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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether digoxin, a medication typically used for heart conditions, can reduce inflammation in individuals with severe acute alcoholic hepatitis, a serious liver condition caused by excessive alcohol use. The study will compare administering digoxin through an IV to not administering it. The goal is to determine if digoxin can affect cytokine levels, which are markers of inflammation in the body. Individuals diagnosed with alcoholic hepatitis and experiencing symptoms like jaundice (yellowing of the skin or eyes) due to heavy drinking might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on assessing digoxin's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

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 there any evidence suggesting that digoxin is likely to be safe for humans?

Research has shown that a low dose of oral digoxin can affect the immune system in healthy individuals without causing harmful side effects, suggesting its potential safety. Although primarily used for heart problems, digoxin is also being tested for its impact on liver inflammation, such as in alcoholic hepatitis. One study found higher death rates in heart attack patients using digoxin, but this may not apply to its use in liver conditions. As this trial is in the early stages, researchers are carefully monitoring the treatment's safety in people with alcoholic hepatitis. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for alcoholic hepatitis?

Unlike the standard treatments for alcoholic hepatitis, which typically focus on managing symptoms and complications with steroids or supportive care, digoxin offers a unique approach by targeting the heart tissue. Researchers are excited about digoxin because it has the potential to improve liver function by enhancing blood flow and reducing inflammation. This treatment is administered intravenously, allowing for precise dosing based on weight and kidney function, which might result in a more personalized and effective therapy.

What evidence suggests that digoxin might be an effective treatment for alcoholic hepatitis?

Research has shown that digoxin may help reduce liver damage and swelling in animals with alcoholic liver disease. In these studies, animals given digoxin experienced less liver swelling, a major issue in alcoholic hepatitis. One study found that even small amounts of digoxin significantly lowered liver swelling and reduced certain immune cells responsible for this damage. Although no studies have yet examined digoxin for alcoholic hepatitis in humans, this trial will explore its potential benefits. Participants will be randomized into two groups: one will receive digoxin, while the other will not receive any study drug or placebo. Digoxin's ability to reduce liver swelling in other contexts is promising, suggesting it might help manage swelling in alcoholic hepatitis. ^{1 2 5 6 7}

Who Is on the Research Team?

Bubu Banini, MD, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-3-hepatitis-a-9-2021-980b2

Digoxin for Alcoholic Hepatitis (DIGIT-AlcHep Trial) It has been shown to reduce liver damage and inflammation in animal models, suggesting a novel approach compared to existing therapies.

2. cdek.liu.edu cdek.liu.edu/trial/NCT05014087/

Trial | NCT05014087 To date, there have been no clinical studies of digoxin use in patients with alcohol associated hepatitis.

3. journals.lww.com journals.lww.com/hep/fulltext/2014/10001/low_dose_digoxin_protects_from_nash_and_alcoholic.656.aspx

Low dose digoxin protects from NASH and alcoholic ... Starting digoxin after 4 weeks HFD still showed significant reduction in liver inflammation (neutrophil 24.6% in HFD vs 14.3% in HFD+DIG; monocytes 31.6% in HFD ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04216693

Digoxin for Patients With Non-alcoholic Steatohepatitis ... Study Overview. The purpose of this study is to assess if digoxin is safe and efficacious in treating patients with non-alcoholic steatohepatitis (NASH) within ...

5. researchgate.net researchgate.net/publication/335186915_Digoxin_improves_steatohepatitis_with_differential_involvement_of_liver_cell_subsets_in_mice_through_inhibition_of_PKM2_transactivation

Digoxin improves steatohepatitis with differential ... Digoxin significantly reduced HFD-induced hepatic damage, steatosis and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9321089/

Digoxin use and outcomes after myocardial infarction in ... Patients using digoxin after MI had a higher cumulative all‐cause mortality (77.4% vs. 72.3%; hazard ratio [HR]: 1.19; confidence interval [CI]: 1.07–1.32; p = ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06588699

Study Details | NCT06588699 | Digoxin In NASH (CODIN) The investigators preliminary data in healthy human subject indicate an immunomodulatory effect of low dose oral digoxin with no adverse side effects. This ...