Neoplasms

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Participants in the screening or surveillance population that receive the Seattle protocol, then WATS3D brushings, during the same procedure.

Participants in the screening or surveillance population that receive the WATS3D brushings, then the Seattle protocol, during the same procedure.

Participants undergo 4-quadrant biopsies with standard biopsy forceps taken at 2 cm intervals. For participants undergoing a confirmatory endoscopy for cases in which discordant results are noted (WATS3D positive for dysplasia/cancer and Seattle biopsy negative for dysplasia/cancer), repeat biopsies will be taken at 1 cm intervals along with target biopsies from any visible lesions.

Seattle protocol

Participants undergo 2 WATS3D biopsies of every 5 cm segment of Barrett's esophagus, starting from the gastroesophageal junction and moving proximally through the entire segment of Barrett's.

WATS3D brushings

Alexa R DeBord, MS

Sandra Boimbo, MPH

Mankanwal Sachdev, MD

Virender Sharma, MD

Raman Muthusamy, MD

Venkataraman Muthusamy, MD

Adarsh M Thaker, MD

Kevin A Ghassemi, MD

Howard Chang, MD

Gene Ma, MD

Mitchell Liverant, MD

Alexa DeBord, MS

Sachin Wani, MD

Steven Edmundowicz, MD

Mihir Wagh, MD

Paul Menard-Katcher, MD

Salam Zakko, MD

Peter Bloom, MD

Liam Zakko, MD

Daniel Smiley, MD

Mark Versland, MD

Eddy Castillo, MD

David Chaletsky, MD

Scott Corbett, MD

Lisa Underwood

Srinadh Komanduri, MD

Justeena Jojo

Prasad Iyer, MD

Melissa Passe

Cadman Leggett, MD

Chamil Codipilly, MD

Molly Stewart, BS

Arvind Trindade, MD

Felice Schnoll-Sussman, MD

Felice H Schnoll-Sussman, MD

Philip O Katz, MD

Amir Soumekh, MD

Vivek Kaul, MD

Shivangi Kothari, MD

Nicholas Shaheen, MD

Katie Danis

Nicholas J Shaheen, MD

Swathi Eluri, MD

Cary C Cotton, MD

Harshit Khara, MD

Joshua Obuch, MD

Kathy Karnes, BSN, RN

John M Haydek, MD

Raj I Narayani, MD

The purpose of this research study is to learn about the best approach to sample patients with known or suspected Barrett's esophagus (BE) by comparing the standard Seattle biopsy protocol to sampling using wide area transepithelial sampling (WATS3D).

Barrett's esophagus is a common condition that is used to spot patients at increased risk of developing a type of cancer in the esophagus (swallowing tube) called esophageal adenocarcinoma. The 5-year survival rate is as low as 18% for patients who get esophageal adenocarcinoma, but the rate may be improved if the cancer is caught in its early stages. Barrett's esophagus can lead to dysplasia, or precancerous changes, which occurs when cells look abnormal but have not developed into cancer. If the abnormal cells increase from being slightly abnormal (low-grade dysplasia), to being very abnormal (high-grade dysplasia), the risk of developing cancer (esophageal adenocarcinoma) goes up. Therefore, catching dysplasia early is very important to prevent cancer.

Endoscopic surveillance is a type of procedure where endoscopists run a tube with a light and a camera on the end of it down a patients throat and remove a small piece of tissue. The piece of tissue, called a biopsy, is about the size of the tip of a ball-point pen and is checked for abnormal cells and cancer cells.

Patients are being asked to be in this research study because they have been diagnosed with BE or suspected to have BE, and will need an esophagogastroduodenoscopy (EGD).

Patients with BE undergo sampling using the Seattle biopsy protocol during which samples are obtained from the BE in a four quadrant fashion every 2 cm along with target biopsies from any abnormal areas within the BE. Another sampling approach is WATS3D which utilizes brushings from the BE.

While both of these procedures are widely accepted approaches to sampling patients with BE during endoscopy, there is not enough research to show if one is better than the other.

Participants in this study will undergo sampling of the BE using both approaches (Seattle biopsy protocol and WATS-3D); the order of the techniques will be randomized.

