Digoxin for Alcoholic Hepatitis

(DIGIT-AlcHep Trial)

Overseen By Camalene Chrysostoum

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must not be taking: Antiarrhythmics, Thyroid supplements, Sympathomimetics, others

Disqualifiers: Pregnancy, Cancer, HIV, Renal failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 28 days

60 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including antiarrhythmics, parathyroid hormone analogs, thyroid supplements, sympathomimetics or ionotropic drugs, neuromuscular blocking agents, calcium supplements, ivabradine, and disulfiram.

Is digoxin generally safe for humans?

Digoxin has been used for many years, but it can be toxic if not dosed correctly, especially in people with liver or kidney problems. Women and older adults may be at higher risk for digoxin toxicity, which can lead to serious health issues. However, modern treatments can effectively manage toxicity if it occurs. ^{1 2 3 4 5}

How does the drug digoxin differ from other treatments for alcoholic hepatitis?

Digoxin is unique because it targets a specific pathway (PKM2-HIF-1α) involved in liver inflammation and damage, which is different from other treatments for alcoholic hepatitis. It has been shown to reduce liver damage and inflammation in animal models, suggesting a novel approach compared to existing therapies. ^{2 6 7 8 9}

Research Team

Bubu Banini, MD, PhD

Principal Investigator

Yale University

Eligibility Criteria

Adults aged 21-70 with severe acute alcohol-associated hepatitis can join this trial. They must have a history of regular heavy drinking and specific blood test results indicating liver damage. Excluded are pregnant or breastfeeding individuals, those allergic to digoxin, with certain infections including COVID-19, other liver diseases, HIV, cancer, serious heart conditions or on conflicting medications.

Inclusion Criteria

- AST > 50 IU/l

- AST: ALT > 1.5 and both values < 400 IU/l

I am between 21 and 70 years old.

Exclusion Criteria

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

I am currently taking specific medications.

I am not taking any specific heart rhythm medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous digoxin dosed by weight and renal function for a maximum of 28 days

Up to 28 days

Daily monitoring during hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 90 days

Treatment Details

Interventions

• Digoxin

Trial Overview The study is testing if intravenous digoxin is safe and effective for treating severe acute alcoholic hepatitis compared to no treatment. Participants will be randomly assigned to receive either digoxin (with doses adjusted based on kidney function) or no digoxin in an open-label format for up to 28 days.

Participant Groups

Group I: Arm A: Digoxin Experimental Treatment 1 Intervention

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.

Group II: Arm B: No Digoxin Active Control 1 Intervention

In the no digoxin arm, no study drug or placebo will be administered.

Digoxin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Lanoxin for:

• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia
• Congestive heart failure

Approved in United States as Lanoxin for:

• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia
• Congestive heart failure

Approved in Canada as Lanoxin for:

• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia
• Congestive heart failure

Approved in Japan as Lanoxin for:

• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia
• Congestive heart failure

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Findings from Research

The incidence of digoxin toxicity has significantly declined due to a lower therapeutic range, better drug therapies for heart failure, and improved dosing methods, making it less common and less fatal than in the past.

Modern treatments, such as the emergency use of antidigoxin Fab fragments, allow for quick and effective management of digoxin toxicity, and there is potential to use these treatments for non-life-threatening cases to enhance patient comfort and reduce costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Bauman, JL., Didomenico, RJ., Galanter, WL.[2018]

In a study involving 24 participants (12 with cirrhosis and 12 healthy volunteers), patients with cirrhosis showed significantly higher serum levels of metildigoxin compared to healthy individuals, indicating altered drug metabolism due to liver impairment.

The research suggests that patients with cirrhosis are at a greater risk of digitalis toxicity when treated with standard doses of metildigoxin, as their liver function affects the drug's clearance and distribution, unlike beta-acetyldigoxin which did not show significant differences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in metildigoxin pharmacokinetics in cirrhosis of the liver: a comparison with beta-acetyldigoxin. Rameis, H., Woodcock, B., Bonelli, J., et al.[2013]

A study of 727 patients from 2000 to 2020 revealed that digoxin toxicity remains a significant public health concern, with a 12.7% in-hospital mortality rate and 42.7% mortality at one year after admission.

Patients treated with digoxin immune fab (DIF) had more severe health issues, but showed nonsignificant trends toward lower in-hospital mortality and reduced early readmissions compared to a matched cohort, indicating potential benefits of DIF in high-acuity cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics and Outcomes of Suspected Digoxin Toxicity and Immune Fab Treatment Over the Past Two Decades-2000-2020. Peters, AE., Chiswell, K., Hofmann, P., et al.[2022]

In a study of nearly 3 million hospital admissions in The Netherlands from 2001-2004, digoxin intoxication was found in only 0.04% of cases, indicating that such incidents are infrequent among patients receiving digoxin therapy.

Women were found to be 1.4 times more likely to experience digoxin intoxication compared to men, highlighting a gender-specific risk factor in digoxin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age- and gender-specific incidence of hospitalisation for digoxin intoxication. Aarnoudse, AL., Dieleman, JP., Stricker, BH.[2018]

In a study of 530 heart transplant patients, those who received digitalis therapy (digoxin or digitoxin) for at least 3 months prior to transplantation had significantly lower survival rates at both 30 days and 2 years post-transplant compared to those who did not receive digitalis.

Digitalis therapy was identified as an independent risk factor for increased mortality after heart transplantation, with a hazard ratio of 2.097, indicating that patients on digitalis had more than double the risk of dying within 30 days post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic digitalis therapy in patients before heart transplantation is an independent risk factor for increased posttransplant mortality. Rivinius, R., Helmschrott, M., Ruhparwar, A., et al.[2022]

Oral digoxin significantly reduced liver damage, steatosis, and inflammation in mice with nonalcoholic steatohepatitis (NASH) induced by a high-fat diet, demonstrating its therapeutic potential.

The mechanism of action involves digoxin binding to pyruvate kinase isoform 2 (PKM2), inhibiting its activation of the hypoxia-inducible factor-1α (HIF-1α) pathway, which is linked to liver injury and inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation. Zhao, P., Han, SN., Arumugam, S., et al.[2020]

Digoxin, a commonly used cardiac glycoside, shows potential for repurposing in treating various non-cardiac conditions, including gastrointestinal diseases, obesity, cancer, and viral infections.

Recent research highlights digoxin's anti-inflammatory, antineoplastic, metabolic, and antimicrobial properties, suggesting it could significantly impact the treatment of several diseases beyond its traditional cardiac applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New uses for an old remedy: Digoxin as a potential treatment for steatohepatitis and other disorders. Jamshed, F., Dashti, F., Ouyang, X., et al.[2023]

In a review of 219 patients diagnosed with digoxin intoxication, only 20% were confirmed to have definite intoxication, indicating a high rate of misdiagnosis among those labeled as intoxicated.

Among 994 heart failure patients receiving digoxin, only 0.8% were definitively diagnosed with intoxication, suggesting that the actual incidence of digoxin intoxication may be much lower than previously reported rates of 6% to 23%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Mahdyoon, H., Battilana, G., Rosman, H., et al.[2019]

In a study involving 24 participants (12 patients with stable cirrhosis and 12 healthy volunteers), patients taking beta-methyldigoxin had significantly higher serum digoxin levels compared to healthy individuals, indicating altered drug metabolism in cirrhosis.

The study suggests that patients with cirrhosis are at a greater risk of digitalis toxicity when treated with beta-methyldigoxin due to factors like longer elimination half-life and reduced renal clearance, while beta-acetyldigoxin did not show this increased risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacokinetics of beta-methyldigoxin and beta-acetyldigoxin in patients with cirrhosis of the liver (author's transl)]. Rameis, H., Bonelli, J., Waginger, H., et al.[2013]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Mechanisms, manifestations, and management of digoxin toxicity in the modern era. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Changes in metildigoxin pharmacokinetics in cirrhosis of the liver: a comparison with beta-acetyldigoxin. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Characteristics and Outcomes of Suspected Digoxin Toxicity and Immune Fab Treatment Over the Past Two Decades-2000-2020. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Age- and gender-specific incidence of hospitalisation for digoxin intoxication. [2018]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Chronic digitalis therapy in patients before heart transplantation is an independent risk factor for increased posttransplant mortality. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

New uses for an old remedy: Digoxin as a potential treatment for steatohepatitis and other disorders. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. [2019]

9. Austria pubmed.ncbi.nlm.nih.gov

[Pharmacokinetics of beta-methyldigoxin and beta-acetyldigoxin in patients with cirrhosis of the liver (author's transl)]. [2013]