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

Trial Summary

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 digoxin generally safe for humans?

Digoxin has been used for many years, primarily for heart conditions, and its safety profile is well-known. However, there is a risk of toxicity, especially in women and people with liver issues, so monitoring and proper dosing are important. ^{1 2 3 4 5}

How is the drug Digoxin unique for treating fatty liver disease?

Digoxin is unique for treating fatty liver disease because it is traditionally used for heart conditions, and its use for liver disease is novel, as there are no standard drug treatments specifically approved for fatty liver disease. ^{6 7 8 9 10}

What is the purpose of this trial?

Nonalcoholic steatohepatitis (NASH) is a severe subtype of nonalcoholic fatty liver disease (NAFLD) which affects 1 in 3 Americans. The mainstay of treatment for NASH, which was recently renamed metabolic associated steatohepatitis (MASH), involves lifestyle interventions to promote weight loss and to treat comorbidities such as hypertension, hyperlipidemia, and diabetes mellitus. There is thus, a substantial unmet need for pharmacological therapies that are effective for treatment of NASH, especially in those with fibrosis which is the main predictor of disease progression and mortality among NASH patients. The repurposing of presently available drugs would help expedite the search for agents effective in treating NASH. The cardiac glycoside digoxin is currently used in the management of heart failure and supraventricular tachyarrhythmias. The investigators and other groups have demonstrated that digoxin protects the liver from various forms of acute and chronic liver injury. The investigators preliminary data in healthy human subject indicate an immunomodulatory effect of low dose oral digoxin with no adverse side effects. 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 NASH.

Research Team

Bubu A Banini, MD, PhD

Principal Investigator

Yale University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Changes in digoxin pharmacokinetics associated with hepatic P-glycoprotein upregulation in rats with non-alcoholic fatty liver disease. [2022]

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

The effect of digoxin on the quality of life in patients with heart failure. [2015]

4. Germany pubmed.ncbi.nlm.nih.gov

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

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

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

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

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Treatment options for managing atherogenic dyslipidemia and fatty liver disease. [2018]

9. Netherlands 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. [2021]

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

Efficacy and safety of semaglutide in non-alcoholic fatty liver disease. [2023]