Acute Alcoholic Hepatitis, Alcohol-Induced Disorders, Chemical and Drug Induced Liver Injury, Steatohepatitis Caused by Ingestible Alcohol
Conditions
Keywords
Acute alcoholic hepatitis, Liver injury, Liver inflammation, Liver disease, Digoxin
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.
Detailed 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 randomized control study of digoxin versus no digoxin in patients with severe alcohol associated hepatitis is to explore whether digoxin treatment affects cytokine levels as biomarkers of inflammation in patients hospitalized with severe alcohol associated hepatitis.
Interventions
DRUGIntravenous 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.
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, single center, open label, randomized 1:1 controlled trial.
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
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 \* 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.
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in biomarkers of inflammation | day 3 | 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 . |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of digoxin dosing in a timely manner. | Up to 28 days | Time to 90% of patients receive every scheduled dose of the drug |
| Feasibility of digoxin dose adjustments in renal insufficiency. | Up to 28 days | 90% of necessary dose adjustments were made appropriately in response to digoxin levels |
| Practicality of daily digoxin measurements | Up to 28 days | Time to 90% of patients have digoxin checked levels within the pre-specified time window |
| Development of ECG abnormalities | Up to 28 days | The number and proportion of patients in the digoxin and control groups with ECG changes compared to baseline |
| Recruitment | up to 90 days | Ability to recruit 4 patients per month IS THIS A YES/NO or can we present it as the mean number of participants recruited per month? |
| Mortality at 7, 14, 28, 90 days. All cause mortality of patients enrolled in the trial. | Up to 90 days | The mortality rates at different time points in the digoxin group and in the control group |
Other
| Measure | Time frame | Description |
|---|---|---|
| Organ Dysfunction (Multi-Organ) with the Multi-Organ Dysfunction Score (MODS) | 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). |
| Organ dysfunction (Liver - Lille Score) | 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). |
| Racial and ethnic diversity in subject recruitment and retention. | 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. |
| Development of new or recurrent renal failure. | Up to 28 days | Creatinine rise ≥ 0.5 mg/dL or ≥ 20% from baseline or requiring renal replacement therapy. |
| Organ dysfunction (Liver) with Model for End-stage Liver Disease (MELD) | 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) | 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]) | 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]) | 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]) | 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) | 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). |
Countries
United States
Outcome results
None listed