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

NCT ID: NCT03308916

Last Updated: 2022-09-01

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

6500 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-10-06

Study Completion Date

2035-10-30

Brief Summary

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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

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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.

Conditions

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Liver Diseases, Alcoholic Fibrosis

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Single intervention group selected for screening with a historical control group
Primary Study Purpose

DIAGNOSTIC

Blinding Strategy

NONE

Study Groups

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Liver stiffness measurement

Transient elastography in fasting state

Group Type EXPERIMENTAL

transient elastography

Intervention Type 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

Enhanced liver fibrosis test

Intervention Type 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)

Indirect serum markers of liver fibrosis

Intervention Type DIAGNOSTIC_TEST

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

Direct serum markers of liver fibrosis

Intervention Type DIAGNOSTIC_TEST

Serum markers that reflect liver extracellular matrix turnover and -accumulation

LiverTRAIL

Intervention Type 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.

Cytokeratin 18

Intervention Type 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)

Omics markers

Intervention Type DIAGNOSTIC_TEST

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

Interventions

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transient elastography

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

Intervention Type DIAGNOSTIC_TEST

Enhanced liver fibrosis 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)

Intervention Type DIAGNOSTIC_TEST

Indirect serum markers of liver fibrosis

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

Intervention Type DIAGNOSTIC_TEST

Direct serum markers of liver fibrosis

Serum markers that reflect liver extracellular matrix turnover and -accumulation

Intervention Type DIAGNOSTIC_TEST

LiverTRAIL

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.

Intervention Type DIAGNOSTIC_TEST

Cytokeratin 18

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)

Intervention Type DIAGNOSTIC_TEST

Omics markers

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

Intervention Type DIAGNOSTIC_TEST

Other Intervention Names

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FibroScan TE ELF Forns index FIB-4 APRI AST-ALT ratio Age-platelet ratio Neoepitopes Collagen products Extracellular matrix CK18 M30 M65 Multi-omics markers Lipidomics Microbiomics Genomics Metagenomics Metatranscriptomics Transcriptomics miRNA-omics Metabolomics Proteomics

Eligibility Criteria

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Inclusion Criteria

* 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.
Minimum Eligible Age

30 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Horizon 2020 - European Commission

OTHER

Sponsor Role collaborator

Novo Nordisk A/S

INDUSTRY

Sponsor Role collaborator

University of Southern Denmark

OTHER

Sponsor Role collaborator

Esbjerg University Hospital of South-West Jutland

UNKNOWN

Sponsor Role collaborator

Odense Municipality Alcohol Rehabilitation Unit

UNKNOWN

Sponsor Role collaborator

Svendborg Municipality Alcohol Rehabilitation Unit

UNKNOWN

Sponsor Role collaborator

University of Copenhagen

OTHER

Sponsor Role collaborator

University of Oslo

OTHER

Sponsor Role collaborator

Nordic Bioscience A/S

INDUSTRY

Sponsor Role collaborator

VLV Bio, Peviva AB

UNKNOWN

Sponsor Role collaborator

Manatee APS

UNKNOWN

Sponsor Role collaborator

Siemens Healthcare A/S

INDUSTRY

Sponsor Role collaborator

Steno Diabetes Center Copenhagen

OTHER

Sponsor Role collaborator

Biomedical Research Foundation, Academy of Athens

OTHER

Sponsor Role collaborator

European Molecular Biology Laboratory, EMBL, University of Heidelberg

UNKNOWN

Sponsor Role collaborator

Maja Thiele

OTHER

Sponsor Role lead

Responsible Party

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Maja Thiele

Associate professor

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Maja Thiele, MD, PhD, Professor

Role: PRINCIPAL_INVESTIGATOR

Department of Gastroenterology and Hepatology, Odense University Hospital

Locations

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Department of Gastroenterology and Hepatology, Odense University Hospital

Odense, , Denmark

Site Status RECRUITING

Countries

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Denmark

Central Contacts

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Maja Thiele, MD, PhD, Professor

Role: CONTACT

+4524998068

Facility Contacts

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Maja Thiele, MD, PhD

Role: primary

65412752 ext. 45

References

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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 Jul 5:S0168-8278(25)02319-0. doi: 10.1016/j.jhep.2025.06.020. Online ahead of print.

Reference Type DERIVED
PMID: 40618958 (View on PubMed)

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.

Reference Type DERIVED
PMID: 37088311 (View on PubMed)

Other Identifiers

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S-20170087

Identifier Type: -

Identifier Source: org_study_id

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