Complex Exploratory Study of Alcohol-Associated Hepatitis (CESAH)

Alcohol-associated hepatitis is a clinical syndrome distinct from steatohepatitis or liver cirrhosis. It is associated with high mortality and characterized by an absence of effective treatment, while corticosteroids, which are currently used as the first-line treatment are effective only in a subpopulation of patients and only on 28-days survival - their effect on survival does not last beyond this interval. The proposed study is a complex exploratory study of alcohol-associated hepatitis with several epidemiology- and prognosis-related aims.

Study Overview

• Status: Not yet recruiting
• Conditions: Alcoholic Hepatitis

Detailed Description

Alcohol-associated hepatitis is a clinical syndrome distinct from steatohepatitis or liver cirrhosis. It is associated with high mortality and characterized by an absence of effective treatment, while corticosteroids, which are currently used as the first-line treatment are effective only in a subpopulation of patients and only on 28-days survival - their effect on survival does not last beyond this interval. The proposed study is a complex exploratory study of alcohol-associated hepatitis with the following aims: (1) to estimate the standardized annual incidence of (severe) AH in the Kosice Urban Area, (2) to estimate the threshold of alcohol consumption associated with (an increased risk of) developing AH, (3) to compare the diagnostic accuracy of NIAAA vs NIAAAm-CRP against liver biopsy, (4) to perform a head-to-head comparison of widely-accepted prognostic models and to develop prognostic models, (5) to observe prognosis of nonsevere alcohol-associated hepatitis, (6) to observe the evolution of severe alcohol-associated hepatitis, (7) to describe the association of hypothalamus-hypopituitary-adrenal axis and Gut-Liver Microbiome Axis and Prognosis of Alcohol-associated Hepatitis, (8) to describe the adherence to outpatient psychiatric management and its impact on long-term prognosis, (9) to perform a longitudinal evaluation of nutritional status, its changes, and its impact on long-term prognosis.

Study Design This is a multicenter observational study of patients with alcohol-associated hepatitis. The total trial duration for each subject is approximately 53 weeks. This includes a screening period of a maximum of one week (7 days), during which the diagnosis of AH will be confirmed, followed by a 52 weeks (365 days) observational period.

Diagnosis of Alcohol-associated Hepatitis The diagnosis of alcohol-associated hepatitis will be established using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) diagnostic criteria: onset of jaundice within prior 8 weeks; ongoing consumption of >40 (females) or >60 (males) g alcohol/day ≥ 6 months, with less than 60 days of abstinence before the onset of jaundice; aspartate aminotransferase >0.83µkat/L (but less than 6.64 µkat/L), AST/ALT > 1.5, and total serum bilirubin > 51.3 mmol/L.

NIAAA definitions for AH differentiate between possible AH (clinically diagnosed with potential confounding factors), in which transjugular liver biopsy is indicated, probable AH (clinically diagnosed without potential confounding factors), and definite AH (clinically diagnosed and biopsy proven).

Considerations Regarding Patient Admission and Discharge Local standards dictate that patients with acute liver injury or acute liver failure are typically admitted to the 2nd Department of Internal Medicine, which specializes in gastroenterology and hepatology. This admission is carried out to facilitate further differentiation and provide specific treatment tailored to their condition. However, patients have the option to decline admission and, in such cases, will be discharged and managed as outpatients.

Once patients provide their consent to participate in the study, the screening period will commence. This screening phase may have a variable duration and will persist until a definitive diagnosis of AH is confirmed (either with or without results from histopathological evaluation of liver specimen).

The observational period will begin as soon as the diagnosis of AH will be confirmed with specific treatment in cases of sAH.

Patients diagnosed with nAH will undergo evaluation for potential discharge starting on Day 4 of the observational period. In contrast, patients with sAH will be assessed for their therapeutic response, as well as for the possibility of discharge, using the Lille score on Day 7 of the observational period. If patients do not respond to treatment, it will be discontinued.

For patients who respond positively to treatment, it will be sustained until Day 28 of the observational period. Following this period, treatment will be gradually tapered down by reducing the dosage by half each week, continuing for a total of three weeks.

The decision to discharge patients will be based on the absence of significant complications or serious events, such as gastrointestinal bleeding, overt hepatic encephalopathy, infection, kidney injury, and similar conditions. Similarly, if any of these events occur after discharge, patients will be promptly readmitted and receive appropriate treatment.

