Digoxin In NASH (CODIN) (CODIN)

Clinical Trial of Oral Digoxin In NASH (CODIN)

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.

Study Overview

• Status: Recruiting
• Conditions: NAFLD; NASH; Fatty Liver Disease; Fatty Liver Disease, Nonalcoholic; MASLD; MASH With Fibrosis; MASH - Metabolic Dysfunction-Associated Steatohepatitis; Mash
• Intervention / Treatment: Drug: Digoxin; Drug: Placebo

Detailed Description

Prospective, randomized, double-blind, placebo-controlled, single center trial of digoxin in patients with nonalcoholic steatohepatitis (NASH).

Primary objective:

To compare the effect of digoxin oral, administered once daily (QD) either as titration-based or weight-based dose, versus placebo on histologic resolution of NASH

Key secondary objectives:

To investigate the effect of digoxin oral, administered once daily (QD) either as titration-based or weight-based dose, compared to placebo on histologic, imaging, and biochemical markers of NASH, and to assess the safety and tolerability of digoxin compared to placebo

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bubu Banini, MD, PhD; Phone Number: 203-737-6063 or 203-215-7749; Email: bubu.banini@yale.edu
• Study Contact Backup: Name: Tara McPartland; Email: tara.mcpartland@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale New Haven Hospital
      • Contact: Bubu Banini, MD; Email: bubu.banini@yale.edu
      • Principal Investigator: Bubu Banini, MD
      • Contact: Aida Rodriguez Murillo; Email: aida.rodriguezmurillo@yale.edu
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale New Haven Health
      • Contact: Bubu Banini, MD; Email: bubu.banini@yale.edu
      • Principal Investigator: Bubu Banini, MD
      • Contact: Aida Rodriguez Murillo; Email: aida.rodriguezmurillo@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• 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
• Agrees to have a liver biopsy performed to assess baseline histology if one has not been performed up to 6 months before screening, and at 24 weeks after randomization Exclusion Criteria

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
• Current diagnosis of permanent atrial fibrillation
• Any of the following within the previous 6 months of signing informed consent: myocardial infarction, percutaneous intervention, pacemaker/implantable cardiac device implantation, cardiac surgery, or stroke
• Current use of the following medications: inotropic drugs such as (dopamine, dobutamine, noradrenaline, milrinone), anti-arrhythmics (amiodarone, dofetilide, sotalol, dronedarone, digoxin), parathyroid hormone analog (teriparatide), sympathomimetics (epinephrine, norepinephrine, dopamine), neuromuscular blocking agents (succinylcholine), calcium supplement, nondihydropyridine calcium channel blockers, ivabradine, and disulfiram.

Obesity related:

• Treatment initiation (in the 30 days prior to signing the informed consent or 30 days prior to liver biopsy) with orlistat, zonisamide, topiramate, phentermine, bupropion, and naltrexone alone or in combination or any other medication that could promote weight loss in the opinion of the investigator
• Participation (in the 30 days prior to signing the informed consent or 30 days prior to liver biopsy) in an organized diet-based weight reduction program (e.g., WeightWatchers, Optifast)
• Recent surgical treatment (<6 months of signing informed consent) for obesity

General safety related:

• Presence or history of malignant neoplasms (in the past 5 years prior to screening), except basal and squamous cell skin cancer and any carcinoma in-situ
• Surgery scheduled or anticipated during the trial period, except for minor surgical procedures, in the opinion of the investigator
• Language barrier, mental incapacity, unwillingness, or inability to adequately understand or comply with study procedures
• Known or suspected hypersensitivity to the trial product or related products including allergy to milk, egg, soy, peanuts, and sulfites
• Recent participation (within 90 days prior to signing the informed consent) in any clinical trial of an approved or non-approved investigational medicinal product
• Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using an adequate contraceptive method
• Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR < 30 ml/min/1.73 m2
• TSH > 6 mIU/L or < 0.4 mIU/L at screening
• Current use of the following medications: calcium supplementation, parathyroid hormone analog (teriparatide), neuromuscular blocking agents (succinylcholine) and disulfiram.
• Claustrophobia to an extent that would prevent tolerance of MRI
• Metallic implant that would prevent MRI examination including, metallic foreign body, aneurysm clips, vascular grafts or cardiac implants, neural stimulator, cochlear implant, metallic contraceptive device, body piercing that cannot be removed, cochlear implant, or any other contraindication to MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Digoxin (titration-based); 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; Taken orally once daily
Experimental: Digoxin (weight-based); 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; Taken orally once daily
Placebo Comparator: Placebo; Placebo, taken orally once daily	Drug: Placebo; Matched Placebo taken orally once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in liver fibrosis without worsening of NASH	Proportion of participants with improvement in liver fibrosis by ≥ 1 stage with no worsening of NASH (yes/no). Worsening of NASH is defined as ≥ 1 increase in lobular inflammation or hepatocyte ballooning according to criteria by the NASH clinical research network (NASH CRN)	24 weeks
Improvement in NAS without worsening of fibrosis	Proportion of participants with improvement in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 2 with no worsening of fibrosis after 24 weeks (yes/no)	24 weeks
Change in enhanced liver fibrosis (ELF) score	Change in Enhanced Liver Fibrosis (ELF) score.	24 weeks
Change in alanine aminotransferase (ALT)	Change in serum alanine aminotransferase (ALT) concentration (pg/ml)	24 weeks
Change in aspartate aminotransferase (AST)	Change in serum aspartate aminotransferase (AST) concentration (pg/ml)	24 weeks
Change in gamma glutamyl transferase (GGT)	Change in serum gamma glutamyl transferase (GGT) concentration (pg/ml)	24 weeks
Change in liver stiffness measure (LSM) and controlled attenuation parameter (CAP)	Change in liver stiffness measure (LSM) and controlled attenuation parameter (CAP) from baseline as measured by transient elastography.	24 weeks
Change in magnetic resonance imaging proton density fat fraction (MRI-PDFF)	Change in magnetic resonance imaging proton density fat fraction (MRI-PDFF)	24 weeks
Change in Magnetic resonance elastography (MRE)	Change from baseline in magnetic resonance elastography (MRE)	24 weeks

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Bubu A Banini, MD, PhD, Yale University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: September 6, 2024
• First Submitted That Met QC Criteria: September 6, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: NAFLD; NASH; Digoxin; Liver fibrosis; Fatty liver disease; Drug repurposing; MASH; Metabolic dysfunction associated steatohepatitis
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Fibrosis; Fatty Liver; Pathological Conditions, Signs and Symptoms; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Carbohydrates; Polycyclic Compounds; Glycosides; Steroids; Fused-Ring Compounds; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Digoxin
• Other Study ID Numbers: 2000038275; 1R01DK134624-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.
• IPD Sharing 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.
• IPD Sharing Access Criteria: Data from this study may be requested from researchers by contacting banini.research@yale.edu.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No