Up to 2700 participants will take part in this research. This is a multicenter study involving several academic, community and private hospitals around the country.

Methodology:

Patients with non-dysplastic Barrett's esophagus (BE) undergoing surveillance and patients meeting criteria for screening for BE with columnar-lined esophagus detected at endoscopy will be recruited in this multicenter randomized controlled trial.

All patients will undergo upper endoscopy using high-definition white light endoscopy and electronic chromoendoscopy (NBI/FICE). The findings (detection of visible lesions/abnormal mucosal or vascular pattern) with electronic chromoendoscopy will be recorded.

Patients will be randomized to receive sampling using either the Seattle biopsy protocol or WATS3D. The Seattle protocol will entail obtaining random biopsies every 2 cm in a 4-quadrant fashion. Biopsies will be taken from any visible lesion (no matter how subtle) and will be submitted in separate jars and excluded from the comparative analysis of the study. The WATS3D procedure will be conducted using a standardized protocol. Patients will then receive sampling using the technique to which they were not assigned to by randomization. This allows for all patients to receive standard of care (sampling using the Seattle biopsy protocol), and to determine concordance between the two sampling techniques acknowledging that one sampling technique could potentially affect the results of other sampling technique.

In patients with discordant results (WATS3D positive and random biopsy negative), repeat upper endoscopy with sampling using the Seattle biopsy protocol will be performed in an attempt to confirm the findings noted at WATS3D. This will be performed in the surveillance and screening population. Biopsy specimens will be submitted for histopathologic examination for routine clinical care. For the purpose of this study, all biopsy specimens will be sent to the Cleveland Clinic for interpretation by a central GI pathologist who will be blinded to patient details and to reading by the WATS3D pathologist.

Study Duration:

Interventions performed as described above will be performed during one endoscopic procedure. The endpoints in this study will include progression to dysplasia, cancer, need for endoscopic eradication therapy, and death.

Planned enrollment period: 2.5 years. Planned duration of the study: 3 years.

Study Centers:

To maximize the generalizability of results, this randomized controlled trial will be conducted across different practice settings that include tertiary care centers, closed healthcare networks and large community practices at approximately 14 sites.

Anticipated Number of Participants:

2298 (see Statistical Methodology below)

* 1982 to compare diagnostic yield of dysplasia between the two approaches in BE patients undergoing surveillance
* 316 to compare diagnostic yield of intestinal metaplasia between the two approaches in patients undergoing screening for BE

Statistical Methodology:

For a prospective randomized trial in detecting LGD, HGD or EAC comparing the Seattle protocol, the current standard practice, to wide-area transepithelial sampling (WATS3D) where all positive results for dysplasia or EAC with WATS3D sampling not detected on Seattle biopsy protocol at index endoscopy will require confirmation by repeat sampling using the Seattle biopsy protocol at repeat endoscopy, the following sample sizes were calculated assuming α=0.05 and power of 0.8. All calculations are completed using PROC POWER in SAS 9.4 for Fisher's exact test unless otherwise noted.

For the primary aim (surveillance population), the investigators will compare the proportion of positive results between the Seattle protocol and WATS3D where all positive results for dysplasia or EAC with WATS3D sampling not detected on Seattle biopsy protocol at index endoscopy will require confirmation by repeat sampling using the Seattle biopsy protocol at repeat endoscopy with either Pearson's chi-square test or Fisher's exact test for proportions. Positive findings of dysplasia or EAC on WATS not detected on Seattle biopsy protocol at index endoscopy or subsequent repeat endoscopy with sampling using the Seattle biopsy protocol will not be considered as dysplasia or EAC detected by WATS for the primary analysis. Previous pooled estimates indicated a 2.5% detection rate with Seattle protocol and 4.9% with WATS3D, resulting in a need for 828 participants for each arm (a total of 1656). However, the investigators are restricting to WATS3D cases which are confirmed with target biopsy or Seattle protocol at the initial visit or a follow-up sample when results are discordant. Assuming a 95% confirmation rate, 991 participants are need for each arm to compare a 2.5% detection rate for Seattle protocol and 4.655% for WATS3D (a total of 1982).

