Validation of a Molecular Test for Risk-stratification of Patients With High-risk Intestinal Metaplasia (GCEP2 Study)

April 7, 2024 updated by: National University Hospital, Singapore

This study is carried out to find out if a customized molecular test can identify a subgroup of patients with very-high-risk of developing stomach cancer within patients with intestinal metaplasia (IM). The investigators hypothesise that the incidence of dysplasia and GC cases in the molecular-test-positive group will be significantly higher than that in the molecular-test-negative group.

Such a test has the potential to guide clinicians to better manage patients with IM by allowing endoscopic surveillance to be focused on individuals at very-high-risk of developing stomach cancer, at the same time avoiding or reducing endoscopies for those at lower risk.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Objectives:

The main objective of this study is to determine whether a customised molecular test can identify prospectively, within patients with intestinal metaplasia (IM), a subgroup of patients with very high risk of dysplasia or gastric cancer (GC). The secondary objectives of this study are to validate the predictive value of a panel of blood microRNA biomarkers for predicting risk of GC, as well as to determine the accuracy of detection of Helicobacter pylori infection using next-generation sequencing, and compare it with the current gold standard, urea breath test.

Study Design:

An international, multicenter cohort to evaluate the clinical utility of a customized molecular test to identify a subset of IM patients at very high risk of GC. Target recruitment is 500 subjects with IM of OLGIM Stage 2 to 4.

As the Updated Sydney biopsy protocol is not routinely performed for clinical purposes and most subjects will be recruited prior to confirming their OLGIM staging at baseline, some subjects will be withdrawn from the study if detected to have no IM, or IM assessed to be OLGIM Stage 1, at baseline OGD.

Collaborating sites are requested to provide the following specimens with associated demographic and clinic-pathological data (as indicated in Case Report Form): Snap-frozen tissue and FFPE tissue from antrum site for DNA extraction, serum for H. pylori antibody test and miRNA profiling, and buffy coat for DNA extraction.

Enrollment:

Patients seen by investigators during clinics will be considered for enrollment.

To minimize the number of subjects who are withdrawn after baseline endoscopy due to failure to detect at least Stage 2-4 OLGIM at baseline, patients with history of moderate or severe IM at either antrum or body can be prioritized for recruitment.

Baseline:

  1. Questionnaire Subjects will be asked to complete a baseline questionnaire, providing information on the demographics, personal medical history, lifestyle, and family history of GC. Clinical data and identifiers will be recorded.
  2. Urea Breath Test Subjects will fast for 6 hours or overnight before undergoing the Urea Breath Test (UBT). Breath collection will be performed before ingestion of 13C urea, and at 10min, 20min and 30min after ingestion.
  3. OGD and biopsies

Subjects will undergo a baseline OGD under high-definition white-light (1080p) and biopsy to ascertain OLGIM status. A video-recording of the OGD will be carried out during the procedure for validation of diagnosis. Gastric mucosal biopsies will be taken as follows:

  • 1 biopsy each from AL, AG, IA, BL, BG according to the Updated Sydney System will be fixed in 4% paraformaldehyde (PFA) and sent for histological examination
  • 2 adjacent biopsies at AL, and 2 adjacent biopsies at BL, will be snap-frozen in liquid nitrogen

The locations are defined as follows:

  • AL - lesser curvature of the antrum, within 2-3cm of the pylorus
  • AG - greater curvature of the antrum, within 2-3cm of the pylorus
  • IA - incisura angularis
  • BL - lesser curvature of the corpus, 4cm proximal to the angulus
  • BG - middle portion of the greater curvature of the corpus, 8cm from the cardia

Should the endoscopist observe suspected areas of IM in the antrum and/or corpus that are within the above-defined Updated Sydney System locations, then biopsies for histological examination, as well as 2 adjacent frozen biopsies, should be taken from these suspected areas of IM instead.

Should the endoscopist observe suspected areas of IM in the antrum and/or corpus that are outside of the above-defined Updated Sydney System locations, then the 2 adjacent frozen biopsies should be taken from these suspected areas of IM instead.

