Trial Title:
Validation of a Molecular Test for Risk-stratification of Patients With High-risk Intestinal Metaplasia (GCEP2 Study)
NCT ID:
NCT05782465
Condition:
Stomach Neoplasm
Conditions: Official terms:
Stomach Neoplasms
Metaplasia
Conditions: Keywords:
Gastric Cancer
Stomach Neoplasm
Intestinal Metaplasia
Study type:
Observational
Overall status:
Active, not recruiting
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Procedure
Intervention name:
Blood Collection, processing and analyses
Description:
20ml of blood will be drawn from study participant at the baseline visit for molecular
analyses.
Arm group label:
Participants with IM of OLGIM Stage 2 to 4
Intervention type:
Procedure
Intervention name:
Gastroscopy and biopsies collection
Description:
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.
Arm group label:
Participants with IM of OLGIM Stage 2 to 4
Intervention type:
Diagnostic Test
Intervention name:
Urea Breath Test
Description:
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.
Arm group label:
Participants with IM of OLGIM Stage 2 to 4
Summary:
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.
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.
Criteria for eligibility:
Study pop:
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.
Sampling method:
Non-Probability Sample
Criteria:
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.
Gender:
All
Minimum age:
50 Years
Maximum age:
75 Years
Locations:
Facility:
Name:
Stanford University
Address:
City:
Stanford
Zip:
94305
Country:
United States
Facility:
Name:
The Chinese University of Hong Kong
Address:
City:
Hong Kong
Country:
Hong Kong
Facility:
Name:
Nihon University School of Medicine
Address:
City:
Tokyo
Country:
Japan
Facility:
Name:
Yonsei University, Republic of Korea
Address:
City:
Seoul
Country:
Korea, Republic of
Facility:
Name:
National University Hospital
Address:
City:
Singapore
Zip:
119074
Country:
Singapore
Facility:
Name:
Singapore General Hospital
Address:
City:
Singapore
Zip:
169608
Country:
Singapore
Facility:
Name:
Tan Tock Seng Hospital, Singapore
Address:
City:
Singapore
Zip:
308433
Country:
Singapore
Facility:
Name:
National Taiwan University Hospital
Address:
City:
Taipei
Country:
Taiwan
Start date:
August 23, 2019
Completion date:
December 2033
Lead sponsor:
Agency:
National University Hospital, Singapore
Agency class:
Other
Collaborator:
Agency:
Tan Tock Seng Hospital
Agency class:
Other
Collaborator:
Agency:
Singapore General Hospital
Agency class:
Other
Collaborator:
Agency:
Yonsei University
Agency class:
Other
Collaborator:
Agency:
Stanford University
Agency class:
Other
Collaborator:
Agency:
Chinese University of Hong Kong
Agency class:
Other
Collaborator:
Agency:
Nihon University
Agency class:
Other
Collaborator:
Agency:
National Taiwan University Hospital
Agency class:
Other
Source:
National University Hospital, Singapore
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05782465
