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

Primary Purpose

Liver Diseases, Alcoholic, Fibrosis

Status

Recruiting

Phase

Not Applicable

Locations

Denmark

Study Type

Interventional

Intervention

transient elastography

Enhanced liver fibrosis test

Indirect serum markers of liver fibrosis

Direct serum markers of liver fibrosis

LiverTRAIL

Cytokeratin 18

Omics markers

About this trial

This is an interventional diagnostic trial for Liver Diseases, Alcoholic focused on measuring 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

Eligibility Criteria

30 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Department of Gastroenterology and Hepatology, Odense University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Liver stiffness measurement

Arm Description

Transient elastography in fasting state

Outcomes

Primary Outcome Measures

Biopsy-verified advanced fibrosis

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

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

Secondary Outcome Measures

Liver related outcomes

Mortality

Overall number of deaths 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).

Full Information

NCT ID

NCT03308916

First Posted

February 4, 2016

Last Updated

August 29, 2022

Sponsor

Maja Thiele

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT03308916

Brief Title

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

Acronym

SIPHON

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 6, 2017 (Actual)

Primary Completion Date

December 30, 2025 (Anticipated)

Study Completion Date

October 30, 2035 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Maja Thiele

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Model Description

Single intervention group selected for screening with a historical control group

Masking

None (Open Label)

Allocation

N/A

Enrollment

6500 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Liver stiffness measurement

Arm Type

Experimental

Arm Description

Transient elastography in fasting state

Intervention Type

Diagnostic Test

Intervention Name(s)

transient elastography

Other Intervention Name(s)

FibroScan, TE

Intervention Description

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

Intervention Name(s)

Enhanced liver fibrosis test

Other Intervention Name(s)

ELF

Intervention Description

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

Intervention Name(s)

Indirect serum markers of liver fibrosis

Other Intervention Name(s)

Forns index, FIB-4, APRI, AST-ALT ratio, Age-platelet ratio

Intervention Description

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

Intervention Type

Diagnostic Test

Intervention Name(s)

Direct serum markers of liver fibrosis

Other Intervention Name(s)

Neoepitopes, Collagen products, Extracellular matrix

Intervention Description

Serum markers that reflect liver extracellular matrix turnover and -accumulation

Intervention Type

Diagnostic Test

Intervention Name(s)

LiverTRAIL

Intervention Description

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

Intervention Name(s)

Cytokeratin 18

Other Intervention Name(s)

CK18, M30, M65

Intervention Description

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

Intervention Name(s)

Omics markers

Other Intervention Name(s)

Multi-omics markers, Lipidomics, Microbiomics, Genomics, Metagenomics, Metatranscriptomics, Transcriptomics, miRNA-omics, Metabolomics, Proteomics

Intervention Description

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

Primary Outcome Measure Information:

Title

Biopsy-verified advanced fibrosis

Description

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

Time Frame

5 years

Title

Liver-related outcomes

Description

Time Frame

10 years

Secondary Outcome Measure Information:

Title

Liver related outcomes

Description

Time Frame

10 years

Title

Mortality

Description

Time Frame

10 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

30 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Maja Thiele, MD, PhD, Professor

Phone

+4524998068

maja.thiele@rsyd.dk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Maja Thiele, MD, PhD, Professor

Organizational Affiliation

Department of Gastroenterology and Hepatology, Odense University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Gastroenterology and Hepatology, Odense University Hospital

City

Odense

ZIP/Postal Code

5000

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Maja Thiele, MD, PhD

Phone

65412752

Ext

maja.thiele@rsyd.dk

First Name & Middle Initial & Last Name & Degree

Maja Thiele, MD PhD

First Name & Middle Initial & Last Name & Degree

Aleksander Krag, MD PhD Professor

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

OPEN - Odense Patient Exploratory data Network, managed by Odense University Hospital

IPD Sharing Time Frame

After publication of study results

IPD Sharing Access Criteria

Accessible after contact to OPEN, who will pass on the request to primary investigator. No criteria.

IPD Sharing URL

https://open.rsyd.dk/OpenProjects/da/openProject.jsp?openNo=475

Learn more about this trial

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

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