All mucosal lesions identified during OGD will be biopsied separately as a part of normal clinical practice and sent for histopathological assessment.

Frozen biopsy samples will be stored at a high-quality tissue bank.

Investigators will follow the above protocol. However, they may deviate from protocol if the interests of the patient require so.

Blood Collection, Processing and Analyses:

20mls of blood will be drawn from each subject. Serum, plasma and buffy coat will be extracted.

Histological Assessment:

All biopsy samples will be assessed for degree of chronic gastritis, atrophic gastritis, presence of H. pylori organisms, IM and dysplasia. These will be scored using the Updated Sydney System. Presence of IM is indicated by presence of globet cells based on hematoxylin and eosin (H&E) staining or Alcian Blue (AB) positive expression, and will be classified into mild, moderate and marked. Dysplasia will be graded by the revised Vienna classification, and classification of carcinoma will be according to the WHO classification of tumors and AJCC staging system. The percentage of gastric epithelial mucosa showing the features of IM in biopsies will be evaluated to derive OLGIM stage.

Molecular test:

Three main genomic alterations - increased mutation frequencies, somatic copy number alterations (sCNAs) and telomere shortening - were previously established to show associations with disease progression of IM to dysplasia or GC, or persistence of IM. A significant proportion of sCNAs in IM samples were found to be located at chromosome 8q, where the oncogene Myc resides. A customised molecular test will be developed based on a panel primarily targeting genomic regions with recurrently mutated genes and chromosome 8q amplification in IM patients. The customized test aims to further stratify IM patients. Total genomic DNA will be extracted from biopsies (frozen tissue and FFPE) and matched blood samples. A targeted gene panel will be applied so that specific genomic regions of interest are captured, reducing the cost and amount of data analysis significantly. Library preparation will be performed using the target enrichment assays according to manufacturer instructions. Mutation calls and chromosome 8q amplification will be determined using the Genome Analysis Toolkit (GATK) software. Subjects are classified as test-positive if a somatic variant with at least 10 variant supporting reads or a copy number variant with segmented mean coverage of at least 2 standard deviations away from the copy neutral mean is identified.

miRNA profiling: Total RNA from serum is isolated and converted to cDNA, which is then quantified. Target miRNA expression levels after normalization of both technical and biological variations are analysed to identify panels of miRNAs with the highest discriminatory power between healthy and disease states. Each subject will be assigned a score based on miRNA expression profile, indicating the possibility of having GC. The result will be compared with OGD and histology which is the gold standard for diagnosis of GC.

Follow-up:

Subjects will be followed-up at the clinic or via telephone for status update at Years 1 and 3. Clinical data will be collected through a questionnaire. A window period of 6 months before or after the anniversary baseline OGD date is acceptable.

Subjects will undergo a surveillance OGD at Years 2 and 4 to assess whether subject has reached endpoint. Biopsies will be taken following the protocol described. Clinical data will be collected through a questionnaire and the database updated. A window period of 6 months before or after the anniversary baseline OGD date is acceptable.

Subjects will be followed-up yearly at the clinic or via telephone for status update for Years 5-10. Clinical data will be collected through a questionnaire. A window period of 6 months before or after the anniversary baseline OGD date is acceptable. Should the incidence of GC at or after Year 4 among the cohort be sufficient to reject the null hypothesis with the level of significance and power as described, yearly follow-up for Years 5-10 may be discontinued.

Sample size calculation:

The proposed sample size for the prospective cohort study was estimated using the logrank test for the time-to-progression outcome. Assuming a 4-year cumulative incidence of progression of 10% in the test positive group and 3% in the test negative group respectively (i.e. hazard ratio, HR = 3.5), a sample size of 480 will be required based on a level of significance of 5% and a power of 85%. Further assuming an attrition of 5%, the overall sample size will be 500.

Statistical Analysis:

Categorical variables will be analysed using chi-square test or Fisher's exact test. Continuous variables will be analysed using Student's t-test or Mann-Whitney U test. Parameters with P value <0.05 in the univariate analysis will be included in the multivariate analysis. Multivariate analysis will be performed using Cox regression analysis. P <0.05 is considered to be statistically significant.

