Digoxin In Treatment of Alcohol Associated Hepatitis (DIGIT-AlcHep)
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|ClinicalTrials.gov Identifier: NCT05014087|
Recruitment Status : Recruiting
First Posted : August 20, 2021
Last Update Posted : December 16, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Acute Alcoholic Hepatitis Chemical and Drug Induced Liver Injury Alcohol-Induced Disorders Steatohepatitis Caused by Ingestible Alcohol||Drug: Intravenous digoxin||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||60 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Prospective, single center, open label, randomized 1:1 controlled trial.|
|Masking:||None (Open Label)|
|Official Title:||Digoxin In Treatment of Alcohol Associated Hepatitis (DIGIT-AlcHep)|
|Actual Study Start Date :||October 8, 2021|
|Estimated Primary Completion Date :||February 2023|
|Estimated Study Completion Date :||August 2024|
Experimental: Arm A: Digoxin
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
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.
Other Name: Lanoxin
No Intervention: Arm B: No Digoxin
In the no digoxin arm, no study drug or placebo will be administered.
- Ability to recruit 4 patients a month. [ Time Frame: 15 months ]The number of subjects recruited per month will be summarized to assess the study's primary recruitment feasibility objective.
- Practicality of daily digoxin measurements [ Time Frame: Up to 28 days ]90% of patients have digoxin checked levels within the pre-specified time window
- Feasibility of digoxin dosing in a timely manner. [ Time Frame: Up to 28 days ]90% of patients receive every scheduled dose of the drug
- Feasibility of digoxin dose adjustments in renal insufficiency. [ Time Frame: Up to 28 days ]90% of necessary dose adjustments were made appropriately in response to digoxin levels
- Mortality at 7, 14, 28, 90 days [ Time Frame: Up to 90 days ]The mortality rates at different time points in the digoxin group and in the control group
- Development of ECG abnormalities [ Time Frame: Up to 28 days ]The number and proportion of patients in the digoxin and control groups with ECG changes compared to baseline
- Organ dysfunction (Liver - Lille Score) [ Time Frame: Up to 28 days ]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).
- Organ dysfunction (Liver) with Model for End-stage Liver Disease (MELD) [ Time Frame: Up to 28 days ]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).
- Organ dysfunction (Liver Enzyme: Bilirubin) [ Time Frame: Up to 28 days ]Changes in liver-related function will be determined through assessment of the liver enzyme bilirubin
- Organ dysfunction (Liver Enzyme: Alkaline Phosphatase [ALP]) [ Time Frame: Up to 28 days ]Changes in liver-related function will be determined through assessment of liver enzymes (alkaline phosphatase [ALP])
- Organ dysfunction (Liver Enzyme: Aspartate Aminotransferase [AST]) [ Time Frame: Up to 28 days ]Changes in liver-related function will be determined through assessment of liver enzymes (aspartate aminotransferase [AST])
- Organ dysfunction (Liver Enzyme: Alanine Aminotransferase [ALT]) [ Time Frame: Up to 28 days ]Changes in liver-related function will be determined through assessment of liver enzymes (alanine aminotransferase [ALT])
- Organ Dysfunction (Multi-Organ) with Sequential Organ Failure Assessment (SOFA) [ Time Frame: Up to 28 days ]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).
- Organ Dysfunction (Multi-Organ) with the Multi-Organ Dysfunction Score (MODS) [ Time Frame: Up to 28 days ]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).
- Development of new or recurrent renal failure. [ Time Frame: Up to 28 days ]Creatinine rise ≥ 0.5 mg/dL or ≥ 20% from baseline or requiring renal replacement therapy.
- Racial and ethnic diversity in subject recruitment and retention. [ Time Frame: Up to 90 days ]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.
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|Ages Eligible for Study:||21 Years to 70 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
1. Diagnosis of alcohol associated hepatitis based on clinical criteria or histologic evidence
- 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
2. MDF >32 or MELD ≥ 20 to ≤ 35 on Day 0 of the trial
3. Age between 21 and 70 years, inclusive
- - 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
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:
- Antiarrthymics (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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05014087
|Contact: Bubu Banini, MD, PhDfirstname.lastname@example.org|
|Contact: Catherine Doucetemail@example.com|
|United States, Connecticut|
|Yale New Haven Hospital, Yale School of Medicine||Recruiting|
|New Haven, Connecticut, United States, 06510|
|Contact: Bubu Banini, MD, PhD 203-737-6063 firstname.lastname@example.org|
|Principal Investigator: Bubu Banini, MD, PhD|
|Sub-Investigator: Wajahat Mehal, MD PhD|
|Sub-Investigator: Simona Jakab, MD|
|Principal Investigator:||Bubu Banini, MD, PhD||Yale University, Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine|
|Responsible Party:||Bubu Banini, MD, PhD, Assistant Professor of Internal Medicine, Yale University|
|Other Study ID Numbers:||
|First Posted:||August 20, 2021 Key Record Dates|
|Last Update Posted:||December 16, 2022|
|Last Verified:||December 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Acute alcoholic hepatitis
Chemical and Drug Induced Liver Injury
Digestive System Diseases
Hepatitis, Viral, Human
RNA Virus Infections
Liver Diseases, Alcoholic
Drug-Related Side Effects and Adverse Reactions
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs