Digoxin In Treatment of Alcohol Associated Hepatitis

NCT05014087 | Terminated Phase 2 DMC FDA Drug

• 1 other identifier: 2000030659
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Prospective, single center, open label, randomized controlled trial to explore whether digoxin treatment affects cytokine levels as biomarkers of inflammation in patients with acute alcohol associated hepatitis, digoxin administration and dose adjustment. The study intervention will be intravenous digoxin (renal-based dosing for maximum of 28 days) versus no digoxin in an open-label 1:1 randomized allocation of patients with severe acute alcohol associated hepatitis.

Conditions

Acute Alcoholic Hepatitis; Chemical and Drug Induced Liver Injury; Alcohol-Induced Disorders; Steatohepatitis Caused by Ingestible Alcohol

Keywords

Acute alcoholic hepatitis; Liver injury; Liver inflammation; Liver disease; Digoxin

Outcome Measures

Primary Outcomes (1)

• Change in biomarkers of inflammation

  Change in biomarkers of inflammation cytokine levels (pg/mL) in participants with acute alcohol associated hepatitis treated with digoxin versus no digoxin at day 3 of the study .

  day 3

Secondary Outcomes (6)

• Practicality of daily digoxin measurements

  Up to 28 days

• Feasibility of digoxin dosing in a timely manner.

  Up to 28 days

• Feasibility of digoxin dose adjustments in renal insufficiency.

  Up to 28 days

• Mortality at 7, 14, 28, 90 days. All cause mortality of patients enrolled in the trial.

  Up to 90 days

• Development of ECG abnormalities

  Up to 28 days

Other Outcomes (10)

• Organ dysfunction (Liver - Lille Score)

  Up to 28 days

• Organ dysfunction (Liver) with Model for End-stage Liver Disease (MELD)

  Up to 28 days

• Organ dysfunction (Liver Enzyme: Bilirubin)

  Up to 28 days

Study Arms (2)

Arm A: Digoxin

EXPERIMENTAL

In the digoxin arm, the intervention to be administered will be intravenous digoxin dosed by weight and by renal function using an adaption of the established FDA nomogram. Participants randomized to digoxin will receive an intravenous digoxin loading dose administered in 3 doses over 24 hours starting on Day 1. Digoxin levels will be monitored daily throughout the participant's hospital stay, to a maximum of 28 days. Digoxin will be discontinued at the time discharge if before 28 days.

Drug: Intravenous digoxin

Arm B: No Digoxin

NO INTERVENTION

In the no digoxin arm, no study drug or placebo will be administered.

Interventions

Intravenous digoxin DRUG

Loading dose: the total loading dose of digoxin will be determined using the Loading nomogram. The FDA-recommended total IV digoxin loading dose range is 8 to 12 mcg/kg. The lowest recommended dose of 8 mcg/kg was used in constructing the digoxin Loading nomogram that will be used in this trial. Maintenance dose: the maintenance dose will be started approximately 24 hours after initiation of digoxin loading. The post-loading digoxin trough will be reviewed prior to starting maintenance dosing. Subjects on P-gp inhibitors or spironolactone, will have an additional digoxin level performed 12-hours after any dose adjustment. Once digoxin levels are stable, 24-hour blood draws will be performed.

Also known as: Lanoxin

Arm A: Digoxin

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Diagnosis of alcohol associated hepatitis based on clinical criteria or histologic evidence
• Clinical criteria:
• Onset of jaundice (bilirubin \>3 mg/dL) within the prior 8 weeks
• Regular alcohol use \> 6 months, with intake of \> 40 g/day (\>280 g/week) for women; and \> 60 g/day (\>420 g/week) for men
• AST \> 50 IU/l
• AST: ALT \> 1.5 and both values \< 400 IU/l
• Histological evidence of alcohol associated hepatitis\*
• \. MDF \>32 or MELD ≥ 20 to ≤ 35 on Day 0 of the trial
• \. Age between 21 and 70 years, inclusive
• \* In patients with possible alcohol associated hepatitis with confounding factors such as possible ischemic hepatitis, possible DILI, uncertain history of alcohol use, or atypical/abnormal laboratory tests (e.g., AST \< 50 IU/IU/L or \> 400 IU/IU/L, AST/ALT ratio \< 1.5), antinuclearantibody \> 1:160 or SMA \> 1:80, standard of care liver biopsy may be performed as per discretion of the primary attending physician to confirm alcohol associated hepatitis and exclude competing etiologies. The decision to perform liver biopsy will be made by the primary team and will occur regardless of the study. As per current SOC, a liver biopsy may be obtained to confirm suspected alcohol-associated hepatitis and to rule out other potential etiologies of liver disease.
• If a liver biopsy is performed for clinically indicated reasons, we will store liver tissue that is left over after the portion needed for the primary indication has been identified.

You may not qualify if:

• \- Currently pregnant or breastfeeding
• \- Inability of patient, legally authorized representative or next-of-kin to provide informed consent
• \- Allergy or intolerance to digoxin
• \- Clinically active C. diff infection
• \- Positive test for COVID-19 within 14 days prior to the screening visit
• \- Acute hepatitis E, Cytomegalovirus, Epstein Barr Virus, Herpes Simplex Virus
• History of other liver diseases including hepatitis B (positive HBsAg or HBV DNA), hepatitis 8-C (positive HCV RNA), autoimmune hepatitis, Wilson disease, genetic hemochromatosis, alpha1-antitrypsin deficiency.
• Diagnosis of Drug Induced Liver Injury (DILI), or other etiologies seen on liver imaging.
• History of HIV infection (positive HIV RNA or on treatment for HIV infection)
• Current diagnosis of cancer
• Renal failure defined by GFR \<30 mL/min
• Refractory ascites, defined as having more than 4 paracenteses in the preceding 8 weeks despite diuretic therapy
• Prior exposure to experimental therapies or other clinical trial in last 3 months
• Current acute or chronic pancreatitis
• Active gastrointestinal bleeding unless resolved for \>48 hours

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale New Haven Hospital, Yale School of Medicine

New Haven, Connecticut, 06510, United States

Location

Related Publications (25)

• Maddrey WC, Boitnott JK, Bedine MS, Weber FL Jr, Mezey E, White RI Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology. 1978 Aug;75(2):193-9.

  PMID: 352788 BACKGROUND

• Sahlman P, Nissinen M, Pukkala E, Farkkila M. Incidence, survival and cause-specific mortality in alcoholic liver disease: a population-based cohort study. Scand J Gastroenterol. 2016 Aug;51(8):961-6. doi: 10.3109/00365521.2016.1157889. Epub 2016 May 16.

  PMID: 27181618 BACKGROUND

• Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S, Masson S, McCune A, Mellor J, O'Grady J, Patch D, Ratcliffe I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S, Forrest EH; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619-28. doi: 10.1056/NEJMoa1412278.

  PMID: 25901427 BACKGROUND

• Scalese MJ, Salvatore DJ. Role of Digoxin in Atrial Fibrillation. J Pharm Pract. 2017 Aug;30(4):434-440. doi: 10.1177/0897190016642361. Epub 2016 Apr 10.

  PMID: 27067743 BACKGROUND

• 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 BACKGROUND

• Arteel GE, Iimuro Y, Yin M, Raleigh JA, Thurman RG. Chronic enteral ethanol treatment causes hypoxia in rat liver tissue in vivo. Hepatology. 1997 Apr;25(4):920-6. doi: 10.1002/hep.510250422.

  PMID: 9096598 BACKGROUND

• Lee YS, Kim JW, Osborne O, Oh DY, Sasik R, Schenk S, Chen A, Chung H, Murphy A, Watkins SM, Quehenberger O, Johnson RS, Olefsky JM. Increased adipocyte O2 consumption triggers HIF-1alpha, causing inflammation and insulin resistance in obesity. Cell. 2014 Jun 5;157(6):1339-1352. doi: 10.1016/j.cell.2014.05.012.

  PMID: 24906151 BACKGROUND

• Nath B, Levin I, Csak T, Petrasek J, Mueller C, Kodys K, Catalano D, Mandrekar P, Szabo G. Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology. 2011 May;53(5):1526-37. doi: 10.1002/hep.24256.

  PMID: 21520168 BACKGROUND

• Palmer BF, Clegg DJ. Ascent to altitude as a weight loss method: the good and bad of hypoxia inducible factor activation. Obesity (Silver Spring). 2014 Feb;22(2):311-7. doi: 10.1002/oby.20499. Epub 2013 Oct 15.

  PMID: 23625659 BACKGROUND

• Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012 Feb 3;148(3):399-408. doi: 10.1016/j.cell.2012.01.021.

  PMID: 22304911 BACKGROUND

• Hollman A. Drugs for atrial fibrillation. Digoxin comes from Digitalis lanata. BMJ. 1996 Apr 6;312(7035):912. doi: 10.1136/bmj.312.7035.912. No abstract available.

  PMID: 8611904 BACKGROUND

• Digoxin FDA insert. . [cited 2021 3/15/2021]

  BACKGROUND

• (CDC)., C.f.D.C.a.P. Alcohol and Public Health: Alcohol-Related Disease Impact (ARDI). Annual Average for United States 2011-2015 Alcohol-Attributable Deaths Due to Excessive Alcohol Use, All Ages. [cited 2021 3/20/2021]

  BACKGROUND

• (NIH)., N.I.o.H. Alcohol Facts and Statistics. [cited 2021 3/20/2021]

  BACKGROUND

• Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003 Feb 19;289(7):871-8. doi: 10.1001/jama.289.7.871.

  PMID: 12588271 BACKGROUND

• Ouyang AJ, Lv YN, Zhong HL, Wen JH, Wei XH, Peng HW, Zhou J, Liu LL. Meta-analysis of digoxin use and risk of mortality in patients with atrial fibrillation. Am J Cardiol. 2015 Apr 1;115(7):901-6. doi: 10.1016/j.amjcard.2015.01.013. Epub 2015 Jan 14.

  PMID: 25660972 BACKGROUND

• Dasgupta A. Endogenous and exogenous digoxin-like immunoreactive substances: impact on therapeutic drug monitoring of digoxin. Am J Clin Pathol. 2002 Jul;118(1):132-40. doi: 10.1309/3VNP-TWFQ-HT9A-1QH8.

  PMID: 12109847 BACKGROUND

• Yang SS, Hughes RD, Williams R. Digoxin-like immunoreactive substances in severe acute liver disease due to viral hepatitis and paracetamol overdose. Hepatology. 1988 Jan-Feb;8(1):93-7. doi: 10.1002/hep.1840080119.

  PMID: 2828215 BACKGROUND

• Rosenkranz B, Frolich JC. Falsely elevated digoxin concentrations in patients with liver disease. Ther Drug Monit. 1985;7(2):202-6. doi: 10.1097/00007691-198506000-00011.

  PMID: 4024214 BACKGROUND

• Nikou GC, Vyssoulis GP, Venetikou MS, Karga HI, Karoutsos KA, Toutouzas PK. Digoxin-like substance(s) interfere(s) with serum estimations of the drug in cirrhotic patients. J Clin Gastroenterol. 1989 Aug;11(4):430-3. doi: 10.1097/00004836-198908000-00016.

  PMID: 2547866 BACKGROUND

• Digoxin conversion calculator.

  BACKGROUND

• O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology. 2010 Jan;51(1):307-28. doi: 10.1002/hep.23258. No abstract available.

  PMID: 20034030 BACKGROUND

• Bode C, Bode JC. Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol. 2003 Aug;17(4):575-92. doi: 10.1016/s1521-6918(03)00034-9.

  PMID: 12828956 BACKGROUND

• Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcohol associated Hepatitis (AlcHepNet). [cited 2021 03/29]

  BACKGROUND

• R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing 2020

  BACKGROUND

MeSH Terms

Conditions

Chemical and Drug Induced Liver Injury; Alcohol-Induced Disorders; Fatty Liver, Alcoholic; Hepatitis; Liver Diseases

Interventions

Digoxin

Condition Hierarchy (Ancestors)

Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning; Alcohol-Related Disorders; Substance-Related Disorders; Fatty Liver; Liver Diseases, Alcoholic

Intervention Hierarchy (Ancestors)

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

Study Officials

• Bubu Banini, MD, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

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: Assistant Professor of Internal Medicine

Model Details: Prospective, single center, open label, randomized 1:1 controlled trial.

Study Record Dates

• First Submitted: July 20, 2021
• First Posted: August 20, 2021
• Study Start: October 8, 2021
• Primary Completion: June 22, 2025
• Study Completion: September 12, 2025
• Last Updated: October 9, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)