Digoxin In Treatment of Alcohol Associated Hepatitis

Alcohol-Induced Disorders Clinical Trial

— DIGIT-AlcHep  

Official title:

Digoxin In Treatment of Alcohol Associated Hepatitis (DIGIT-AlcHep)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05014087
• Other study ID #: 2000030659
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 8, 2021
• Est. completion date: April 2025

Study information

• Verified date: June 2024
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Prospective, single center, open label, randomized controlled trial to determine the feasibility of conducting a future study with respect to patient recruitment, 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.

Description:

Severe alcohol associated hepatitis is a condition of acute on chronic immune liver dysfunction that is associated with high mortality, necessitating a search for drugs that may prove safe and efficacious in treating this disease. Pre-clinical studies suggest that digoxin, which is currently used for treating cardiac conditions, is also effective in improving alcohol-associated liver injury. To date, there have been no clinical studies of digoxin use in patients with alcohol associated hepatitis. The primary objective of this study of digoxin versus no digoxin in patients with severe alcohol associated hepatitis is to assess the feasibility of conducting a large randomized trial to detect efficacy with respect to patient recruitment, digoxin administration and dose adjustment in patients hospitalized with severe alcohol associated hepatitis.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: April 2025
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of alcohol associated hepatitis based on clinical criteria or histologic evidence

1. 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

2. Histological evidence of alcohol associated hepatitis

2. MDF >32 or MELD = 20 to = 35 on Day 0 of the trial

3. Age between 21 and 70 years, inclusive

Exclusion Criteria:

1. - Currently pregnant or breastfeeding

2. - Inability of patient, legally authorized representative or next-of-kin to provide informed consent

3. - Allergy or intolerance to digoxin

4. - Clinically active C. diff infection

5. - Positive test for COVID-19 within 14 days prior to the screening visit

6. - Acute hepatitis E, Cytomegalovirus, Epstein Barr Virus, Herpes Simplex Virus

7- 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.

8-Diagnosis of Drug Induced Liver Injury (DILI), or other etiologies seen on liver imaging.

9 - History of HIV infection (positive HIV RNA or on treatment for HIV infection)

10 - Current diagnosis of cancer

11- Renal failure defined by GFR <30 mL/min

12 - Refractory ascites, defined as having more than 4 paracenteses in the preceding 8 weeks despite diuretic therapy

13 - Prior exposure to experimental therapies or other clinical trial in last 3 months

14 - Current acute or chronic pancreatitis

15 - Active gastrointestinal bleeding unless resolved for >48 hours

16 - Experiencing withdrawal seizures or considered at high risk for alcohol withdrawal seizures or delirium tremens

17 - Heart rate less than 60 bpm at screening visit or at baseline

18 - Current diagnosis of atrial fibrillation

19 - Cardiomyopathy

20 - Heart failure

21 - Severe aortic valve disease

22 - Presence of Accessory arterio-ventricular pathway (eg Wolf-Parkinson-White syndrome)

23 - Complete heart block or second degree arterio-ventricular block without pacemaker or implantable cardiac device

24 - Any of the following within the previous 6 months: myocardial infarction, percutaneous intervention, pacemaker/implantable cardiac device implantation, cardiac surgery or stroke

25 - Current use of the following medications:

• Antiarrhythmic (amiodarone, dofetilide, sotalol, dronedarone)

• Parathyroid hormone analog (teriparatide)

• Thyroid supplement (thyroid, levothyroxine sodium)

• Sympathomimetics or ionotropic drugs (epinephrine, norepinephrine, dopamine, dobutamine, milrinone)

• Neuromuscular blocking agents (succinylcholine)

• Calcium supplement

• Ivabradine

• Disulfiram

Related Conditions & MeSH terms

• Acute Alcoholic Hepatitis
• Alcohol-Induced Disorders
• Chemical and Drug Induced Liver Injury
• Fatty Liver
• Hepatitis
• Hepatitis A
• Hepatitis, Alcoholic

Intervention

Drug:
• Intravenous digoxin
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.

