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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03308916
Recruitment Status : Recruiting
First Posted : October 13, 2017
Last Update Posted : October 13, 2017
Sponsor:
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
Information provided by (Responsible Party):
Maja Thiele, Odense University Hospital

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.

Condition or disease Intervention/treatment Phase
Liver Diseases, Alcoholic Fibrosis 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 Not Applicable

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 patients from at-risk populations and 1000 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 patients with elevated liver stiffness (≥8.0 kiloPascal; estimated 200 patients with alcoholic liver disease, 400 patients with non-alcoholic fatty liver disease and 80 patients 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. Participants with a positive screening elastography will be followed for disease progression with repeated liver stiffness measurements and serum fibrosis markers after one year. All participants will be followed for 10 years to assess liver-related outcomes and all-course mortality.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 4000 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single intervention group selected for screening with a historical control group
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Screening At-risk Populations for Hepatic Fibrosis With Non-invasive Markers
Actual Study Start Date : October 6, 2017
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : October 30, 2032

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Diseases

Arm Intervention/treatment
Experimental: Liver stiffness measurement
Transient elastography in fasting state
Diagnostic Test: 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
Other Names:
  • FibroScan
  • TE

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)
Other Name: ELF

Diagnostic Test: Indirect serum markers of liver fibrosis
Diagnostic markers using combination of routine liver biochemistry: age, AST, ALT, platelet count, cholesterol, GGT
Other Names:
  • Forns index
  • FIB-4
  • APRI
  • AST-ALT ratio
  • Age-platelet ratio

Diagnostic Test: Direct serum markers of liver fibrosis
Serum markers that reflect liver extracellular matrix turnover and -accumulation
Other Names:
  • Neoepitopes
  • Collagen products
  • Extracellular matrix

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.

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)
Other Names:
  • CK18
  • M30
  • M65

Diagnostic Test: Omics markers
Markers combining signatures of liver fibrosis and hepatic inflammation from many 'omics technologies
Other Names:
  • Multi-omics markers
  • Lipidomics
  • Microbiomics
  • Genomics
  • Metagenomics
  • Metatranscriptomics
  • Transcriptomics
  • miRNA-omics
  • Metabolomics
  • Proteomics




Primary Outcome Measures :
  1. Biopsy-verified advanced fibrosis [ Time Frame: 5 years ]
    Number of patients with biopsy-verified, advanced fibrosis (Kleiner fibrosis score ≥F3) detected by screening

  2. 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


Secondary Outcome Measures :
  1. 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

  2. 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   30 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 45-75)
  • 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 8.0 kPa from screening to time of planned liver biopsy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03308916


Contacts
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Contact: Maria Kjaergaard, MD +4528345541 maria.kjaergaard@rsyd.dk
Contact: Maja Thiele, MD, PhD +4524998068 maja.thiele@rsyd.dk

Locations
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Denmark
Department of Gastroenterology and Hepatology, Odense University Hospital Recruiting
Odense, Denmark, 5000
Contact: Maja Thiele, MD, PhD    65412752 ext 45    maja.thiele@rsyd.dk   
Principal Investigator: Maja Thiele, MD PhD         
Sub-Investigator: Aleksander Krag, MD PhD Professor         
Sponsors and Collaborators
Maja Thiele
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
Investigators
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Principal Investigator: Maja Thiele, MD PhD Department of Gastroenterology and Hepatology, Odense University Hospital
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Responsible Party: Maja Thiele, Associate professor, Odense University Hospital
ClinicalTrials.gov Identifier: NCT03308916    
Other Study ID Numbers: S-20170087
First Posted: October 13, 2017    Key Record Dates
Last Update Posted: October 13, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: OPEN - Odense Patient Exploratory data Network, managed by Odense University Hospital
Supporting Materials: Study Protocol
Clinical Study Report (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.
URL: https://open.rsyd.dk/OpenProjects/da/openProject.jsp?openNo=475

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Maja Thiele, Odense University Hospital:
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
Additional relevant MeSH terms:
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Liver Diseases
Liver Diseases, Alcoholic
Fibrosis
Pathologic Processes
Digestive System Diseases
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Liver Extracts
Hematinics