- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03308916
Screening At-risk Populations for Hepatic Fibrosis With Non-invasive Markers (SIPHON)
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Maja Thiele, MD, PhD, Professor
- Phone Number: +4524998068
- Email: maja.thiele@rsyd.dk
Study Locations
-
-
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Odense, Denmark, 5000
- Recruiting
- Department of Gastroenterology and Hepatology, Odense University Hospital
-
Contact:
- Maja Thiele, MD, PhD
- Phone Number: 45 65412752
- Email: maja.thiele@rsyd.dk
-
Principal Investigator:
- Maja Thiele, MD PhD
-
Sub-Investigator:
- Aleksander Krag, MD PhD Professor
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Liver stiffness measurement
Transient elastography in fasting state
|
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
Other Names:
Patented, commercially available algorithm of hyaluronic acid (HA), N-terminal propeptide of collagen type 3 (P3NP) and tissue inhibitor of metalloproteinase 1 (TIMP-1)
Other Names:
Diagnostic markers using combination of routine liver biochemistry: age, AST, ALT, platelet count, cholesterol, GGT
Other Names:
Serum markers that reflect liver extracellular matrix turnover and -accumulation
Other Names:
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 from liver cell cytoskeleton; when cells undergo apoptosis, caspase-cleaved CK18 is released (M30), whereas full-length CK18 is realised during necrosis (M65)
Other Names:
Markers combining signatures of liver fibrosis and hepatic inflammation from many 'omics technologies
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Biopsy-verified advanced fibrosis
Time Frame: 5 years
|
Number of patients with biopsy-verified, advanced fibrosis (Kleiner fibrosis score ≥F3) detected by screening
|
5 years
|
Liver-related outcomes
Time Frame: 10 years
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Liver related outcomes
Time Frame: 10 years
|
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
|
Mortality
Time Frame: 10 years
|
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).
|
10 years
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Maja Thiele, MD, PhD, Professor, Department of Gastroenterology and Hepatology, Odense University Hospital
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
- collagen
- NAFLD
- liver fibrosis
- screening
- microbiome
- non-alcoholic fatty liver disease
- alcoholic liver disease
- metabolomics
- fibroscan
- elastography
- ALD
- ultrasound elastography
- non-invasive markers
- gut-liver-axis
- cost-benefit
- aixplorer
- advanced fibrosis
- enhanced liver fibrosis test
- direct liver fibrosis markers
- ELF
- cytokeratin-18
- neoepitopes
Additional Relevant MeSH Terms
Other Study ID Numbers
- S-20170087
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- Study Protocol
- Clinical Study Report (CSR)
- Analytic Code
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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