Locations

Country	Name	City	State
United States	Yale New Haven Hospital, Yale School of Medicine	New Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Yale University

Country where clinical trial is conducted

United States, 

References & Publications (25)

(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]

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

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. — View Citation

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. — View Citation

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. — View Citation

Digoxin conversion calculator.

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View 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. Erratum In: Cell Metab. 2018 May 1;27(5):1156. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Organ dysfunction (Liver - Lille Score)	Changes in liver-related function will be determined through assessment of Lille score. The model is based on: Age, Albumin, Bilirubin (initial), Bilirubin (day 7), Creatinine, PT. Survival probability at 6 months is defined by a cutoff of 0.45: 6-month survival probability of patients with a Lille model above 0.45 is about 25% contrary to patients with a Lille model below this cutoff (85% survival).	Up to 28 days
Other	Organ dysfunction (Liver) with Model for End-stage Liver Disease (MELD)	Changes in liver-related function will be determined through assessment of Model for End-stage Liver Disease (MELD) score, a number that ranges from 6 (least sick) to 40 (most sick) based on blood tests. The lab tests used to determine the MELD score are creatinine, bilirubin, sodium and international normalized ratio (INR).	Up to 28 days
Other	Organ dysfunction (Liver Enzyme: Bilirubin)	Changes in liver-related function will be determined through assessment of the liver enzyme bilirubin	Up to 28 days
Other	Organ dysfunction (Liver Enzyme: Alkaline Phosphatase [ALP])	Changes in liver-related function will be determined through assessment of liver enzymes (alkaline phosphatase [ALP])	Up to 28 days
Other	Organ dysfunction (Liver Enzyme: Aspartate Aminotransferase [AST])	Changes in liver-related function will be determined through assessment of liver enzymes (aspartate aminotransferase [AST])	Up to 28 days
Other	Organ dysfunction (Liver Enzyme: Alanine Aminotransferase [ALT])	Changes in liver-related function will be determined through assessment of liver enzymes (alanine aminotransferase [ALT])	Up to 28 days
Other	Organ Dysfunction (Multi-Organ) with Sequential Organ Failure Assessment (SOFA)	Dysfunction in other organs will be assessed using Sequential Organ Failure Assessment (SOFA) score which is calculated based on a person's liver function, kidney function, nervous system, coagulation, circulation, and respiratory status. The score ranges from 0 (least sick) to 24 (most sick).	Up to 28 days
Other	Organ Dysfunction (Multi-Organ) with the Multi-Organ Dysfunction Score (MODS)	Dysfunction in other organs will be assessed using Multi-organ dysfunction score (MODS), calculated based on a person's liver function, kidney function, nervous system, coagulation, circulation, and respiratory status. The score ranges from 0 (least sick) to 24 (most sick).	Up to 28 days
Other	Development of new or recurrent renal failure.	Creatinine rise = 0.5 mg/dL or = 20% from baseline or requiring renal replacement therapy.	Up to 28 days
Other	Racial and ethnic diversity in subject recruitment and retention.	Race and ethnicity of enrolled subjects and subjects who completed the study will be summarized using count and proportion to assess the study's objective of enrolling and retaining at least 10% Black and at least 10% Hispanic participants to study completion (90-days follow-up)follow-up.	Up to 90 days
Primary	Ability to recruit 4 patients a month.	The number of subjects recruited per month will be summarized to assess the study's primary recruitment feasibility objective.	15 months
Secondary	Practicality of daily digoxin measurements	90% of patients have digoxin checked levels within the pre-specified time window	Up to 28 days
Secondary	Feasibility of digoxin dosing in a timely manner.	90% of patients receive every scheduled dose of the drug	Up to 28 days
Secondary	Feasibility of digoxin dose adjustments in renal insufficiency.	90% of necessary dose adjustments were made appropriately in response to digoxin levels	Up to 28 days
Secondary	Mortality at 7, 14, 28, 90 days	The mortality rates at different time points in the digoxin group and in the control group	Up to 90 days
Secondary	Development of ECG abnormalities	The number and proportion of patients in the digoxin and control groups with ECG changes compared to baseline	Up to 28 days