Patients will be offered psychiatric inpatient or outpatient care before discharge.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Jakub Gazda, MD, PhD; Phone Number: +421911115288; Email: jakub.gazda@upjs.sk
• Study Contact Backup: Name: Martin Janicko, MD, PhD; Email: martin.janicko@upjs.sk

Study Locations

• Slovakia
  • Kosice, Slovakia, 04012
    • Pavol Jozef Safarik University
    • Contact: Jakub Gazda, MD, PhD; Phone Number: +421911115288; Email: jakub.gazda@upjs.sk
    • Contact: Martin Janicko, MD, PhD; Email: martin.janicko@upjs.sk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with Alcohol-Associated Hepatitis

Description

Inclusion Criteria:

• Patients older than 18 years with acute liver injury / acute liver failure with later confirmation of the AH diagnosis according to the NIAAA diagnostic criteria [14] who provided written informed consents for admission and further differentiation, and for study participation

Exclusion Criteria:

• Patients not confirmed to have alcohol-associated hepatitis
• Patients with malignancies (specifically those with life-expectancy limitation)
• Patients who withdrew consent for study participation

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Alcohol-associated hepatitis patients; Inclusion criterion • Patients older than 18 years with acute liver injury / acute liver failure with later confirmation of the AH diagnosis according to the NIAAA diagnostic criteria [14] who provided written informed consents for admission and further differentiation, and for study participation Exclusion criteria; Patients not confirmed to have alcohol-associated hepatitis; Patients with malignancies (specifically those with life-expectancy limitation); Patients who withdrew consent for study participation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized annual incidence of (severe) alcoholic hepatitis in the Kosice Urban Area	Number of patients with (severe) alcoholic hepatitis	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Threshold of alcohol consumption associated with (an increased risk of) developing AH	Grams of alcohol per week	Baseline
Diagnostic accuracy of NIAAA and NIAAAm-CRP	Accuracy against liver biopsy	Baseline
Prognostic performance of Maddrey, MELD, MELD-Na, MELD 3.0, GAHS, ABIC, Lille score	Discriminatory characteristics (area under receiver operating characteristics curve) and calibration (calibration belts) with respect to 30 and 90 days mortality	Baseline, Days 2, 4, 7
Prognostic performance of SOFA and CLIF-C	Discriminatory characteristics (area under receiver operating characteristics curve) and calibration (calibration belts) with respect to 30 and 90 days mortality	Baseline, Days 2, 4, 7
An update of Maddrey, MELD, MELD-Na, MELD 3.0, GAHS, ABIC, Lille score	To reevaluate independent variables in prognostic models aiming for improved discriminatory characteristics (area under receiver operating characteristics curve) and calibration (calibration belts)	Baseline
Alternative to Lille model	Regression model with 30 day mortality as exploratory variable	Baseline, Day 2
Prognostic model for 90 day survival	Regression model with 90 day mortality as exploratory variable	Baseline
Uper limit of MELD or Maddrey scores beyond which patients no longer derive any therapeutic benefit from corticosteroid treatment	Upper threshold value of MELD and Maddrey scores associated with increased risk of mortality	Baseline
Natural course of nonsevere alcoholic hepatitis	Mortality (and prevalence of ascites, hepatic encephalopathy, variceal bleeding, bacterial infection, acute kidney injury and proportion of patients with progression to severe alcoholic hepatitis)	1 year
Natural course of severe alcoholic hepatitis	Mortality (and prevalence of ascites, hepatic encephalopathy, variceal bleeding, bacterial infection, acute kidney injury and proportion of patients with progression to severe alcoholic hepatitis or with withdrawal syndrome, or with relapse of alcohol drinking)	1 year
Risk score for bacterial infection before corticosteroid treatment in patients with alcoholic hepatitis	30-days regression model for infection as exploratory variable	Baseline
Distinguishing sterile Inflammation from infection in alcoholic hepatitis	Ratio of inflammatory markers	1 year
GUT microbiome and treatment response in alcoholic hepatitis	Differences in GUT microbiome between corticosteroid responders and nonresponders	Baseline, Day 90
Hypothalamus-pituitary-adrenal axis and treatment response in alcoholic hepatitis	Differences in cortisol levels between corticosteroid responders and nonresponders	Baseline, Day 28
Adherence to outpatient psychiatric management	Proportion of patients adhering to outpatient psychiatric management	1 year
Nutritional status and treatment response in alcoholic hepatitis	Differences in nutritional status between corticosteroid responders and nonresponders	Baseline

Collaborators and Investigators

• Sponsor: Pavol Jozef Safarik University
• Collaborators: University of Roma La Sapienza; Western University; L Pasteur University Hospital; Hospital Agel Kosice-Saca; Technical University in Kosice
• Investigators: Principal Investigator: Jakub Gazda, MD, PhD, Pavol Jozef Safarik University

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 30, 2025
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: March 28, 2024
• First Submitted That Met QC Criteria: April 6, 2024
• First Posted (Actual): April 10, 2024

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 6, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: treatment; nutritional status; prognosis; epidemiology; alcoholic hepatitis; hypothalamus-hypopituitary-adrenal axis; gut-Liver Microbiome Axis
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis; Hepatitis A; Hepatitis, Alcoholic
• Other Study ID Numbers: CESAH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No