For the primary aim (screening population), the investigators will compare the proportion of positive results between techniques to which patients are randomized with Fisher's exact test for proportions. Previous pooled estimates indicated a 40% intestinal metaplasia detection rate with Seattle protocol and 60% with WATS3D. However, the investigators are restricting to WATS3D cases which are confirmed with target biopsy or Seattle protocol at the initial visit or a follow-up sample when results are discordant. Assuming a 95% confirmation rate, 158 participants are need for each arm to compare a 40% detection rate for Seattle protocol and 57% for WATS3D (a total of 316).

The investigators will conduct one interim analysis using Lan and DeMet's alpha spending function approximating O'Brien-Fleming boundaries. Based the sample size estimates above, the investigators expect the interim analysis will occur after the data for 991 participants (50% enrollment) has been collected. This interim analysis will be restricted to the primary aim in the surveillance population. No interim analysis will be conducted to address the primary aim in the screening population. In the case where study enrollment does not stop early due to efficacy, all participating physicians will be blinded to the results of this interim analysis.

As a secondary analysis, the investigators will use results from both the randomized procedure and the follow-up procedure with the protocol to which patients were not randomized to perform a paired analysis of the concordance between the two diagnostic tests. Although an important analysis for determining whether WATS3D could be used instead of the Seattle protocol, due to the risk of the initial biopsy affecting these results of the follow up procedure this is a secondary analysis. Given the sample size of 1982 for the primary outcome, there is greater than 99.9% power to detect a difference in the paired results between proposed discordant proportions of 0.3575% for Seattle protocol positive and WATS3D negative to 3.11% for WATS3D positive and Seattle protocol negative using McNemar's test for paired nominal data. These discordant proportion estimates are derived from prior pooled data for dysplasia detection rates of 4.9% for WATS3D alone and 2.5% for Seattle protocol alone, with the discordant proportions of test results derived from data reported in Vennalaganti assuming that only 80% of WATS3D positive and Seattle protocol negative cases are verified with targeted follow-up biopsies to confirm the diagnosis.

The comparison of yield of dysplasia will also be conducted based on expert pathology review for biopsy and WATS3D specimens. The overall proportion of cases with visible lesions with their associated pathology results will be recorded and will not be a part of the analyses comparing the diagnostic yield of dysplasia between the Seattle biopsy protocol with WATS3D.

The primary outcome comparing diagnostic yield of any dysplasia and intestinal metaplasia between the two randomized arms will use either Pearson's chi-square or Fisher's exact test for portions. The secondary analysis for paired data will use McNemar's test and will exclude cases that were WATS3D positive but could not be confirmed by a concurrent (Seattle protocol) or follow-up endoscopic biopsies using the Seattle biopsy protocol. A sensitivity analysis will be completed which includes WATS3D positive cases that did not have diagnostic confirmation with biopsy. Comparison for the detection of intestinal metaplasia between the two strategies will use McNemar's test for paired data including all cases.

Seattle Biopsy Protocol Versus Wide-Area Transepithelial Sampling in Patients With Barrett's Esophagus Undergoing Surveillance

A Multicenter Randomized Trial of Seattle Biopsy Protocol Versus Wide-Area Transepithelial Sampling in Patients With Barrett's Esophagus Undergoing Surveillance (The SWAT-BE Study)

Individual participant data that underlie the results reported in original publications after deidentification (text, tables, figures, appendixes).

Proportion of positive results between the Seattle protocol and WATS3D technique. Positive results include low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC). All positive results for dysplasia or EAC with WATS3D sampling not detected on Seattle biopsy protocol at index endoscopy will require confirmation by repeat sampling using the Seattle biopsy protocol.

Proportion of positive results between the Seattle protocol and WATS3D technique. Positive results include intestinal metaplasia. All positive results for intestinal metaplasia/dysplasia or esophageal adenocarcinoma (EAC) with WATS3D sampling not detected on Seattle biopsy protocol at index endoscopy will require confirmation by repeat sampling using the Seattle biopsy protocol.

Proportion of positive results between the Seattle protocol and WATS3D technique. Positive results include intestinal metaplasia.

