Digoxin In NASH (CODIN)

NCT06588699 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: 20000382751R01DK134624-01A1
• Study Type: interventional
• Target: 144
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

NASH; NAFLD; MASH - Metabolic Dysfunction-Associated Steatohepatitis; Mash; MASH With Fibrosis; MASLD; Fatty Liver Disease; Fatty Liver Disease, Nonalcoholic

Keywords

NASH; MASH; Metabolic dysfunction associated steatohepatitis; Digoxin; Drug repurposing; Liver fibrosis; Fatty liver disease; NAFLD

Outcome Measures

Primary Outcomes (1)

• Resolution of nonalcoholic steatohepatitis (NASH) without worsening of fibrosis

  Proportion of participants who achieve resolution of NASH (defined by the NASH Clinical research network \[CRN\] as a score of 0-1 for inflammation, 0 for hepatocyte ballooning, and any value for steatosis) with no worsening of fibrosis (yes/no).

  24 weeks

Secondary Outcomes (9)

• Improvement in liver fibrosis without worsening of NASH

  24 weeks

• Improvement in NAS without worsening of fibrosis

  24 weeks

• Change in enhanced liver fibrosis (ELF) score

  24 weeks

• Change in alanine aminotransferase (ALT)

  24 weeks

• Change in aspartate aminotransferase (AST)

  24 weeks

Study Arms (3)

Digoxin (titration-based)

EXPERIMENTAL

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.

Drug: Digoxin

Digoxin (weight-based)

EXPERIMENTAL

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

Drug: Digoxin

Placebo

PLACEBO COMPARATOR

Placebo, taken orally once daily

Drug: Placebo

Interventions

Digoxin DRUG

Taken orally once daily

Digoxin (titration-based); Digoxin (weight-based)

Placebo DRUG

Matched Placebo taken orally once daily

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Stable body weight (≤ 5% self-reported change in body weight) in the 30 days prior to screening
• Biopsy-confirmed non-alcoholic steatohepatitis (NASH) as defined by the NASH clinical research network (NASH CRN) histological scoring system, with non-alcoholic fatty liver disease score (NAS) ≥4 and with a score ≥1 for each of the three components (steatosis, hepatocellular ballooning, and lobular inflammation) on a liver biopsy performed within 6 months of screening
• Histological fibrosis stage 2 or 3 based on pathologist evaluation of a liver biopsy performed up to 6 months before screening

You may not qualify if:

• Liver-related:
• Documented causes of chronic liver disease other than NASH
• History or clinical evidence of cirrhosis or portal hypertension
• History of positive HBsAg, positive anti-HIV, positive HCV-RNA
• AST or ALT \> 5 times upper limit of normal (ULN) at screening
• Total bilirubin \> 1.5 mg/dL at screening unless conjugated bilirubin is \< 1.5 × ULN
• International normalized ratio (INR) \> 1.3 at screening
• Known or suspected alcohol use \> 20 g/day for women or \> 30 g/day for men
• Treatment initiation or dose adjustment of vitamin E, pioglitazone, GLP-1RA, or SGLT-2 inhibitors within 30 days of signing the informed consent or 30 days prior to liver biopsy
• Treatment initiation or anticipated treatment (\>14 consecutive days) with medications known to affect steatosis (e.g., systemic corticosteroids, tamoxifen, valproic acid, methotrexate, tetracycline or amiodarone) within 30 days of signing the informed consent or 30 days prior to liver biopsy
• Cardiac related:
• Heart rate less than 60 bpm at screening (visit 1) or at baseline (visit 2)
• Current diagnosis of severe aortic valve disease
• History of Accessory arterio-ventricular pathway (e.g., Wolf-Parkinson-White syndrome)
• History of complete heart block or second degree arterio-ventricular block without pacemaker or implantable cardiac device

Sponsors & Collaborators

• Yale University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (2)

Yale New Haven Health

New Haven, Connecticut, 06510, United States

RECRUITING

Yale New Haven Hospital

New Haven, Connecticut, 06510, United States

RECRUITING

Related Publications (4)

• Jamshed F, Dashti F, Ouyang X, Mehal WZ, Banini BA. New uses for an old remedy: Digoxin as a potential treatment for steatohepatitis and other disorders. World J Gastroenterol. 2023 Mar 28;29(12):1824-1837. doi: 10.3748/wjg.v29.i12.1824.

  PMID: 37032732 BACKGROUND

• Dashti F, Jamshed F, Ouyang X, Mehal WZ, Banini BA. Digoxin as an emerging therapy in noncardiac diseases. Trends Pharmacol Sci. 2023 Apr;44(4):199-203. doi: 10.1016/j.tips.2022.10.002. Epub 2022 Nov 14.

  PMID: 36396496 BACKGROUND

• Agyapong G, Dashti F, Banini BA. Nonalcoholic liver disease: Epidemiology, risk factors, natural history, and management strategies. Ann N Y Acad Sci. 2023 Aug;1526(1):16-29. doi: 10.1111/nyas.15012. Epub 2023 Jul 3.

  PMID: 37400359 BACKGROUND

• Ilagan-Ying YC, Banini BA, Do A, Lam R, Lim JK. Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice. Curr Gastroenterol Rep. 2023 Oct;25(10):213-224. doi: 10.1007/s11894-023-00883-8. Epub 2023 Sep 28.

  PMID: 37768417 BACKGROUND

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Liver Cirrhosis

Interventions

Digoxin

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates

Study Officials

• Bubu A Banini, MD, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bubu Banini, MD, PhD

CONTACT

203-737-6063 or 203-215-7749; bubu.banini@yale.edu

Tara McPartland

CONTACT

tara.mcpartland@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The trial is a double-blind placebo controlled trial to assess the effect of digoxin oral, versus placebo, on histologic improvement of NASH. Study team members will be blinded except for the unblinded pharmacist and the individual monitoring digoxin level.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: A centrally administered randomization strategy will be used to randomize patients.

Study Record Dates

• First Submitted: September 6, 2024
• First Posted: September 19, 2024
• Study Start: June 5, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029
• Last Updated: October 31, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data from this study may be requested from researchers 2 years after the completion of the primary endpoint by contacting banini.research@yale.edu.
• Access Criteria: Data from this study may be requested from researchers by contacting banini.research@yale.edu.

Locations

US (2)