Multicenter Randomized Controlled Trial of Surveillance Versus Endoscopic Therapy for Barrett’s Esophagus With Low-grade Dysplasia: The SURVENT Trial: Study Rationale, Methodology, Innovation, and Implications

Abstract

The incidence of esophageal adenocarcinoma (EAC) has increased dramatically over the last 5 decades, making it one of the most rapidly increasing cancers in the Western world.1Kolb J.M. Han S. Scott F.I. et al.Early-onset esophageal adenocarcinoma presents with advanced-stage disease but has improved survival compared with older individuals.Gastroenterology. 2020; 159: 2238-2240Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Barrett’s esophagus (BE), the only identifiable premalignant condition for EAC, is remarkably common and progresses to EAC in a stepwise fashion from nondysplastic BE to low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and then to EAC. Despite advances in the field of biomarkers and risk stratification, the degree of dysplasia is the most widely used biomarker to predict progression and to guide further management. Endoscopic eradication therapy (EET) for patients with BE-related dysplasia and intramucosal EAC is endorsed by multiple society guidelines,2Shaheen N.J. Falk G.W. Iyer P.G. et al.Diagnosis and management of Barrett's esophagus: an updated ACG guideline.Am J Gastroenterol. 2022; 117: 559-587Crossref PubMed Scopus (27) Google Scholar,3Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar a practice that has broadly and meaningfully impacted clinical care worldwide. Although substantial data support using EET in patients with BE and HGD or intramucosal EAC, a central unresolved issue in this field is whether BE patients with LGD also benefit from EET. Establishing the best therapy for these “middle ground” patients is highly clinically relevant, because approximately 40% of BE patients are diagnosed with LGD at some point during follow-up.4Wani S. Rubenstein J.H. Vieth M. et al.Diagnosis and management of low-grade dysplasia in Barrett's esophagus: expert review from the Clinical Practice Updates Committee of the American Gastroenterological Association.Gastroenterology. 2016; 151: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar In BE with LGD, progression rates to EAC are lower (<1% per patient-year) as opposed to 6%–20% per patient-year in BE with HGD.3Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Several issues make management of LGD challenging: high interobserver variability among pathologists; lack of well-defined risk stratification tools to define individuals most likely to benefit from EET; the phenomenon of regression, in which those diagnosed with LGD using endoscopic biopsy do not demonstrate LGD on follow-up biopsies; and highly variable published rates of progression to HGD and EAC.4Wani S. Rubenstein J.H. Vieth M. et al.Diagnosis and management of low-grade dysplasia in Barrett's esophagus: expert review from the Clinical Practice Updates Committee of the American Gastroenterological Association.Gastroenterology. 2016; 151: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Recent guidelines suggest that both EET and surveillance are acceptable approaches to the management of LGD patients.2Shaheen N.J. Falk G.W. Iyer P.G. et al.Diagnosis and management of Barrett's esophagus: an updated ACG guideline.Am J Gastroenterol. 2022; 117: 559-587Crossref PubMed Scopus (27) Google Scholar,3Standards of Practice Committee Wani S. Qumseya B. et al.Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar The lack of strongly directive statements for 1 strategy over another is due to the limited comparative data between the 2 strategies. Despite the common nature of BE with LGD, studies focusing on treatment options in BE with LGD are limited. Critical limitations of existing trials are lack of adequate power to assess differences in outcomes6Shaheen N.J. Sharma P. Overholt B.F. et al.Radiofrequency ablation in Barrett's esophagus with dysplasia.N Engl J Med. 2009; 360: 2277-2288Crossref PubMed Scopus (1092) Google Scholar and limited generalizability.5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar,7Barret M. Pioche M. Terris B. et al.Endoscopic radiofrequency ablation or surveillance in patients with Barrett's oesophagus with confirmed low-grade dysplasia: a multicentre randomised trial.Gut. 2021; 70: 1014-1022Crossref PubMed Scopus (10) Google Scholar The argument for EET in BE with LGD is largely based on a single European randomized controlled trial (RCT) comparing EET with endoscopic surveillance.5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar,8Pouw R.E. Klaver E. Phoa K.N. et al.Radiofrequency ablation for low-grade dysplasia in Barrett's esophagus: long-term outcome of a randomized trial.Gastrointest Endosc. 