Digoxin for Patients With Non-alcoholic Steatohepatitis (NASH)

NCT04216693 | Withdrawn Phase 2

• 1 other identifier: v1.0 20200101
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to assess if digoxin is safe and efficacious in treating patients with non-alcoholic steatohepatitis (NASH) within the approved target range of 0.7 to 1 ng/ml.

Conditions

Nonalcoholic Steatohepatitis

Keywords

Nonalcoholic Steatohepatitis; Digoxin; Non-Alcoholic Fatty Liver Disease

Outcome Measures

Primary Outcomes (2)

• Two point change in histological NAFLD activity score (NAS)

  Non-alcoholic fatty liver disease score (NAS) is a histological classification to assess the severity of liver steatosis, lobular inflammation and ballooning in the liver biopsy, which ranges from 0-8 with the increase in number representing a worse outcome. Therefore, the efficacy improvement was to be at least 2 points in lowering the score.

  Baseline, 24 weeks

• Proportion of subjects with at least a 30% change in % steatosis relative to screening

  Liver steatosis is graded based on the percentage of fat within the hepatocytes: grade 0 (healthy, \<5%), grade 1 (mild, 5%-33%), grade 2 (moderate, 34%-66%), and grade 3 (severe, \>66%). the efficacy improvement was to be proportion of subjects with at least a 30% decrease in % steatosis relative to screening.

  Baseline, 24 weeks

Secondary Outcomes (3)

• Change in the mean concentration of serum aspartate aminotransferase (AST)

  0, 2, 4, 6, 11, 24 weeks

• Change in the mean concentration of serum alanine aminotransferase (ALT)

  0, 2, 4, 6, 11, 24 weeks

• Change in liver histological fibrosis staging

  Baseline, 24 weeks

Other Outcomes (1)

• Change in the mean concentration of serum inflammation markers

  0, 2, 4, 6, 11, 24 weeks

Study Arms (2)

Digoxin tablet

EXPERIMENTAL

Patients will be given digoxin orally daily for 24 weeks. The initial dose will be selected with the goal of achieving a serum digoxin concentration of 0.7-1 ng/ml, a dose range recommended for heart failure patients. A dose of 0.0625, 0.125 or 0.25 mg daily will be selected based on a normogram.

Drug: Digoxin tablet

Placebo

PLACEBO COMPARATOR

Digoxin-like oral placebo

Other: Placebo

Interventions

Digoxin tablet DRUG

The NASH patients in experimental group will take digoxin tablets orally with the goal of achieving a serum digoxin concentration of 0.7-1 ng/ml for 24 weeks.

Digoxin tablet

Placebo OTHER

The control group will receive the digoxin-like placebo treatment.

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to understand and willing to voluntarily sign an informed consent form (ICF) and Health Insurance Portability and Accountability Act (HIPAA) authorization.
• Males or females between 18-70 years old with a clinically confirmed diagnosis of NASH within the last 12 months of Screening Visit.
• BMI between 25 and 45 kg/m2.
• Negative urine drugs-of-abuse screen.
• Negative alcohol screen.
• Negative urine pregnancy test and agree to use a medically acceptable method of contraception throughout the study and for 1 month after completing the study. Medically acceptable methods of contraception that may be used by the subject and/or partner include, but are not limited to: abstinence, oral contraception, NuvaRing® or transdermal systems, diaphragm with vaginal spermicide, intra uterine device, condom and partner using vaginal spermicide, at least 6 months after surgical sterilization, progestin implant or injection, or postmenopausal female (no menstrual period for \> 2 years) or vasectomy (\>6 months).
• Normal EKG.
• Deemed normal age-adjusted creatinine level.
• NAS score greater than 5.
• Steatosis greater than 8% on liver biopsy. Able and willing to comply with the protocol and available for all scheduled clinic visits and telephone calls.

You may not qualify if:

• Known cardiovascular disease
• Subjects who have previously received digoxin or who have history of hypersensitivity, allergy, intolerance or contraindication to digoxin.
• Requiring any of the following medications during the duration of the study:
• Potassium-depleting diuretics
• Calcium, particularly if administered rapidly by the intravenous route
• Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, erythromycin, clarithromycin (and possibly other macrolide antibiotics), tetracycline, propantheline, diphenoxylate, antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, metoclopramide, rifampin, quinine, penicillamine, thyroid hormone, sympathomimetics. Succinylcholine, calcium channel blockers, beta-blockers, carvedilol, and any drug that may cause a significant deterioration in renal function.
• History of cirrhosis based on imaging or clinical criteria and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding.
• Platelet count \< 100,000/ul
• Albumin below 3.5 g/dl
• Serum ferritin \> 800 ng/mL
• Anti-neutrophil antibody above 1: 160
• International normalized ratio (INR) \> 1.2History of liver transplantation
• History of hepatocellular carcinoma (HCC)
• History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous carcinoma at the time of Screening visit
• Active, serious infections that requires parenteral antibiotic or antifungal therapy within 30 days prior to Screening visit.

Sponsors & Collaborators

• The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School: lead
• Yale University: collaborator

Study Sites (1)

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Nanjing, Jiangsu, 210008, China

Location

Related Publications (1)

• Ouyang X, Han SN, Zhang JY, Dioletis E, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Starkel P, Caballeria J, Pongratz RL, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Garcia-Martinez I, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ. Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1alpha Transactivation in Steatohepatitis. Cell Metab. 2018 Feb 6;27(2):339-350.e3. doi: 10.1016/j.cmet.2018.01.007.

  PMID: 29414684 RESULT

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Digoxin

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor; Director of the department of hepatobiliary surgery; Doctor

Study Record Dates

• First Submitted: December 31, 2019
• First Posted: January 3, 2020
• Study Start: June 1, 2020
• Primary Completion: December 1, 2022
• Study Completion: June 1, 2023
• Last Updated: February 22, 2023

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)