Proportion of positive results of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC) between the Seattle protocol and WATS3D technique Vs. the WATS3D technique alone. All positive results for intestinal metaplasia/dysplasia or EAC with WATS3D sampling not detected on Seattle biopsy protocol at index endoscopy will require confirmation by repeat sampling using the Seattle biopsy protocol.

Total sampling time for the Seattle protocol is measured by the time the first forceps biopsy was placed into the channel to the time the final forceps biopsy was removed from the channel. Total sampling time for the WATS3D technique is measured by the time the first WATS3D brush was placed into the channel to the time the final WATS3D brush was removed from the channel.

The investigators will conduct a cost-effectiveness analysis between the two sampling techniques using data collected from the randomized control trial (cost for procedures and follow-up, detection of dysplasia or cancer, need for endoscopic eradication therapies, biopsy and pathology costs, complications, among others). The primary endpoint for the cost-effectiveness analysis will be the incremental cost-effectiveness ratio with a predefined willingness to pay off $100k per quality adjusted life years.

Proportion of patients referred for endoscopic eradication therapy (EET) in patients positive only on Seattle biopsy protocol for low-grade dysplasia (LGD), high-grade dysplasia (HGD), or esophageal adenocarcinoma (EAC) compared to proportion of patients referred for EET in patients positive only on WATS3D. All positive results for intestinal metaplasia/dysplasia or EAC with WATS3D sampling not detected on Seattle biopsy protocol at index endoscopy will require confirmation by repeat sampling using the Seattle biopsy protocol.

Interobserver agreement among pathologists with be assessed using Kappa statistics.

Clinical and endoscopic variables collected as a part of the SWAT-BE study will be utilized to identify predictors associated with increased risk of progression to dysplasia or esophageal adenocarcinoma (EAC).

Specimens collected during the SWAT-BE study (WATS3D specimens) will be analyzed for biomarkers for improved risk stratification (i.e., identify patients at increased risk of progression to high-grade dysplasia or esophageal adenocarcinoma).

University of Colorado, Denver

Symptoms and General Pathology

Rare Diseases

Esophageal Neoplasms

Metaplasia

Hyperplasia

Esophageal Cancer

Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Micronutrients

Vitamins

Acetic Acid

Retinol acetate

Vitamin A

Retinol palmitate

Anti-Bacterial Agents

Adjuvants, Immunologic

Immunologic Factors

Protective Agents

Retinol

Acetic acid is prepared at a concentration of 2.5%, after initial cleaning is done, it will be applied with a 7 French spray catheter, starting the proximal application performing a uniform application on the area of intestinal metaplasia an then will be timed for mucous visualization in search of areas of loss of acetowhitening, in case of finding such area will be registered the time in which there was loss of acetowhitening, the distance at which it is located from the upper dental arch in addition to the esophageal face on which the area is located, subsequently evaluation of the glandular pattern is performed only by classifying as normal (glands evenly distributed with normal or abnormal crypt density (compact crypts with increased density; focal irregularity or disorganized crypts; absence of a cryptic pattern), once this evaluation has been carried out, biopsies are directed to these areas to be sent to the pathology service.

Take random biopsies by quadrants every 2 centimeters biopsy of the intestinal metaplasia areas 1cm above the esophagogastric junction begins, taking tissue every 2cm from the 4 quadrants, separating the biopsies in different bottles based on the length in which they were taken, to later be sent to the pathology service.

Acetic acid is prepared at a concentration of 2.5% in a 20ml syringe, it will be applied with a 7 french spray catheter compatible with a working channel 2.8mm onwards, starting the proximal application When distally performing a uniform application on the area of intestinal metaplasia and the timed time for mucous visualization in search of areas of loss of acetowhitening begins, in case of finding such area will be registered the time in which there was loss of acetowhitening, the distance at which it is located from the upper dental arch in addition to the face on which the area is located, subsequently evaluation of the glandular pattern is performed only by classifying as normal or abnormal, once this evaluation has been carried out, biopsies are directed to these areas to be sent to the pathology service.

Acetic acid chromoendoscopy

Take random biopsies by quadrants every 2 centimeters. Biopsy of the intestinal metaplasia areas 1cm above the esophagogastric junction will be initiated, taking tissue every 2cm from the four quadrants, separating the biopsies in different bottles based on the length in which they were taken, to later be sent to the pathology service.

Oscar V Hernández Mondragón, MD

Raul Alberto Gutiérrez Aguilar, Fellow

Oscar V Hernandez Mondragon, MD

Barrett's esophagus is a complication of chronic gastroesophageal reflux disease that occurs in up to 10% to 15% of patients with this pathology. Well-defined risk factors have been established and are important because they are considered a precancerous lesion (intestinal metaplasia). The conventional diagnostic methods are ineffective in reliably detecting potentially treatable lesions. Investigators propose the use of vital chromoendoscopy with acetic acid using the simplified classification of Portsmouth looking for areas with loss of acetowhitening and taking targeted biopsies to increase the detection of esophageal neoplastic lesions.

Barrett's esophagus is a complication of chronic gastroesophageal reflux disease that occurs in up to 10 to 15% of patients with this disease, well-defined risk factors have been established and are important because they are considered a precancerous condition (metaplasia intestinal). Chromoendoscopy is postulated as an effective way for the detection of esophageal precancerous lesions, early detection and timely treatment with chromoendoscopy with acetic acid being a seemingly reliable alternative, so the investigators will use with the simplified classification of Portsmouth looking for areas with loss of acetowhitening and targeted biopsy to increase the detection of esophageal neoplastic lesions, our main objective being to compare the diagnostic effectiveness of directed biopsies of dysplastic lesions with acetic acid in patients with Barrett's esophagus compared to taking non-directed protocolized biopsies.

A clinical trial will be carried out, including all those patients older than 18 years who go to perform a superior endoscopy with diagnosis of Barrett's esophagus where patients will be up and B Seattle protocol group(four quadrant biopsy every 2 centimeters starting 1 centimeter from above the esophagogastric junction), then proton pump inhibitor washout and crossover allocation with the opposite corresponding manoeuver. Histopathological results of both groups will be compared.

Demographic data of the participants will be collected and the evaluated areas of Barrett's esophagus with each method will be recorded in a data collection sheet detailing in a specific way the number of biopsies taken, specifying if there was loss of acetowhitening and alterations in the mucous pattern and in the case of the opposite arm, the total number of biopsies taken based on the Seattle protocol, said data will be condensed into a database for subsequent statistical analysis and publication of results.

A clinical trial will be carried out, including all those patients older than 18 years who go to perform a superior endoscopy with diagnosis of Barrett's esophagus where patients will be randomized into two groups, one of acetic acid and the other of the Seattle protocol as a method Initially and subsequently, a second endoscopy will be performed with the opposite method and the histopathological results of both groups will be compared.

Participant will be initially allocated in either group without knowing its initial manoeuver

Acetic Acid for the Detection of Esophageal Neoplasms

Acetic Acid vs Seattle Protocol for Neoplastic Lesions in Barrett Esophagus

First the investigators will detect the incidence of dysplasia in Barrett esophagus in patients with acetic acid chromoendoscopy, using the Vienna Classification system by the pathologist.

The second maneuver consist on taking non directed biopsies by the Seattle protocol in the same patient. And the incidence of dysplasia on biopsies will be looked for using Vienna Classification system again.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Seattle Biopsy Protocol Versus Wide-Area Transepithelial Sampling in Patients With Barrett's Esophagus Undergoing Surveillance	NCT05530343	Barrett Esophag... Barretts Esopha... Esophageal Aden...	Seattle protoco... WATS3D brushing...	18 Years - 89 Years	University of Colorado, Denver
Acetic Acid for the Detection of Esophageal Neoplasms	NCT04054713	Barretts Esopha... Dysplasia Intestinal Meta...	Acetic acid chr... Seattle protoco...	18 Years -	Coordinación de Investigación en Salud, Mexico
Seattle Biopsy Protocol Versus Wide-Area Transepithelial Sampling in Patients With Barrett's Esophagus Undergoing Surveillance	NCT05530343	Barrett Esophag... Barretts Esopha... Esophageal Aden...	Seattle protoco... WATS3D brushing...	18 Years - 89 Years	University of Colorado, Denver

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