Circulating Cell-free DNA-based Epigenetic Biomarker mSEPT9 for Hepatocellular Carcinoma Detection in Cirrhosis

NCT03311152 | Completed

• 1 other identifier: 2017-A01885-48
• Study Type: interventional
• Target: 639
• Locations: 1 country
• Sites: 1

Brief Summary

Brief Summary (Plain-Language Version - Compliant with ClinicalTrials.gov Guidelines) The goal of this observational study is to learn whether a blood test called methylated SEPT9 (mSEPT9) can help diagnose hepatocellular carcinoma (HCC), the most common type of liver cancer, in people who already have cirrhosis. The study also compares how well this new test works compared with the current standard blood test called alpha-fetoprotein (AFP). The main questions the study aims to answer are:

• Tier 1 (high sensitivity): A positive result if either AFP or mSEPT9 was high.
• Tier 2 (high specificity): A positive result only if both AFP and mSEPT9 were high. Researchers used statistical models to measure how well the tests identified cancer. This included estimating the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and predictive values (how likely a result is to be correct). These calculations were repeated 10,000 times using computer simulations to ensure reliability. Advanced Bayesian statistical models were also used to confirm the stability and strength of the results and to compare the performance of mSEPT9 and AFP. A risk model (called a nomogram) was created to estimate each participant's probability of having liver cancer based on their test results. All analyses were planned before the study started and carried out using the software R (version 4.3.0) and Python (PyCharm environment) with validated scripts to ensure accuracy and reproducibility.

Conditions

Hepatocellular Carcinoma; Cirrhosis

Keywords

Hepatocellular carcinoma; Cirrhosis; Circulating epigenetic biomarker; Plasma biomarker; SEPT9; Septin9; DNA methylation biomarker; Circulating DNA methylation biomarker; Alpha-fetoprotein

Outcome Measures

Primary Outcomes (1)

• Presence of hepatocellular carcinoma.

  Hepatocellular carcinoma (HCC) diagnosis was established according to international AASLD/EASL criteria, based on characteristic imaging findings or histopathologic confirmation. All HCC determinations were adjudicated by experienced hepatologists blinded to mSEPT9 test results to prevent assessment bias. The primary outcome was the presence of HCC at inclusion, confirmed by imaging or histopathology. An exploratory outcome (Primary outcome M12) was prespecified, including both baseline HCC and new HCC diagnosed within 12 months after inclusion, to minimize potential misclassification related to early or subclinical disease and to assess the temporal stability of diagnostic performance. For both outcomes, a "strict" analytical variant excluded controls who developed HCC within 12 months, ensuring temporal consistency and avoiding contamination bias.

  The diagnosis of HCC will be based on overall patient's evaluation including clinical, biological and imaging workup which will be carried out during the consultation and/or the three months preceding or following the inclusion consultation.

Secondary Outcomes (1)

• Presence of early hepatocellular carcinoma (HCC). Early HCC will be defined as a tumor smaller than 30 mm according to Kudo M (Liver Cancer. 2013;2:69-72). This definition has been updated to align with the BCLC staging system 2022, stages 0-A.

  The diagnosis will be based on an overall patient's evaluation including clinical, biological and imaging workup which will be carried out during the consultation and/or the three months preceding or following the inclusion consultation.

Study Arms (2)

HCC-free cirrhotic patients (Controls)

EXPERIMENTAL

Patients with cirrhosis without evidence of hepatocellular carcinoma (HCC) were enrolled as part of an established HCC surveillance program involving abdominal ultrasonography and alpha-fetoprotein measurement every six months in the participating centers. Each participant underwent testing with the plasma methylated SEPT9 (mSEPT9) assay (Epi proColon 2.0 CE; Epigenomics, Berlin, Germany).

Diagnostic Test: "Epi proColon 2.0 CE" test from Epigenomics, Inc (Berlin, Germany)

HCC-positive cirrhotic patients (Cases)

EXPERIMENTAL

Patients with cirrhosis and a diagnosis of hepatocellular carcinoma established according to the American Association for the Study of Liver Diseases (AASLD) guidelines were enrolled at the participating centers. Each participant underwent testing with the plasma methylated SEPT9 (mSEPT9) assay (Epi proColon 2.0 CE; Epigenomics, Berlin, Germany).

Diagnostic Test: "Epi proColon 2.0 CE" test from Epigenomics, Inc (Berlin, Germany)

Interventions

"Epi proColon 2.0 CE" test from Epigenomics, Inc (Berlin, Germany) DIAGNOSTIC_TEST

The mSEPT9 assay consists of DNA extraction from plasma, bisulfite conversion of DNA, purification of bis-DNA, and real-time PCR.

Also known as: Plasma mSEPT9 test

HCC-free cirrhotic patients (Controls); HCC-positive cirrhotic patients (Cases)

Eligibility Criteria

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

You may qualify if:

• Patient aged 18 and over.
• Patient with a diagnosis of cirrhosis (alcohol, HBV, HBC, NASH, hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) with or without hepatocellular carcinoma (for each arm).
• Affiliation to the French Social Security System (Health Insurance)
• Malignant liver tumor other than HCC: cholangiocarcinoma, hepatic metastasis of a carcinoma (e.g., colorectal adenocarcinoma);
• History of HCC treated by surgical resection, focal destruction \[radiofrequency, stereotactic radiotherapy (CYBERKNIFE®)\], arterial chemoembolization, or radioembolization within the last five years.
• Legal protection measures;
• Pregnant woman;
• Hemodialysis, ongoing (possibility of interference with the test);
• Presence of associated cancer (e.g., colorectal adenocarcinoma, urothelial carcinoma, breast carcinoma, etc.) since less than five years;
• Presence of a hematological malignancy (no time limit).

Sponsors & Collaborators

• Central Hospital, Nancy, France: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator
• Groupement Interrégional de Recherche Clinique et d'Innovation: collaborator
• Epigenomics, Inc: collaborator
• New Day Diagnostics: collaborator

Study Sites (1)

University Hospital of Nancy (CHRU de Nancy)

Vandœuvre-lès-Nancy, 54511, France

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Fibrosis

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Abderrahim OUSSALAH, MD, PhD

  University Hospital of Nancy, INSERM UMR_S 1256, Faculty of Medicine of Nancy, University of Lorraine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: The index test (mSEPT9) will be reported at the final step of the research, at time of data analysis.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: OUSSALAH Abderrahim, MD, PhD

Model Details: Cross-sectional

Study Record Dates

• First Submitted: October 5, 2017
• First Posted: October 17, 2017
• Study Start: February 12, 2018
• Primary Completion: October 17, 2024
• Study Completion: October 17, 2024
• Last Updated: June 10, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Final report after data completion.
• Access Criteria: After the publication of study results.

Locations

FR (1)