Digoxin In Treatment of Alcohol Associated Hepatitis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Digoxin In Treatment of Alcohol Associated Hepatitis (DIGIT-AlcHep)

Conditions
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Acute Alcoholic Hepatitis, Chemical and Drug Induced Liver Injury, Alcohol-Induced Disorders, Steatohepatitis Caused by Ingestible Alcohol

Intervention / Treatment
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* Drug: Intravenous digoxin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Diagnosis of alcohol associated hepatitis based on clinical criteria or histologic evidence 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 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: - Currently pregnant or breastfeeding - Inability of patient, legally authorized representative or next-of-kin to provide informed consent - Allergy or intolerance to digoxin - Clinically active C. diff infection - Positive test for COVID-19 within 14 days prior to the screening visit - 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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, single center, open label, randomized 1:1 controlled trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Digoxin<br>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. | Drug: Intravenous digoxin<br>* 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.<br>* Other names: Lanoxin;|
| No Intervention: Arm B: No Digoxin<br>In the no digoxin arm, no study drug or placebo will be administered. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ability to recruit 4 patients a month. | The number of subjects recruited per month will be summarized to assess the study's primary recruitment feasibility objective. | 15 months | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute alcoholic hepatitis, Liver injury, Liver inflammation, Liver disease, Digoxin