2020; 92: 569-574Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar This trial reported that EET markedly reduced the risk of progression to a combined endpoint of HGD/EAC. However, several aspects of this study call into question its generalizability to the United States. First, there was a remarkably high rate of neoplastic progression in the surveillance arm (25%–34%), far higher than that reported in any American cohort. Second, despite this rather high rate of progression, patients in the surveillance arm overall fared well. Only 1 patient required esophagectomy, which was curative. Therefore, 211 radiofrequency ablation sessions were required in the treatment arm to prevent 1 esophagectomy. Third, this study found no difference in mortality between the arms. Fourth, EET was associated with an adverse event rate of 19%, with 3% being serious adverse events. Fifth, health-related quality of life, patient preference data, and other patient-centered outcomes (PCOs) were not assessed systematically. Additionally, this study was performed in highly specialized, tertiary care centers, and we have limited data on the effectiveness and safety of EET in other settings. For these reasons, although this was a well-designed and executed trial, its generalizability to a US population is unclear. A second RCT of EET in LGD from France is of limited utility because of a small sample size, use of a nontraditional primary endpoint, and remarkably low rates of complete eradication of intestinal metaplasia, far lower than that reported in any American cohort (including expert centers and community practices).7Barret M. Pioche M. Terris B. et al.Endoscopic radiofrequency ablation or surveillance in patients with Barrett's oesophagus with confirmed low-grade dysplasia: a multicentre randomised trial.Gut. 2021; 70: 1014-1022Crossref PubMed Scopus (10) Google Scholar Additionally, it should be noted that endoscopic surveillance is still required after successful completion of EET, given the concerns regarding durability of EET.9Wani S. Han S. Kushnir V. et al.Recurrence is rare following complete eradication of intestinal metaplasia in patients with Barrett's esophagus and peaks at 18 months.Clin Gastroenterol Hepatol. 2020; 18: 2609-2617Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 10van Munster S. Nieuwenhuis E. Weusten B. et al.Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation ± endoscopic resection: results from the national Dutch database in a 10-year period.Gut. 2022; 71: 265-276Crossref PubMed Scopus (34) Google Scholar, 11Sami S.S. Ravindran A. Kahn A. et al.Timeline and location of recurrence following successful ablation in Barrett's oesophagus: an international multicentre study.Gut. 2019; 68: 1379-1385Crossref PubMed Scopus (52) Google Scholar For these reasons, it remains unclear whether the costs and side effects associated with EET are worth the likely modest benefit in cancer prevention in LGD. The common nature of LGD and the wide availability of EET means that, on a daily basis, clinicians and patients are making the challenging treatment decision of EET vs surveillance with inadequate data to guide them. The degree of dysplasia, the most widely used current biomarker to risk-stratify patients with BE and to guide further management, is inadequately accurate, and reliance on dysplasia continues to be a critical barrier to risk-based management of these patients.4Wani S. Rubenstein J.H. Vieth M. et al.Diagnosis and management of low-grade dysplasia in Barrett's esophagus: expert review from the Clinical Practice Updates Committee of the American Gastroenterological Association.Gastroenterology. 2016; 151: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar It is well established that certain molecular and cellular alterations associated with carcinogenesis in BE can be detected years before the tissue exhibits morphologic changes of dysplasia, suggesting that an appropriate biomarker could identify BE patients who are destined for malignancy.12Redston M. Noffsinger A. Kim A. et al.Abnormal TP53 predicts risk of progression in patients with Barrett's esophagus regardless of a diagnosis of dysplasia.Gastroenterology. 2022; 162: 468-481Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar However, most of studies of biomarkers in BE have been case-control or retrospective in nature. Little is known about the comparative efficacy of various commercially available biomarkers to predict either the risk of progression to EAC or the effectiveness of EET in BE with LGD patients. Thus, the appropriate use of molecular or imaging biomarkers for risk stratification and prediction of effectiveness of EET continues to be a gap in our current knowledge, one that is best addressed through a well-controlled prospective study. Despite the fact that none of the BE biomarkers has fulfilled the Early Detection Research Network criteria for validation,13Pepe M.S. Etzioni R. Feng Z. et al.Phases of biomarker development for early detection of cancer.J Natl Cancer Inst. 2001; 93: 1054-1061Crossref PubMed Scopus (1232) Google Scholar,14Timmer M.R. Sun G. Gorospe E.C. et al.Predictive biomarkers for Barrett's esophagus: so near and yet so far.Dis Esophagus. 2013; 26: 574-581Crossref PubMed Scopus (22) Google Scholar p53 immunohistochemistry (IHC), wide-area transepithelial sampling (WATS3D), and TissueCypher Barrett’s Esophagus Assay (Castle Biosciences, Pittsburgh, PA) are in clinical use, and 2 (p53 IHC and WATS3D) have been endorsed in guideline documents by the British Society of Gastroenterology15Fitzgerald R.C. di Pietro M. Ragunath K. et al.British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.Gut. 2014; 63: 7-42Crossref PubMed Scopus (837) Google Scholar and the American Society for Gastrointestinal Endoscopy.16Qumseya B. Sultan S. Bain P. et al.ASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar The detection of p53 abnormalities has the largest body of evidence as a biomarker for risk stratification. p53 is an important tumor suppressor gene whose inactivation appears to be a key event, occurring early and often during Barrett’s carcinogenesis.17Stachler M.D. Camarda N.D. Deitrick C. et al.Detection of mutations in Barrett's esophagus before progression to high-grade dysplasia or adenocarcinoma.Gastroenterology. 2018; 155: 156-167Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Immunostaining of esophageal biopsy specimens revealing aberrant (either overexpression or absence of expression) staining of p53 protein is evidence of p53 inactivation.12Redston M. Noffsinger A. Kim A. et al.Abnormal TP53 predicts risk of progression in patients with Barrett's esophagus regardless of a diagnosis of dysplasia.Gastroenterology. 2022; 162: 468-481Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In LGD patients with aberrant p53 IHC in baseline biopsies, prospective cohort and case-control studies reported an elevated risk of progression to HGD/EAC.12Redston M. Noffsinger A. Kim A. et al.Abnormal TP53 predicts risk of progression in patients with Barrett's esophagus regardless of a diagnosis of dysplasia.Gastroenterology. 2022; 162: 468-481Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,18Snyder P. Dunbar K.B. Cipher D.J. et al.Aberrant p53 immostaining in Barrett's esophagus predicts neoplastic progression: systematic review and meta-analyses.Dig Dis Sci. 2019; 64: 1089-1097Crossref PubMed Scopus (26) Google Scholar WATS3D is a recently developed test that can improve the identification of dysplasia. WATS3D uses a cytology brush to sample an extensive area of the BE segment, with analysis aided by a neural network–based, high-speed computer scan that generates a 3-dimensional image of the tissue and identifies abnormal cells based on cellular morphology and molecular diagnostics. Hence, WATS3D assists the pathologist in making a diagnosis of dysplasia. A retrospective cohort study recently reported that LGD diagnosed with WATS3D is a better predictor of progression to HGD/EAC than that diagnosed with forceps biopsy.19Shaheen N.J. Smith M.S. Odze R.D. Progression of Barrett's esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by wide-area transepithelial sampling with 3-dimensional computer-assisted analysis: a retrospective analysis.Gastrointest Endosc. 2022; 95: 410-418Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar TissueCypher detects potentially carcinogenic molecular and cellular changes in BE biopsy specimens that can precede the appearance of dysplasia. It uses a computational pathology platform that rapidly extracts and integrates quantitative data on nuclear morphology and 9 protein-based biomarkers (p16, AMACR, p53, CD68, COX-2, CD45RO, HIF-1α, HER2/neu, and K20) to provide a risk score ranging from 0 to 10 that is used to classify patients as low, intermediate, and high risk for progression to HGD or EAC within 5 years.20Critchley-Thorne R.J. Duits L.C. Prichard J.W. et al.A tissue systems pathology assay for high-risk Barrett's esophagus.Cancer Epidemiol Biomarkers Prev. 2016; 25: 958-968Crossref PubMed Scopus (32) Google Scholar A recent pooled analysis of data on TissueCypher’s performance in predicting both prevalent and incident progression to HGD/EAC