Screening At-risk Populations for Hepatic Fibrosis With Non-invasive Markers

NCT03308916 | Recruiting DMC

• 1 other identifier: S-20170087
• Study Type: interventional
• Target: 6,500
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• Biopsy-verified advanced fibrosis

  Number of patients with biopsy-verified, advanced fibrosis (Kleiner fibrosis score ≥F3) detected by screening

  5 years

• Liver-related outcomes

  Number of liver-related clinical outcomes during 10 years of follow up after the first screened patient, compared to a matched, historical control group (The Inter99 study and the Copenhagen and Odense alcohol rehabilitation cohorts). Liver-related outcomes are defined as liver-related death, liver transplant, progression to liver-related complications (ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, jaundice, bleeding from esophagastric varices, hepatocellular carcinoma) or MELD-Na score \>15

  10 years

Secondary Outcomes (2)

• Liver related outcomes

  10 years

• Mortality

  10 years

Study Arms (1)

Liver stiffness measurement

EXPERIMENTAL

Transient elastography in fasting state

Diagnostic Test: transient elastography; Diagnostic Test: Enhanced liver fibrosis test; Diagnostic Test: Indirect serum markers of liver fibrosis; Diagnostic Test: Direct serum markers of liver fibrosis; Diagnostic Test: LiverTRAIL; Diagnostic Test: Cytokeratin 18; Diagnostic Test: Omics markers

Interventions

transient elastography DIAGNOSTIC_TEST

Ultrasound elastography using shear-wave elastography to measure liver stiffness as a marker of liver fibrosis. Patients with transient elastography above 8.0 kPa selected for liver biopsy to detect advanced liver fibrosis

Also known as: FibroScan, TE

Liver stiffness measurement

Enhanced liver fibrosis test DIAGNOSTIC_TEST

Patented, commercially available algorithm of hyaluronic acid (HA), N-terminal propeptide of collagen type 3 (P3NP) and tissue inhibitor of metalloproteinase 1 (TIMP-1)

Also known as: ELF

Liver stiffness measurement

Indirect serum markers of liver fibrosis DIAGNOSTIC_TEST

Diagnostic markers using combination of routine liver biochemistry: age, AST, ALT, platelet count, cholesterol, GGT

Also known as: Forns index, FIB-4, APRI, AST-ALT ratio, Age-platelet ratio

Liver stiffness measurement

Direct serum markers of liver fibrosis DIAGNOSTIC_TEST

Serum markers that reflect liver extracellular matrix turnover and -accumulation

Also known as: Neoepitopes, Collagen products, Extracellular matrix

Liver stiffness measurement

LiverTRAIL DIAGNOSTIC_TEST

Software that contain 199 diagnostic algorithms, containing combinations of routine tests: age, AST, albumin, alkaline phosphatase, bilirubin, GGT, INR, platelet count, cholesterol and sodium, and specialist tests: transient elastography and direct serum markers of fibrosis.

Liver stiffness measurement

Cytokeratin 18 DIAGNOSTIC_TEST

Cytokeratin 18 from liver cell cytoskeleton; when cells undergo apoptosis, caspase-cleaved CK18 is released (M30), whereas full-length CK18 is realised during necrosis (M65)

Also known as: CK18, M30, M65

Liver stiffness measurement

Omics markers DIAGNOSTIC_TEST

Markers combining signatures of liver fibrosis and hepatic inflammation from many 'omics technologies

Also known as: Multi-omics markers, Lipidomics, Microbiomics, Genomics, Metagenomics, Metatranscriptomics, Transcriptomics, miRNA-omics, Metabolomics, Proteomics

Liver stiffness measurement

Eligibility Criteria

• Age: 30 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Maja Thiele: lead
• Horizon 2020 - European Commission: collaborator
• Novo Nordisk A/S: collaborator
• University of Southern Denmark: collaborator
• Esbjerg University Hospital of South-West Jutland: collaborator
• Odense Municipality Alcohol Rehabilitation Unit: collaborator
• Svendborg Municipality Alcohol Rehabilitation Unit: collaborator
• University of Copenhagen: collaborator
• University of Oslo: collaborator
• Nordic Bioscience A/S: collaborator
• VLV Bio, Peviva AB: collaborator
• Manatee APS: collaborator
• Siemens Healthcare A/S: collaborator
• Steno Diabetes Center Copenhagen: collaborator
• Biomedical Research Foundation, Academy of Athens: collaborator
• European Molecular Biology Laboratory, EMBL, University of Heidelberg: collaborator

Study Sites (1)

Department of Gastroenterology and Hepatology, Odense University Hospital

Odense, 5000, Denmark

RECRUITING

Related Publications (2)

• Hansen CD, Hansen JK, Israelsen M, Andersen P, Pikkupeura LM, Lindvig KP, Stinson SE, Schnefeld HL, Tellerup J, Fogt M, Torp N, Kjaergaard M, Bech KT, Thorhauge KH, Johansen S, Spedtsberg I, Deluran E, Villesen IF, Detlefsen S, Hansen T, Krag A, Thiele M. Prevalence, severity and determinants of steatotic liver disease among individuals with metabolic and alcohol risk from the community. J Hepatol. 2025 Dec;83(6):1278-1291. doi: 10.1016/j.jhep.2025.06.020. Epub 2025 Jul 5.

  PMID: 40618958 DERIVED

• Kjaergaard M, Lindvig KP, Thorhauge KH, Andersen P, Hansen JK, Kastrup N, Jensen JM, Hansen CD, Johansen S, Israelsen M, Torp N, Trelle MB, Shan S, Detlefsen S, Antonsen S, Andersen JE, Graupera I, Gines P, Thiele M, Krag A. Using the ELF test, FIB-4 and NAFLD fibrosis score to screen the population for liver disease. J Hepatol. 2023 Aug;79(2):277-286. doi: 10.1016/j.jhep.2023.04.002. Epub 2023 Apr 21.

  PMID: 37088311 DERIVED

MeSH Terms

Conditions

Liver Diseases, Alcoholic; Fibrosis; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Interventions

Extracellular Polymeric Substance Matrix; Genome

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Fatty Liver

Intervention Hierarchy (Ancestors)

Biofilms; Microbiological Phenomena; Genetic Structures; Genetic Phenomena

Study Officials

• Maja Thiele, MD, PhD, Professor

  Department of Gastroenterology and Hepatology, Odense University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maja Thiele, MD, PhD, Professor

CONTACT

+4524998068; maja.thiele@rsyd.dk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate professor

Model Details: Single intervention group selected for screening with a historical control group

Study Record Dates

• First Submitted: February 4, 2016
• First Posted: October 13, 2017
• Study Start: October 6, 2017
• Primary Completion: December 30, 2025
• Study Completion (Estimated): October 30, 2035
• Last Updated: September 1, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR, ANALYTIC CODE
• Time Frame: After publication of study results
• Access Criteria: Accessible after contact to OPEN, who will pass on the request to primary investigator. No criteria.

Locations

DK (1)