Study Type

Observational

Enrollment (Estimated)

500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong
        • The Chinese University of Hong Kong
  • Japan
      • Tokyo, Japan
        • Nihon University School of Medicine
  • Korea, Republic of
      • Seoul, Korea, Republic of
        • Yonsei University, Republic of Korea
  • Singapore
      • Singapore, Singapore, 169608
        • Singapore General Hospital
      • Singapore, Singapore, 119074
        • National University Hospital
      • Singapore, Singapore, 308433
        • Tan Tock Seng Hospital, Singapore
  • Taiwan
      • Taipei, Taiwan
        • National Taiwan University Hospital
  • United States
    • California
      • Stanford, California, United States, 94305
        • Stanford University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Sampling Method

Non-Probability Sample

Study Population

Participants who have been referred to the participating study sites for gastroscopy for clinical indications, and were detected to have IM of OLGIM Stage 2 to 4 at baseline.

Description

Inclusion Criteria:

  1. The subject is above 50 years old or turns 50 years old in the year of recruitment
  2. The subject is below 76 years old in the year of recruitment
  3. The subject is willing and able to provide signed and dated patient informed consent form indicating that they has been informed of all pertinent aspects of the study

Exclusion Criteria:

  1. The subject who has bleeding disorders, such as haemophilia, in whom biopsies are contraindicated.
  2. The subject with a personal history of high-grade dysplasia or GC.
  3. The subject with liver cirrhosis.
  4. The subject with previous total or partial gastrectomy.
  5. The subject with severe co-morbid illness, such as end-stage renal failure (ESRF), congestive cardiac failure (CCF), severe osteoarthritis (OA), and rheumatoid arthritis (RA) requiring long-term non-steroidal anti-inflammatory drug (NSAID) therapy.
  6. The subject with other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may interfere with the interpretation of study results and in the judgement of the investigator would make the subject unsuitable for entry into the study.
  7. The subject on regular anti-coagulant prophylaxis such as warfarin must be able to undergo a 5-day washout period before each gastroscopy. The subject on aspirin, ticlopidine and clopidogrel must be able to undergo a one-week washout period before each gastroscopy. The subject's physician or study co-investigator will exercise their clinical judgement to ensure subject's safety.
  8. The subject is unwilling or unable to provide signed informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Participants with IM of OLGIM Stage 2 to 4
Participants with Intestinal Metaplasia of Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) that is evaluated to be Stage 2 to 4.
Diagnostic test: Urea Breath Test
Study participant will fast for 6 hours or overnight before undergoing the Urea Breath Test (UBT) to test for current H. pylori infection. Breath collection will be performed before ingestion of 13C urea, and at specified time intervals after ingestion.
Procedure: Blood Collection, processing and analyses
20ml of blood will be drawn from study participant at the baseline visit for molecular analyses.
Procedure: Gastroscopy and biopsies collection
Study participant will undergo gastroscopy with collection of gastric mucosal biopsies at the baseline visit to ascertain OLGIM status and for molecular analyses. Study participant will undergo surveillance gastroscopy for gastric cancer at years 2 and 4 to assess whether they have reached endpoint.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Gastric Cancer
Time Frame: 10 years
Number of patients who develop gastric cancer, including high grade dysplasia, carcinoma in-situ and adenocarcinoma
10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National University Hospital, Singapore

Collaborators

National Taiwan University Hospital
Chinese University of Hong Kong
Singapore General Hospital
Tan Tock Seng Hospital
Stanford University
Yonsei University
Nihon University

Investigators

  • Study Chair: Khay Guan Yeoh, MBBS, MMed, National University Hospital, Singapore
  • Principal Investigator: Jonathan WJ Lee, MBBS, MRCP, National University Hospital, Singapore

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 23, 2019

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

December 1, 2033

Study Registration Dates

First Submitted

March 13, 2023

First Submitted That Met QC Criteria

March 13, 2023

First Posted (Actual)

March 23, 2023

Study Record Updates

Last Update Posted (Actual)

April 9, 2024

Last Update Submitted That Met QC Criteria

April 7, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2019/00629

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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