in 5 published studies involved 590 patients, including 68 patients with LGD. A high-risk TissueCypher score independently predicted a 7.81-fold increase in prevalent and incident HGD/EAC and significantly improved the predictive value of clinical features (age, sex, BE segment length, presence of hiatal hernia, and pathology diagnosis).21Iyer P.G. Codipilly D.C. Chandar A.K. et al.Prediction of progression in Barrett's esophagus using a tissue systems pathology test: a pooled analysis of international multicenter studies [published online ahead of print February 22, 2022]. Clin Gastroenterol Hepatol.https://doi.org/10.1016/j.cgh.2022.02.033Google Scholar In a blinded, retrospective cohort study of BE patients with community-diagnosed LGD enrolled in the surveillance arm of the SURF study,5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar TissueCypher stratified these LGD patients with overall predictive accuracy comparable with that of 3 expert gastrointestinal pathologists.22Frei N.F. Khoshiwal A.M. Konte K. et al.Tissue systems pathology test objectively risk stratifies Barrett's esophagus patients with low-grade dysplasia.Am J Gastroenterol. 2021; 116: 675-682Crossref PubMed Scopus (9) Google Scholar Moreover, TissueCypher provided objective risk stratification, whereas the diagnosis of LGD had significant variability between the 3 expert pathologists.22Frei N.F. Khoshiwal A.M. Konte K. et al.Tissue systems pathology test objectively risk stratifies Barrett's esophagus patients with low-grade dysplasia.Am J Gastroenterol. 2021; 116: 675-682Crossref PubMed Scopus (9) Google Scholar These promising results from retrospective, case-control, and cohort studies suggest that p53 IHC, WATS3D, or TissueCypher may be useful for risk stratification of BE patients with LGD. However, they need to be validated in future RCTs. The presence of clinical equipoise indicates that a trial of endoscopic surveillance vs EET in patients with BE and LGD is an urgent, unmet need. The SURVENT (Surveillance vs Endoscopic Therapy for BE with LGD) trial is being conducted to address this significant gap in our knowledge by comparing the effectiveness of EET with surveillance endoscopy using established oncologic outcomes (specific aim 1), comparing PCOs and costs between the 2 groups (specific aim 2), and improving risk stratification of LGD patients by identifying patient characteristics and biomarkers (p53, TissueCypher, WATS3D) that predict progression and response to treatment (specific aim 3). The SURVENT trial is a multicenter comparative effectiveness Prospective, Randomized, Open with Blinded Endpoint trial of BE patients with LGD (Figure 1). The trial’s primary aim is to determine if patients undergoing EET will demonstrate less neoplastic progression and a lower incidence of EAC compared with patients undergoing surveillance. A maximum of 530 subjects will be enrolled over a 3.5-year period, with a total planned study duration of 5 years. The trial also includes an observational cohort that will follow the same data and biorepository protocols as the randomized trial (cohort 1, endoscopic surveillance [n = 100]; cohort 2, EET [n = 50]). The addition of an observational cohort to the RCT will inform us of potential selection bias, allowing us to make inferences as to the generalizability of the RCT results, and serve as a second, independent group in which to expand and validate the findings related to biomarkers assessed in this trial. The trial aims, outcomes, eligibility, and inclusion and exclusion criteria are highlighted in Table 1. PCOs were selected by key stakeholders (patients, caregivers, clinicians) during the U34 funding phase. The conceptual model of PCOs is highlighted in Supplementary Figure 1 and Supplementary Table 1. Further trial details are provided in Supplementary Methods. Biologic specimens will be obtained from all study subjects in the RCT and observational cohort (blood, saliva, endoscopic biopsies, cytology, and WATS3D brushings) at standardized intervals.Table 1Study SummaryProtocol titleA multicenter RCT of surveillance vs endoscopic therapy for BE with LGDAcronymSURVENT trialStudy sitesTwenty-one clinical centers in the United StatesStudy periodPlanned enrollment period: 3.5 yearsPlanned duration of the study: 5 yearsSubject participation will be a minimum of 1 year (for subjects enrolled in month 42) and maximum of 4 years (for subject enrolled in month 6).Study populationPatients with BE and LGDPrimary study objectiveTo compare the effectiveness of 2 approaches for the management of BE and LGD, endoscopic surveillance and EET, with endpoints of neoplastic progression (HGD/mucosal EAC/invasive EAC) as determined by a blinded central adjudication committeeSecondary study objectiveTo compare PCOs in BE patients with LGD treated with EET with those undergoing surveillanceTo determine the utility of select biomarkers, including the biomarker panel TissueCypher, histologic assessment by WATS3D, and p53 IHC on forceps biopsies and on WATS3D samples, in risk stratificationTo conduct a safety and cost-effectiveness analysisExploratory clinical endpoints will include progression to mucosal or invasive EAC alone, complete eradication rates for intestinal metaplasia (CE-IM) and complete eradication rates for dysplasia, and recurrence of intestinal metaplasia and dysplasia.To establish a biorepository of specimens that include whole blood, serum, plasma, saliva, brushings, and biopsy specimens from the esophagus (squamous and BE), gastric cardia, and duodenum that will allow for future translational research, including time course studies on mechanisms of disease progression and therapeutic response; identification of novel diagnostic markers; and novel therapeutic targets in this patient population.Study designMulticenter comparative effectiveness Prospective, Randomized, Open with Blinded Endpoint trial of EET vs endoscopic surveillance in patients with BE and LGDObservational cohort study: This study will also include a prospective observational cohort study of BE and LGD patients who decline randomization in the RCT but undergo endoscopic surveillance (cohort 1) or EET (cohort 2) and are willing to provide longitudinal observational data,Sample sizeRCT: Using assumptions based on published literature and accounting for an attrition rate of 10%, we estimate that a total of 530 subjects (265 per study arm) would provide a statistical power of at least 80% to detect the hypothesized difference in the primary outcome of neoplastic progression rate between the 2 groups (15% progression rate in the surveillance arm, 6% in the EET arm). A blinded sample size re-estimation will be conducted before the interim analysis to confirm the assumptions of the event rate.Observational cohort study: The maximum enrollment for the observational cohort formed from the patients who decline randomization will be a maximum of 150 subjects total (cohort 1, n = 100; cohort 2, n = 50).Inclusion criteriaAny patient with BE and LGD who provides informed consent and meets all the following criteria will be eligible for enrollment:1. Male or female, age ≥18 years.2. Subject has endoscopic evidence of BE characterized by the presence of salmon-colored mucosa in the tubular esophagus of at least 1 cm in length as well as endoscopic biopsies from the involved areas demonstrating columnar metaplasia with goblet cells. This inclusion criterion will exclude patients with intestinal metaplasia with dysplasia of the gastric cardia.3. Biopsies within the previous 12 months demonstrating BE and LGD.4. Confirmation of LGD by expert central pathology panel from biopsies obtained within the previous 12 months (including those obtained from the referring physician).5. Demonstrated ability to tolerate proton pump inhibitor therapy based on patient self-report.6. Ability to discontinue antiplatelet and anticoagulant therapy based on standard guideline recommendations before and after endoscopic procedures.Exclusion criteria1. Pregnancy2. Prior EET for BE3. History of HGD or EAC4. History of esophageal resection/esophagectomy5. Active erosive esophagitis (Los Angeles grade B or higher): patients eligible on resolution of erosive esophagitis6. Esophageal strictures precluding passage of the endoscope or treatment catheters: patients eligible on resolution of esophageal stricture due to endoscopic dilation or resolution with medical therapy7. Esophageal varices or known portal hypertension8. Life expectancy < 2 years as judged by the site investigatorOf note, the presence of a visible lesion (nodularity) at the index endoscopy is not an exclusion criterion. Subjects with visible lesions will undergo endoscopic mucosal resection to determine pathology; those with HGD or EAC pathology will exit the study after a 30-day safety follow up.Study intervention and follow-upSubjects in the RCT and observational cohort study undergoing surveillance endoscopy will undergo surveillance biopsies in a 4-quadrant fashion every 1 cm throughout the extent of the BE using the Seattle biopsy protocol, along with targeted biopsies from any visible lesions. For incident LGD (newly diagnosed LGD, ie, within 12 months of enrollment), surveillance endoscopies will be performed every 6 months for the first year and then annually until the end of the study period. For