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.

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

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

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.

Data from this study may be requested from researchers 2 years after the completion of the primary endpoint by contacting banini.research@yale.edu.

Data from this study may be requested from researchers by contacting banini.research@yale.edu.

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.