Recruiting
Phase 2

Digoxin

Sponsor:

Yale University

Code:

NCT06588699

Conditions

NASH

NAFLD

MASH - Metabolic Dysfunction-Associated Steatohepatitis

Mash

MASH With Fibrosis

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

Interventions

Digoxin

Placebo

Study Details

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

Study ID

NCT06588699

Start date

Jun 5, 2025

Status verified date

Mar, 2026

Completion date

Jan, 2029

Anticipated

Primary completion date

Jan, 2029

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

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 Design

Enrollment

144 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

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.

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.

placebo comparator: Placebo

Placebo, taken orally once daily

Interventions

Digoxin

Taken orally once daily

Placebo

Matched Placebo taken orally once daily

Primary outcome measure

  • Resolution of nonalcoholic steatohepatitis (NASH) without worsening of fibrosis [ Time Frame: 24 weeks ]

Central Contacts and Locations

Central contacts

Bubu Banini, MD, PhD

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

Tara McPartland

tara.mcpartland@yale.edu

Locations

Yale New Haven Health

Recruiting

New Haven, Connecticut, United States, 06510

Contacts

Bubu Banini, MD

bubu.banini@yale.edu

Aida Rodriguez Murillo

aida.rodriguezmurillo@yale.edu

Principal Investigator:

Bubu Banini, MD

Yale New Haven Hospital

Recruiting

New Haven, Connecticut, United States, 06510

Contacts

Bubu Banini, MD

bubu.banini@yale.edu

Aida Rodriguez Murillo

aida.rodriguezmurillo@yale.edu

Principal Investigator:

Bubu Banini, MD

More Information

Sponsor

Yale University

Last update posted

May 26, 2026

Last verified

Mar, 2026

Keywords

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

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Yale University on 2026-05-26.