Fatty Liver Disease, Fatty Liver Disease, Nonalcoholic, Mash, MASH - Metabolic Dysfunction-Associated Steatohepatitis, MASH With Fibrosis, MASLD, NAFLD, NASH
Conditions
Keywords
NASH, MASH, Metabolic dysfunction associated steatohepatitis, Digoxin, Drug repurposing, Liver fibrosis, Fatty liver disease, NAFLD
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.
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
Interventions
DRUGDigoxin
Taken orally once daily
DRUGPlacebo
Matched Placebo taken orally once daily
Sponsors
Yale University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
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.
Intervention model description
A centrally administered randomization strategy will be used to randomize patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resolution of nonalcoholic steatohepatitis (NASH) without worsening of fibrosis | 24 weeks | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in liver fibrosis without worsening of NASH | 24 weeks | 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) |
| Improvement in NAS without worsening of fibrosis | 24 weeks | 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) |
| Change in enhanced liver fibrosis (ELF) score | 24 weeks | Change in Enhanced Liver Fibrosis (ELF) score. |
| Change in alanine aminotransferase (ALT) | 24 weeks | Change in serum alanine aminotransferase (ALT) concentration (pg/ml) |
| Change in aspartate aminotransferase (AST) | 24 weeks | Change in serum aspartate aminotransferase (AST) concentration (pg/ml) |
| Change in gamma glutamyl transferase (GGT) | 24 weeks | Change in serum gamma glutamyl transferase (GGT) concentration (pg/ml) |
| Change in liver stiffness measure (LSM) and controlled attenuation parameter (CAP) | 24 weeks | Change in liver stiffness measure (LSM) and controlled attenuation parameter (CAP) from baseline as measured by transient elastography. |
| Change in magnetic resonance imaging proton density fat fraction (MRI-PDFF) | 24 weeks | Change in magnetic resonance imaging proton density fat fraction (MRI-PDFF) |
| Change in Magnetic resonance elastography (MRE) | 24 weeks | Change from baseline in magnetic resonance elastography (MRE) |
Countries
United States
Contacts
CONTACTBubu Banini, MD, PhD
CONTACTTara McPartland
PRINCIPAL_INVESTIGATORBubu A Banini, MD, PhD
Yale University
Outcome results
None listed