Clinical trial NCT04216693: Digoxin for Patients With Non-alcoholic Steatohepatitis (NASH)
Official title: Efficacy and Safety of Digoxin in the Treatment of Adults Patients With Non-alcoholic Steatohepatitis: a Multi-center, Randomized, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Keywords: Nonalcoholic Steatohepatitis
Digoxin
Non-Alcoholic Fatty Liver Disease
Lead sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Sponsor class: OTHER
Collaborators: name: Yale University
First posted: 2020-01-03
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: This study is a phase II, open labeled, multi-center, prospective, randomized, placebo controlled clinical trial to evaluate the efficacy and safety of digoxin in the treatment of nonalcoholic steatohepatitis. The participants will take study drug digoxin, which is approved by FDA for the treatment of congestive heart failure (CHF), orally daily based on the body weight, titrated to the level of 0.7 to 1 ng/ml for total of 6 cycles (4 weeks/cycle). A liver biopsy will be performed at the beginning of the study and 24 weeks after randomization to evaluate the efficacy of digoxin in the treatment of nonalcoholic steatohepatitis.

Eligibility criteria: Inclusion Criteria:

1. Able to understand and willing to voluntarily sign an informed consent form (ICF) and Health Insurance Portability and Accountability Act (HIPAA) authorization.
2. Males or females between 18-70 years old with a clinically confirmed diagnosis of NASH within the last 12 months of Screening Visit.
3. BMI between 25 and 45 kg/m2.
4. Negative urine drugs-of-abuse screen.
5. Negative alcohol screen.
6. 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).
7. Normal EKG.
8. Deemed normal age-adjusted creatinine level.
9. NAS score greater than 5.
10. 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.

Exclusion Criteria:

1. Known cardiovascular disease
2. Subjects who have previously received digoxin or who have history of hypersensitivity, allergy, intolerance or contraindication to digoxin.
3. 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.
4. History of cirrhosis based on imaging or clinical criteria and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding.
5. Platelet count \< 100,000/ul
6. Albumin below 3.5 g/dl
7. Serum ferritin \> 800 ng/mL
8. Anti-neutrophil antibody above 1: 160
9. International normalized ratio (INR) \> 1.2History of liver transplantation
10. History of hepatocellular carcinoma (HCC)
11. 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
12. Active, serious infections that requires parenteral antibiotic or antifungal therapy within 30 days prior to Screening visit.
13. Any ≥Grade 3 laboratory abnormality as defined by Toxicity Grading Scale, with the following exceptions unless clinical assessment foresees an immediate health risk to the subject:

    * Subjects with pre-existing diabetes or with asymptomatic glucose ≥Grade 3 elevations;
    * Subjects with asymptomatic triglyceride or cholesterol ≥Grade 3 elevations;
    * Subjects with asymptomatic ALT and/or AST \> 4 time above normal
14. Females who are pregnant or breastfeeding.
15. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (such as systemic corticosteroids, interleukins, interferons).
16. Use of any experimental medications within the last 6 months of Screening Visit.
17. Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the dosing and protocol requirements.
18. Familial dyslipidemia.
19. Weight loss of \>5% within 6 months prior to Screening, based on subject's reporting
20. Currently or participated in a weight loss program within the last 6 months.
21. Any history of bariatric surgery.
22. Diabetes mellitus Type I
23. Daily alcohol intake \>20 ml (2 units)/day for women and 30 ml (3 units)/day for men (on average), as per Alcohol Use Disorders Identification Test (AUDIT) questionnaire at Screening and plan to consume the same alcohol amount referenced above during the trial.
24. Hemoglobin A1c \>9.0%
25. Treatment initiation or dose change within 3 months of Screening with Vitamin E, or any of the following anti- diabetic medications: DPP-4 inhibitor, GLP-1 receptor agonists (such as Januvia \[sitagliptin\], Byetta \[incretin\], etc.), pioglitazone, or SGLT2 inhibitors ("gliflozin" drugs), Metformin, fibrates, statins, insulin, Vitamin D, or sulfonylurea.
26. Use of any immunosuppressive medication, anti-inflammatory monoclonal antibody treatment, or chronic systemic corticosteroids \>10 mg prednisone-equivalent concurrently or within 1 year prior to Screening.
27. Uncontrolled or clinically unstable thyroid disease, in the judgment of the Principal Investigator.
28. History or presence of hepatitis B or C or human immunodeficiency virus (HIV).
29. Uncontrolled arterial hypertension
30. Any severe, acute, or chronic medical or psychiatric condition that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator's opinion, would make the subject inappropriate for entry into this study.

Primary outcomes:
measure: Two point change in histological NAFLD activity score (NAS)
timeFrame: Baseline, 24 weeks
measure: Proportion of subjects with at least a 30% change in % steatosis relative to screening
timeFrame: Baseline, 24 weeks
Secondary outcomes:
measure: Change in the mean concentration of serum aspartate aminotransferase (AST)
timeFrame: 0, 2, 4, 6, 11, 24 weeks
measure: Change in the mean concentration of serum alanine aminotransferase (ALT)
timeFrame: 0, 2, 4, 6, 11, 24 weeks
measure: Change in liver histological fibrosis staging
timeFrame: Baseline, 24 weeks
Other outcomes:
measure: Change in the mean concentration of serum inflammation markers
timeFrame: 0, 2, 4, 6, 11, 24 weeks
Locations:
city: Nanjing
country: China
facility: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
state: Jiangsu
Study officials:
References:
citation: 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.