: 15 months
    • The number of subjects recruited per month will be summarized to assess the study’s primary recruitment feasibility objective.

Secondary Measures

  • Practicality of daily digoxin measurements
    • Time Frame: Up to 28 days
    • 90% of patients have digoxin checked levels within the pre-specified time window
  • Feasibility of digoxin dosing in a timely manner.
    • Time Frame: Up to 28 days
    • 90% of patients receive every scheduled dose of the drug
  • Feasibility of digoxin dose adjustments in renal insufficiency.
    • Time Frame: Up to 28 days
    • 90% of necessary dose adjustments were made appropriately in response to digoxin levels
  • Mortality at 7, 14, 28, 90 days
    • Time Frame: Up to 90 days
    • The mortality rates at different time points in the digoxin group and in the control group
  • Development of ECG abnormalities
    • Time Frame: Up to 28 days
    • The number and proportion of patients in the digoxin and control groups with ECG changes compared to baseline

Participating in This Clinical Trial

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 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

Gender Eligibility: All

Minimum Age: 21 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Yale University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Bubu Banini, MD, PhD, Assistant Professor of Internal Medicine – Yale University
  • Overall Official(s)
    • Bubu Banini, MD, PhD, Principal Investigator, Yale School of Medicine
  • Overall Contact(s)
    • Bubu Banini, MD, PhD, 203-737-6063, bubu.banini@yale.edu

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