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

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:

1. Can the mSEPT9 blood test detect liver cancer earlier or more accurately than AFP in people with cirrhosis?
2. Does combining both tests (AFP and mSEPT9) improve the accuracy of diagnosis?

The study, called SEPT9-CROSS, is a phase III, multicenter, cross-sectional diagnostic accuracy study. It includes 639 adults with cirrhosis who were enrolled across participating hospitals in France. After reviewing eligibility and exclusion criteria, 574 participants were included in the final analysis: 118 people with liver cancer and 456 people with cirrhosis but no liver cancer.

The main outcome (primary outcome) is the presence of liver cancer at the time of study enrollment, confirmed by imaging or biopsy based on international medical guidelines. An exploratory outcome looks at participants who developed liver cancer within 12 months after joining the study. This second measure helps researchers understand whether the test can identify early or hidden disease.

All participants gave written informed consent before joining the study. As part of their regular medical care, participants received clinical exams, blood tests, and imaging studies (such as ultrasound). During routine blood draws, an extra 20 milliliters of blood (about 4 teaspoons) was collected for the mSEPT9 test. These blood samples were processed and safely stored at the CRB Lorrain biobank at the University Hospital of Nancy, France, for later analysis.

The study compares the performance of AFP and mSEPT9 individually and in combination. Two diagnostic strategies were tested:

* 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

Interventions

DIAGNOSTIC_TEST

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

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

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France

  collaborator OTHER_GOV

• Groupement Interrégional de Recherche Clinique et d'Innovation

  collaborator OTHER

• Epigenomics, Inc

  collaborator INDUSTRY

• New Day Diagnostics

  collaborator NETWORK

• Central Hospital, Nancy, France

  lead OTHER

Principal Investigators

• Abderrahim OUSSALAH, MD, PhD · University Hospital of Nancy, INSERM UMR_S 1256, Faculty of Medicine of Nancy, University of Lorraine

Study Design

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-02-12

Primary Completion

2024-10-17

Completion

2024-10-17

Countries

• France

Study Locations