Digoxin for Fatty Liver Disease

(CODIN Trial)

Recruiting at 1 trial location

Overseen By Tara McPartland

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must not be taking: Anti-arrhythmics, Inotropic drugs

Disqualifiers: Chronic liver disease, Cirrhosis, HIV, others

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: 24 weeks

144 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether digoxin, a drug typically used for heart issues, can treat nonalcoholic steatohepatitis (NASH), a serious liver condition linked to nonalcoholic fatty liver disease. Researchers aim to determine if digoxin can improve liver health and reduce liver fibrosis (scarring). The study includes different groups: one taking a placebo (a pill with no medicine) and others taking digoxin in various doses. Suitable candidates for this trial have NASH confirmed by a liver biopsy, stable body weight recently, and moderate liver fibrosis. As a Phase 2 trial, this research focuses on measuring digoxin's effectiveness in an initial, smaller group, offering participants a chance to contribute to potential new treatments for NASH.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot start or change doses of certain medications like vitamin E, pioglitazone, or GLP-1RA within 30 days before joining. Also, you cannot use medications that affect liver fat or certain heart medications during the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that digoxin helped regulate the immune system in healthy people without causing side effects. This finding suggests that low doses of digoxin are safe. Already used to treat heart problems like heart failure and certain irregular heartbeats, digoxin's established safety profile adds confidence. While more research is needed to determine its effectiveness for treating NASH (a type of liver disease), these findings suggest digoxin might be safe for this use as well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for fatty liver disease, which often focus on lifestyle changes and medications like vitamin E or pioglitazone, Digoxin offers a fresh approach by targeting cellular mechanisms differently. Digoxin, traditionally used for heart conditions, is being explored here for its potential to influence liver health via its effects on cellular ion balance and anti-inflammatory properties. Researchers are excited because Digoxin could offer a novel way to manage fatty liver disease, possibly improving outcomes beyond what current options achieve. Moreover, the trial explores two dosing strategies—titration-based and weight-based administration—which might optimize its effectiveness and safety for individual patients.

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

This trial will compare different dosing strategies of digoxin for treating nonalcoholic fatty liver disease (NAFLD). Research has shown that digoxin might help reduce liver damage in people with NAFLD, a condition similar to NASH. Studies have found that digoxin can help regulate the immune system, potentially protecting the liver from harm without causing side effects. Early results in healthy individuals suggest it can improve liver health. This makes digoxin a promising option for treating NASH and related liver scarring. ^{1 3 5 6 7}

Who Is on the Research Team?

Bubu A Banini, MD, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for individuals with a severe type of fatty liver disease called NASH, which can lead to fibrosis and cirrhosis. Participants should be looking for new treatments beyond lifestyle changes and management of related conditions like high blood pressure or diabetes.

Inclusion Criteria

My liver biopsy shows moderate to severe scarring.

My liver biopsy confirms I have NASH with a NAS score of 4 or higher.

I agree to a liver biopsy if I haven't had one in the last 6 months and another at 24 weeks after starting the trial.

Exclusion Criteria

I have a history of cirrhosis or signs of high blood pressure in the liver.

I haven't started or changed doses of certain diabetes or vitamin E medications in the last 30 days.

I understand and can follow the study's procedures.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either digoxin or placebo orally once daily for 24 weeks

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Digoxin

Trial Overview The CODIN trial is testing whether the heart medication digoxin can help treat NASH by protecting the liver and reducing fibrosis. Patients will either receive digoxin or a placebo (a pill without any active drug) to compare effects.

How Is the Trial Designed?

Group I: Digoxin (weight-based) Experimental Treatment 1 Intervention

Digoxin (weight-based) taken orally once daily. In the weight-based digoxin arm, the intervention will be oral digoxin 0.15mcg/kg/day.

Group II: Digoxin (titration-based) Experimental Treatment 1 Intervention

Digoxin (titration-based) taken orally once daily. In this arm, the intervention will be administered dosed by weight and renal function using a well-studied digoxin nomogram.

Group III: Placebo Placebo Group 1 Intervention

Placebo, taken orally once daily

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+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

In a phase 2 trial involving 140 patients with nonalcoholic steatohepatitis (NASH), cilofexor 100 mg daily for 24 weeks significantly reduced liver fat content by 22.7% compared to a placebo, indicating its efficacy in treating hepatic steatosis.

Cilofexor was generally well-tolerated, although moderate to severe itching was reported more frequently in the 100 mg group (14%) compared to the lower dose and placebo, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. Patel, K., Harrison, SA., Elkhashab, M., et al.[2021]

In a randomized double-blind placebo-controlled study of 52 overweight/obese patients with non-alcoholic steatohepatitis (NASH), montelukast significantly improved liver stiffness and various liver function markers after 12 weeks compared to placebo.

Montelukast was well tolerated and did not increase depressive symptoms, suggesting it could be a safe and effective treatment option for patients with NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The leukotriene receptor antagonist montelukast in the treatment of non-alcoholic steatohepatitis: A proof-of-concept, randomized, double-blind, placebo-controlled trial. Abdallah, MS., Eldeen, AH., Tantawy, SS., et al.[2021]

In a substudy of the DIG trial involving 589 patients with heart failure, digoxin therapy did not significantly improve health-related quality of life (HQOL) compared to placebo over 12 months.

While there was a slight improvement in perceived health at 4 months for the digoxin group, this benefit did not persist, and no significant differences were observed in various HQOL measures at the 12-month follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of digoxin on the quality of life in patients with heart failure. Lader, E., Egan, D., Hunsberger, S., et al.[2015]

Semaglutide significantly improves key indicators of non-alcoholic fatty liver disease (NAFLD), including the likelihood of non-alcoholic steatohepatitis (NASH) resolution and reductions in liver stiffness and liver enzymes, based on a meta-analysis of three randomized controlled trials involving 458 patients.

While semaglutide is effective in treating NAFLD and also promotes weight loss and better glycemic control, it does increase gastrointestinal side effects, although the overall risk of serious adverse events remains similar to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of semaglutide in non-alcoholic fatty liver disease. Zhu, K., Kakkar, R., Chahal, D., et al.[2023]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06588699

Study Details | NCT06588699 | Digoxin In NASH (CODIN) This study proposes to demonstrate the clinical benefits of digoxin on NASH and on liver fibrosis, thus supporting the repurposing of digoxin as treatment for ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6842989/

Digoxin improves steatohepatitis with differential ... Collectively, our results indicate that digoxin reduces liver injury in NAFLD ... Thus, digoxin has the ability to improve nonalcoholic fatty liver disease (NAFLD)/ ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04216693

Digoxin for Patients With Non-alcoholic Steatohepatitis ... This study is a phase II, open labeled, multi-center, prospective, randomized, placebo controlled clinical trial to evaluate the efficacy and safety of ...

4. withpower.com withpower.com/trial/digoxin-for-fatty-liver-disease-89ae9

Digoxin for Fatty Liver Disease (CODIN Trial) The investigators preliminary data in healthy human subject indicate an immunomodulatory effect of low dose oral digoxin with no adverse side effects. This ...

5. trial.medpath.com trial.medpath.com/clinical-trial/7e6b45db6d6bd0b1/clinical-trial-oral-digoxin-nash

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

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31411894/

Digoxin improves steatohepatitis with differential involvement ... Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range.

7. journals.plos.org journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0323880&type=printable

Identification of potentially effective drugs for metabolic ... The presence of MASLD was confirmed when a participant exhibited both hepatic steatosis (fatty liver index ≥ 60) and at least one of the five ...