Clinical trial NCT06358196: Complex Exploratory Study of Alcohol-Associated Hepatitis
Official title: Complex Exploratory Study of Alcohol-Associated Hepatitis
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Alcoholic Hepatitis
Keywords: alcoholic hepatitis
prognosis
epidemiology
treatment
hypothalamus-hypopituitary-adrenal axis
gut-Liver Microbiome Axis
nutritional status
Lead sponsor: Pavol Jozef Safarik University
Sponsor class: OTHER
Collaborators: name: L Pasteur University Hospital
name: Hospital Agel Kosice-Saca
name: Technical University in Kosice
name: Western University
name: University of Roma La Sapienza
First posted: 2024-04-10
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients diagnosed with Alcohol-Associated Hepatitis

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Standardized annual incidence of (severe) alcoholic hepatitis in the Kosice Urban Area
timeFrame: 1 year
Secondary outcomes:
measure: Threshold of alcohol consumption associated with (an increased risk of) developing AH
timeFrame: Baseline
measure: Diagnostic accuracy of NIAAA and NIAAAm-CRP
timeFrame: Baseline
measure: Prognostic performance of Maddrey, MELD, MELD-Na, MELD 3.0, GAHS, ABIC, Lille score
timeFrame: Baseline, Days 2, 4, 7
measure: Prognostic performance of SOFA and CLIF-C
timeFrame: Baseline, Days 2, 4, 7
measure: An update of Maddrey, MELD, MELD-Na, MELD 3.0, GAHS, ABIC, Lille score
timeFrame: Baseline
measure: Alternative to Lille model
timeFrame: Baseline, Day 2
measure: Prognostic model for 90 day survival
timeFrame: Baseline
measure: Uper limit of MELD or Maddrey scores beyond which patients no longer derive any therapeutic benefit from corticosteroid treatment
timeFrame: Baseline
measure: Natural course of nonsevere alcoholic hepatitis
timeFrame: 1 year
measure: Natural course of severe alcoholic hepatitis
timeFrame: 1 year
measure: Risk score for bacterial infection before corticosteroid treatment in patients with alcoholic hepatitis
timeFrame: Baseline
measure: Distinguishing sterile Inflammation from infection in alcoholic hepatitis
timeFrame: 1 year
measure: GUT microbiome and treatment response in alcoholic hepatitis
timeFrame: Baseline, Day 90
measure: Hypothalamus-pituitary-adrenal axis and treatment response in alcoholic hepatitis
timeFrame: Baseline, Day 28
measure: Adherence to outpatient psychiatric management
timeFrame: 1 year
measure: Nutritional status and treatment response in alcoholic hepatitis
timeFrame: Baseline
Other outcomes:
Locations:
city: Kosice
country: Slovakia
facility: Pavol Jozef Safarik University
Study officials:
affiliation: Pavol Jozef Safarik University
name: Jakub Gazda, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: