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

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.