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HCC Screening Using DNA Methylation Changes in ctDNA

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ClinicalTrials.gov Identifier: NCT03483922
Recruitment Status : Recruiting
First Posted : March 30, 2018
Last Update Posted : May 4, 2020
Sponsor:
Collaborator:
International Centre for Diarrhoeal Disease Research, Bangladesh
Information provided by (Responsible Party):
HKGepitherapeutics

Brief Summary:

Hepatocellular Carcinoma (HCC) is the fifth most common cancer world-wide. It is particularly prevalent in Asia, and its occurrence is highest in areas where hepatitis B is prevalent, indicating a possible causal relationship. Follow up of high-risk populations such as chronic hepatitis patients and early diagnosis of transitions from chronic hepatitis to HCC would improve cure rates. In most cases HCC is detected late resulting in increased mortality and morbidity.

The purpose of this study is to develop and test non-invasive biomarkers based on methylation changes in PBMC, T-cells and circulated tumor DNA in hepatocellular carcinomas patients.


Condition or disease Intervention/treatment
Hepatocellular Carcinoma Diagnostic Test: ctDNA methylation in and it's Correlation wth Development and prediction of HCC

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Study Type : Observational
Estimated Enrollment : 400 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Clinical Trials on Detection of Hepatocellular Carcinoma With Non-invasive Method Based on DNA Methylation of Circulated Tumor DNA, PBMC and T Cells
Actual Study Start Date : August 20, 2018
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : September 1, 2020

Group/Cohort Intervention/treatment
chronic hepatitis B
This group will include 50 with hepatitis B subjects and the diagnoses will be based on AASLD practice guideline.
Diagnostic Test: ctDNA methylation in and it's Correlation wth Development and prediction of HCC
Blood sample from patients with HCC, healthy individuals and individuals with hepatitis B will be collected, and DNA will extracted from PBMC and circulated tumor DNA will be subjected to bisulfite conversion. DNA from PBMC DNA will be analyzed with primers developed for the AHNAK-STAP1 genes. Plasma samples will be subjected to EZ direct DNA extraction and bisulfite conversion kit and will be amplified with primers developed to amplify the target regions. DNA will be used for the subsequent PCR amplification with specific primer to generate PCR amplicon for sequencing using a double PCR procedure. The product of PCR reaction will be subjected to indexed MiSeq Next-Generation sequencing that will allow us quantify DNA methylation level.

HCC Cases

This group will include 350 in stage 0, stage A, stage B, Stage C+D of hepatocellular carcinoma.

HCC staging will be diagnosed according to EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma

Diagnostic Test: ctDNA methylation in and it's Correlation wth Development and prediction of HCC
Blood sample from patients with HCC, healthy individuals and individuals with hepatitis B will be collected, and DNA will extracted from PBMC and circulated tumor DNA will be subjected to bisulfite conversion. DNA from PBMC DNA will be analyzed with primers developed for the AHNAK-STAP1 genes. Plasma samples will be subjected to EZ direct DNA extraction and bisulfite conversion kit and will be amplified with primers developed to amplify the target regions. DNA will be used for the subsequent PCR amplification with specific primer to generate PCR amplicon for sequencing using a double PCR procedure. The product of PCR reaction will be subjected to indexed MiSeq Next-Generation sequencing that will allow us quantify DNA methylation level.

Healthy
This group will include 50 healthy sex and age matched controls.
Diagnostic Test: ctDNA methylation in and it's Correlation wth Development and prediction of HCC
Blood sample from patients with HCC, healthy individuals and individuals with hepatitis B will be collected, and DNA will extracted from PBMC and circulated tumor DNA will be subjected to bisulfite conversion. DNA from PBMC DNA will be analyzed with primers developed for the AHNAK-STAP1 genes. Plasma samples will be subjected to EZ direct DNA extraction and bisulfite conversion kit and will be amplified with primers developed to amplify the target regions. DNA will be used for the subsequent PCR amplification with specific primer to generate PCR amplicon for sequencing using a double PCR procedure. The product of PCR reaction will be subjected to indexed MiSeq Next-Generation sequencing that will allow us quantify DNA methylation level.




Primary Outcome Measures :
  1. DNA methylation of circulated tumor and PBMC DNA and its Correlation to Development and prediction of HCC [ Time Frame: 6 months to 1 year ]

    We will develop the linear model and a threshold value differentiating breast cancer from control based on the 100 patient training set. The model will be provided to the researchers:

    Methylation score=CG1*b1+CG2*b2+ CG3*b3 + e

    CG1 is the methylation value of the first CG b1 is the regression coefficient for the first CG and e equals the intercept.

    We will develop the regression coefficient and intercept as well as the DNA methylation values for each patient for each CG. We will first compute the polygenic methylation score for each patient. Then based on the computer threshold based on the training cohort will call the samples as liver cancer or not.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
HCC staging will be diagnosed according to EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. The patients will be divided into four groups, including Stage 0 (1) (n=100), stage A (2) (n=100), stage B (3) (n=100) and stage C+D (4) (n=100). As controls we will recruit chronic hepatitis B (n=100), which diagnose will be confirmed using AASLD practice guideline for chronic Hepatitis B, and healthy sex and age matched controls (n=100).
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of HCC by EASL-EORTC guidelines
  • Confirmed hepatitis B diagnosis for HepB patients using AASLD practice guidelines.

Exclusion Criteria for HCC:

  • Cirrhosis, any other known inflammatory disease (bacterial or viral infection with the exception of hepatitis B or C, diabetes, asthma, autoimmune disease, active thyroid disease) which could alter T cells and monocytes characteristics
  • Other cancers.

Exclusion Criteria for HepB:

  • Diagnosis of HCC or any other cancer.

Exclusion Criteria for Healthy Controls:

  • Any known inflammatory or infectious disease including HepB and HepC
  • Chronic diseases,
  • Cancer
  • Medications or drug use

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): NCT03483922


Locations
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Bangladesh
Infectious Diseases Division Recruiting
Dhaka, Bangladesh
Contact: Wasif Ali Khan, PhD    880-2-9827057    wakhan@icddrb.org   
Sponsors and Collaborators
HKGepitherapeutics
International Centre for Diarrhoeal Disease Research, Bangladesh
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Responsible Party: HKGepitherapeutics
ClinicalTrials.gov Identifier: NCT03483922    
Other Study ID Numbers: HKG-Bng-HCC-100
First Posted: March 30, 2018    Key Record Dates
Last Update Posted: May 4, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases