Digoxin In Treatment of Alcohol Associated Hepatitis (DIGIT-AlcHep)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Change in biomarkers of inflammation
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 21 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. 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*
- •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.
排除标准
- •- 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:
- •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
研究组 & 干预措施
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.
干预措施: Intravenous digoxin (Drug)
结局指标
主要结局
Change in biomarkers of inflammation
时间窗: 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 .
次要结局
- Feasibility of digoxin dosing in a timely manner.(Up to 28 days)
- Recruitment(up to 90 days)
- Practicality of daily digoxin measurements(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)
- Feasibility of digoxin dose adjustments in renal insufficiency.(Up to 28 days)
研究者
Bubu Banini, MD, PhD
Assistant Professor of Internal Medicine
Yale University