Digoxina en el tratamiento de la hepatitis asociada al alcohol (DIGIT-AlcHep)
Digoxina en el tratamiento de la hepatitis asociada al alcohol (DIGIT-AlcHep)
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.
Descripción general del estudio
Estado
Estado
Condiciones
Condiciones
Intervención / Tratamiento
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Tipo de estudio
Inscripción (Actual)
Inscripción
Fase
Fase
- Fase 2
Contactos y Ubicaciones
Ubicaciones de estudio
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Connecticut
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New Haven, Connecticut, Estados Unidos, 06510
- Yale New Haven Hospital, Yale School of Medicine
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Criterios de participación
Criterio de elegibilidad
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
1. Diagnosis of alcohol associated hepatitis based on clinical criteria or histologic evidence
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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
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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:
- - 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
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Número de brazos
Armas e Intervenciones
Grupo de participantes/brazoGrupo de participantes/brazo |
Intervención / TratamientoIntervención / Tratamiento |
|---|---|
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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. |
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.
Otros nombres:
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Sin intervención: Arm B: No Digoxin
In the no digoxin arm, no study drug or placebo will be administered. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Change in Biomarkers of Inflammation
Periodo de tiempo: Day 3
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Change in IL-6, IL-10 and TNF-alpha levels (pg/ml) at day 3 in participants with acute alcohol associated hepatitis treated with digoxin vs no digoxin. |
Day 3
|
Medidas de resultado secundarias
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Practicality of Daily Digoxin Measurements
Periodo de tiempo: From Day 2 to Day 28 or until discharge, whichever sooner
|
Practicality of daily digoxin measurements is recorded at the participant level as the proportion of timepoints where serum digoxin levels are checked within the pre-specified time window. It is summarized and reported as the mean and standard deviation of the proportion of eligible timepoints. |
From Day 2 to Day 28 or until discharge, whichever sooner
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Feasibility of Digoxin Dosing in a Timely Manner.
Periodo de tiempo: From Day 1 to Day 28 or until discharge, whichever sooner
|
Feasibility of digoxin dosing is recorded at the participant level as the proportion of eligible timepoints where the scheduled digoxin dose was given. It is summarized and reported as the mean and standard deviation of the proportion of scheduled timepoints. |
From Day 1 to Day 28 or until discharge, whichever sooner
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Feasibility of Digoxin Dose Adjustments in Renal Insufficiency.
Periodo de tiempo: From Day 0 to Day 28 or until discharge, whichever sooner
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Feasibility of digoxin dose adjustments in renal insufficiency is recorded at the participant level as the proportion of timepoints where necessary dose adjustments were made appropriately in response to digoxin levels. Renal insufficiency was defined as a creatinine rise ≥ 0.3 mg/dL over 48 hours or ≥ 20% from baseline or requiring renal replacement therapy. It is reported as the mean and standard deviation of the proportion of timepoints. |
From Day 0 to Day 28 or until discharge, whichever sooner
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Mortality at 7, 14, 28, 90 Days. All Cause Mortality of Patients Enrolled in the Trial.
Periodo de tiempo: Day 7, Day 14, Day 28, and Day 90
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The mortality rates at different time points |
Day 7, Day 14, Day 28, and Day 90
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Development of Arrhythmia
Periodo de tiempo: From Day 0 to Day 28 or until discharge, whichever sooner
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It refers to any type of arrhythmia which represents a change from baseline. It is reported as the proportion of individuals who developed an arrhythmia. |
From Day 0 to Day 28 or until discharge, whichever sooner
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Recruitment
Periodo de tiempo: up to 90 days
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Ability to recruit 4 patients per month to reach anticipated enrollment of 60. Data presented here is the number participants enrolled. |
up to 90 days
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Otras medidas de resultado
Otras medidas de resultado
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Organ Dysfunction (Liver - Lille Score)
Periodo de tiempo: 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). |
Up to 28 days
|
|
Organ Dysfunction (Liver) With Model for End-stage Liver Disease (MELD)
Periodo de tiempo: 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). |
Up to 28 days
|
|
Organ Dysfunction (Liver Enzyme: Bilirubin)
Periodo de tiempo: Up to 28 days
|
Changes in liver-related function will be determined through assessment of the liver enzyme bilirubin |
Up to 28 days
|
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Organ Dysfunction (Liver Enzyme: Alkaline Phosphatase [ALP])
Periodo de tiempo: Up to 28 days
|
Changes in liver-related function will be determined through assessment of liver enzymes (alkaline phosphatase [ALP]) |
Up to 28 days
|
|
Organ Dysfunction (Liver Enzyme: Aspartate Aminotransferase [AST])
Periodo de tiempo: Up to 28 days
|
Changes in liver-related function will be determined through assessment of liver enzymes (aspartate aminotransferase [AST]) |
Up to 28 days
|
|
Organ Dysfunction (Liver Enzyme: Alanine Aminotransferase [ALT])
Periodo de tiempo: Up to 28 days
|
Changes in liver-related function will be determined through assessment of liver enzymes (alanine aminotransferase [ALT]) |
Up to 28 days
|
|
Organ Dysfunction (Multi-Organ) With Sequential Organ Failure Assessment (SOFA)
Periodo de tiempo: 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). |
Up to 28 days
|
|
Organ Dysfunction (Multi-Organ) With the Multi-Organ Dysfunction Score (MODS)
Periodo de tiempo: 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). |
Up to 28 days
|
|
Development of New or Recurrent Renal Failure.
Periodo de tiempo: Up to 28 days
|
Creatinine rise ≥ 0.5 mg/dL or ≥ 20% from baseline or requiring renal replacement therapy. |
Up to 28 days
|
|
Racial and Ethnic Diversity in Subject Recruitment and Retention.
Periodo de tiempo: 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. |
Up to 90 days
|
Colaboradores e Investigadores
Patrocinador
Patrocinador
Investigadores
Investigadores
- Investigador principal: Bubu Banini, MD, PhD, Yale University
Publicaciones y enlaces útiles
Publicaciones Generales
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Digoxin FDA insert. . [cited 2021 3/15/2021]
- (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]
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Digoxin conversion calculator.
- 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.
- Trial of Anakinra (Plus Zinc) or Prednisone in Patients With Severe Alcohol associated Hepatitis (AlcHepNet). [cited 2021 03/29]
- R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing 2020
- 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.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Inicio del estudio
Finalización primaria (Actual)
Finalización primaria
Finalización del estudio (Actual)
Finalización del estudio
Fechas de registro del estudio
Enviado por primera vez
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Publicado por primera vez
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización publicada
Última actualización enviada que cumplió con los criterios de control de calidad
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades del Sistema Digestivo
- Trastornos relacionados con sustancias
- Trastornos inducidos químicamente
- Trastornos relacionados con el alcohol
- Efectos secundarios y reacciones adversas relacionados con los medicamentos
- Envenenamiento
- Hígado graso
- Enfermedades Hepáticas Alcohólicas
- Hepatitis
- Enfermedades del HIGADO
- Daño hepático inducido por sustancias químicas y fármacos
- Trastornos inducidos por el alcohol
- Hígado Graso Alcohólico
- Carbohidratos
- Compuestos policíclicos
- Glucósidos
- Esteroides
- Compuestos de anillo fusionado
- Glicosidos Digitalis
- Cardenólidos
- Glucósidos cardíacos
- Cardanólidos
- Digoxina
Otros números de identificación del estudio
Otros números de identificación del estudio
- 2000030659
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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