prevalent LGD (diagnosed >1 year before enrollment), surveillance endoscopies will be performed annually until the end of the study period. The number of evaluations will depend on a subject’s enrollment time.Subjects undergoing EET will undergo radiofrequency ablation every 2–3 months until CE-IM is achieved or 5 treatments have been delivered, whichever is first. After achieving CE-IM, surveillance endoscopy will performed every 6 months for the first year and annually thereafter until the end of the study period. Surveillance biopsies will be obtained using a standardized protocol.Subjects will be contacted 48–72 hours and 30 days postprocedure. All subjects will also receive follow-up phone calls on a semiannual basis by a blinded central study coordinator.Primary outcome measureThe primary endpoint is neoplastic progression, defined as the occurrence of HGD/mucosal EAC/invasive EAC at any time during the study period after enrollment.Statistical analysisAll randomized subjects who are not identified at the index endoscopy with HGD or EAC are defined as the intention-to-treat population. The time to progression will be calculated from the time of randomization until the endoscopy date on which HGD/mucosal EAC/invasive EAC is detected. The hazard rates will be compared using a log-rank test. One interim analysis for overwhelming efficacy or futility will be conducted. Open table in a new tab Sample size was performed for the primary endpoint of neoplastic progression (the diagnosis of HGD/EAC at any time during the study period after enrollment) using a time-to-event analysis. We estimate that 15% of patients with confirmed LGD will progress to the composite primary endpoint in the surveillance arm compared with 6% in the EET arm.4Wani S. Rubenstein J.H. Vieth M. et al.Diagnosis and management of low-grade dysplasia in Barrett's esophagus: expert review from the Clinical Practice Updates Committee of the American Gastroenterological Association.Gastroenterology. 2016; 151: 822-835Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 5Phoa K.N. van Vilsteren F.G. Weusten B.L. et al.Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial.JAMA. 2014; 311: 1209-1217Crossref PubMed Scopus (427) Google Scholar, 6Shaheen N.J. Sharma P. Overholt B.F. et al.Radiofrequency ablation in Barrett's esophagus with dysplasia.N Engl J Med. 2009; 360: 2277-2288Crossref PubMed Scopus (1092) Google Scholar,23Qumseya B.J. Wani S. Gendy S. et al.Disease progression in Barrett's low-grade dysplasia with radiofrequency ablation compared with surveillance: systematic review and meta-analysis.Am J Gastroenterol. 2017; 112: 849-865Crossref PubMed Scopus (43) Google Scholar We plan to accrue subjects for 3.5 years and follow them over time until progression to the primary endpoint or their censoring time if they do not progress. Follow-up will continue for approximately 1 year after the last subject is enrolled. Assuming an exponential survival curve and the above event rates, 215 subjects in each group are needed to obtain a total of 36 events for analysis to achieve 80% power using a 2-sided .05 alpha level. Using a 10% noncompliance rate, we inflate the sample size by a factor of 1.23 and plan to enroll 530 total subjects. The SURVENT trial is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. The organizational structure includes the Executive, Steering, Biorepository, Trial Operations, Protocol, Ancillary Studies, Publications, and Coordinator Committees with active participation from the principal investigators, NIDDK staff, and site investigators. The Clinical Coordinating Center and Central Biorepository is housed at the University of Colorado and the Statistical and Data Coordinating Center at the Medical University of South Carolina. An NIDDK-appointed Data and Safety Monitoring Board and a study-appointed independent medical safety monitor will oversee the safety in the SURVENT trial. The SURVENT trial will be completed at approximately 21 high-volume regional centers in the United States. All eligible subjects will be offered inclusion without any reference to sex or minority status. The SURVENT trial is the first US-based RCT exclusively for BE with LGD. The importance of PCOs has been recognized by major international health policy and regulatory authorities and patients and can provide valuable evidence to inform shared decision-making, clinical guidelines, and health policy.24Calvert M. Kyte D. Mercieca-Bebber R. et al.Guidelines for inclusion of patient-reported outcomes in clinical trial protocols: the SPIRIT-PRO extension.JAMA. 2018; 319: 483-494Crossref PubMed Scopus (351) Google Scholar This trial will