Clinical trial NCT03308916: Screening At-risk Populations for Hepatic Fibrosis With Non-invasive Markers
Official title: Screening At-risk Populations for Hepatic Fibrosis With Non-invasive Markers
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Liver Diseases, Alcoholic
Fibrosis
Keywords: elastography
screening
non-invasive markers
microbiome
gut-liver-axis
cost-benefit
fibroscan
aixplorer
ultrasound elastography
liver fibrosis
alcoholic liver disease
advanced fibrosis
enhanced liver fibrosis test
direct liver fibrosis markers
ELF
cytokeratin-18
neoepitopes
collagen
NAFLD
ALD
metabolomics
non-alcoholic fatty liver disease
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
Collaborators: name: Horizon 2020 - European Commission
name: Novo Nordisk A/S
name: University of Southern Denmark
name: Esbjerg University Hospital of South-West Jutland
name: Odense Municipality Alcohol Rehabilitation Unit
name: Svendborg Municipality Alcohol Rehabilitation Unit
name: University of Copenhagen
name: University of Oslo
name: Nordic Bioscience A/S
name: VLV Bio, Peviva AB
name: Manatee APS
name: Siemens Healthcare A/S
name: Steno Diabetes Center Copenhagen
name: Biomedical Research Foundation, Academy of Athens
name: European Molecular Biology Laboratory, EMBL, University of Heidelberg
First posted: 2017-10-13
Enrollment: 6500
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single intervention group selected for screening with a historical control group
Primary purpose: DIAGNOSTIC

Brief summary: Prospective screening study at Odense University Hospital to assess the effect of transient elastography and other serum and imaging markers of liver fibrosis to detect advanced fibrosis (Kleiner Fibrosis score F3-F4) in patients at risk of non-alcoholic fatty liver disease, alcoholic fatty liver disease, with a control group of participants recruited from the general population.

Detailed description: This protocol describes a prospective screening study at Odense University Hospital, Department of Gastroenterology and Hepatology. The investigators will use liver stiffness measurements with transient elastography to screen 3000 participants from at-risk populations and 3500 participants from the general population for advanced liver fibrosis. At-risk is defined as either (A) a prior or current alcohol overuse (≥21 units/week for men and ≥14 units/week for women) for more than 5 years, or (B) presence of the metabolic syndrome with or without concomitant type 2 diabetes mellitus.

The study goal is to evaluate the aptitude of transient elastography as a screening tool for advanced liver fibrosis, based on analyses of benefit, harm, detection rate, technical applicability and prognostic potential. Secondary aims are to compare novel serum markers of liver fibrosis as potential screening tools against transient elastography: The Enhanced Liver Fibrosis test, neoepitope markers of extracellular matrix turnover, cytokeratin-18 based markers and indirect indices of fibrosis from algorithms combining routine liver blood test. Screened participants with elevated liver stiffness (≥8.0 kiloPascal; estimated 400 participants with alcoholic liver disease, 400 participants with non-alcoholic fatty liver disease and 280 participants from the general population) will be investigated with 2-dimensional shear-wave elastography and abdominal ultrasonography and a liver biopsy to confirm or reject presence of advanced fibrosis.

All participants with a positive screening elastography will be invited for repeated liver stiffness measurements and serum fibrosis markers after a minimum of one year from inclusion.

Participants at risk of alcoholic and non-alcoholic liver disease, independent of liver stiffness measurement at inclusion, will be invited for repeated liver stiffness measurements and serum fibrosis markers after a minimum of one year from inclusion. At-risk participants with elevated liver stiffness measurements at a follow-up visit (\>6.0 kiloPascal) will be offered a liver biopsy, however no earlier than two years after the index biopsy.

All participants will be followed for 10 years to assess liver-related outcomes and all-course mortality.

Eligibility criteria: INCLUSION CRITERIA

Patients are eligible for screening if the following inclusion criteria are fulfilled:

* Age 30-75 years (except the general population, which should be aged 40-75)
* Informed consent to study investigations
* Ability to read and write Danish AND (only at-risk patients)
* Prior or current alcohol overuse, defined as an average intake of ≥24 grams/day (14 units/week) for women and ≥36 grams/day (21 units/week) for men, for at least 5 years; OR
* Presence of the metabolic syndrome defined by central obesity plus any two of the following four metabolic risk factors: (a) raised triglycerides, (b) reduced HDL cholesterol, (c) raised blood pressure and (d) raised fasting plasma glucose;\[38\] OR
* Type 2 diabetes mellitus defined by either fasting plasma glucose ≥7 mmol/L, HbA1c ≥48 mmol/mol, a random plasma glucose ≥11.1 mmol/L in the presence of classic diabetes or an oral glucose tolerance test with fasting plasma glucose ≥7.0 mmol/L and/or 2 hour plasma glucose ≥11.1 mmol/L.

EXCLUSION CRITERIA

We will exclude patients from screening in case of:

* Evidence of decompensated liver disease, defined by clinically obvious ascites, overt hepatic encephalopathy, jaundice or large esophageal varices with/without variceal bleeding.
* Known concurrent liver disease other than ALD and NAFLD.
* Cancer or other debilitating disease with an expected survival of less than 12 months.
* Inability to comply with the study protocol.

In screened patients with liver stiffness ≥8 kPa we will abstain from a liver biopsy in case of:

* Contraindications for a percutaneous liver biopsy
* Severe alcoholic hepatitis or other hepatic inflammation evidenced by transaminase elevation of more than three times the upper limit of normal.
* Hepatic congestion or bile duct dilation evidenced by ultrasound.
* Decrease of TE below 6.0 kPa from screening to time of planned liver biopsy.

Primary outcomes:
measure: Biopsy-verified advanced fibrosis
timeFrame: 5 years
measure: Liver-related outcomes
timeFrame: 10 years
Secondary outcomes:
measure: Liver related outcomes
timeFrame: 10 years
measure: Mortality
timeFrame: 10 years
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: Department of Gastroenterology and Hepatology, Odense University Hospital
Study officials:
affiliation: Department of Gastroenterology and Hepatology, Odense University Hospital
name: Maja Thiele, MD, PhD, Professor
role: PRINCIPAL_INVESTIGATOR
References: