Non-Endoscopic Surveillance for Barrett's Esophagus Following Ablative Therapy

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT02106910
• Collaborator: University of Cambridge (Other), National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Medtronic (Industry)
• Enrollment: 138
• Location: 1
• Arms: 2
• Actual Duration (Months): 45.6
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

Subjects presenting to University of North Carolina at Chapel Hill (UNC) Hospitals for routine endoscopic surveillance examinations for current Barrett's Esophagus (BE) or after successful radiofrequency ablation (RFA) of dysplastic Barrett's Esophagus (BE) will be offered enrollment in the study. After informed consent, and the same day as the endoscopic procedure, the subject will undergo administration of the Cytosponge assay. The patient will then undergo routine endoscopic surveillance, using a standard Seattle biopsy surveillance protocol. The Cytosponge will be placed in fixative and shipped to the Fitzgerald laboratory at the University of Cambridge for processing according to their established protocols. Tissue biopsies will undergo standard processing and Hematoxylin and Eosin (H&E) staining, with assessment by expert gastrointestinal pathologists at UNC. The primary outcome variables will be sensitivity and specificity of the novel assay, compared against the gold standard of the presence of recurrent BE as detected by upper endoscopy with biopsies. Secondary outcomes include acceptability of the nonendoscopic assay to the patient (assessed by a standardized tool, the Impact of Events Scale, as well as a visual analogue scale), and likelihood of assay positivity as a function of amount of residual disease (as measured by Prague criteria).

Condition or Disease	Intervention/Treatment	Phase
Barrett's Esophagus	Device: Cytosponge	N/A

Detailed Description

Esophageal Adenocarcinoma is a Lethal Cancer with a Rapidly Increasing Incidence. Barrett's Esophagus (BE) is the Strongest Risk Factor for Esophageal Adenocarcinoma. Endoscopic Ablation Induces Reversion of Barrett's Esophagus, and Decreases Progression of Disease. Unfortunately, data demonstrate a risk of recurrence of BE following successful eradication. Recent data published by the candidate and colleagues from the Ablation of Intestinal Metaplasia Containing Dysplasia (AIM Dysplasia) study demonstrate that approximately 25% of subjects who experience successful eradication of dysplastic BE will develop recurrent BE.

Therefore, following successful endoscopic ablation, patients receive ongoing endoscopic surveillance. More recently, a simple, non-endoscopic device, termed the Cytosponge, has been developed for endoscopic screening of subjects at risk for BE. Cytosponge demonstrated a sensitivity of 90% and a specificity of 94% for the detection of BE.

We expect these investigations to lead to a less costly, highly accurate, less invasive and more preferred screening paradigm for the large number of subjects who have undergone endoscopic ablative therapy.

The Cytosponge is a simple, non-endoscopic device developed for endoscopic screening of subjects at risk for Barrett's esophagus (BE) by investigators at the University of Cambridge in the U.K. The Cytosponge is an ingestible capsule enclosing a compressed spherical mesh sponge of 3 cm diameter, the center of which is attached to a string. The capsule and string are swallowed with water. The string is held at the mouth without tension by means of a cardboard tab attached to the string, and esophageal peristalsis and gravity move the capsule into the stomach. After 5 minutes (during which the capsule dissolves and the sponge is liberated), the sponge is withdrawn by gentle traction on the string and as it does so, collects cells from the lining of the esophagus. The sponge is placed in fixative, then the cells are pelleted, and processed into paraffin blocks. The pellets are immunostained with trefoil factor 3, which is interpreted simply as either positive or negative by the presence of any staining.

Study Design

• Study Type: Interventional
• Actual Enrollment: 138 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Non-Endoscopic Surveillance for Barrett's Esophagus Following Ablative Therapy
• Actual Study Start Date: Oct 27, 2014
• Actual Primary Completion Date: Aug 7, 2018
• Actual Study Completion Date: Aug 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Participants with Barrett's and No History of Ablation Participants with a diagnosis of BE, presenting for routine care endoscopy for surveillance or treatment of their BE.	Device: Cytosponge; The Cytosponge is a simple, non-endoscopic device developed for endoscopic screening of subjects at risk for Barrett's esophagus (BE) by investigators at the University of Cambridge in the U.K. The Cytosponge is an ingestible gelatin capsule enclosing a compressed spherical polyurethane mesh sponge of 3 cm diameter, the center of which is attached to a string (Astralen, braided synthetic non-absorbable suture) (Figure 1). The capsule and string are swallowed with water. The string is held at the mouth without tension by means of a 7 cm cardboard tab attached to the string, and esophageal peristalsis and gravity move the capsule into the stomach. After 5 to 7 minutes (during which the gelatin capsule dissolves and the sponge is liberated), the sponge is withdrawn by gentle traction on the string and as it does so, collects cells from the lining of the esophagus. The sponge is placed in fixative for 48 hours, then the cells are pelleted, and processed into paraffin blocks
Experimental: Participants with Barrett's and a History of Ablation Participants with Barrett's Esophagus (BE) with low grade dysplasia (LGD) or high grade dysplasia (HGD) and achieved complete eradication of BE via radiofrequency ablation (RFA).	Device: Cytosponge; The Cytosponge is a simple, non-endoscopic device developed for endoscopic screening of subjects at risk for Barrett's esophagus (BE) by investigators at the University of Cambridge in the U.K. The Cytosponge is an ingestible gelatin capsule enclosing a compressed spherical polyurethane mesh sponge of 3 cm diameter, the center of which is attached to a string (Astralen, braided synthetic non-absorbable suture) (Figure 1). The capsule and string are swallowed with water. The string is held at the mouth without tension by means of a 7 cm cardboard tab attached to the string, and esophageal peristalsis and gravity move the capsule into the stomach. After 5 to 7 minutes (during which the gelatin capsule dissolves and the sponge is liberated), the sponge is withdrawn by gentle traction on the string and as it does so, collects cells from the lining of the esophagus. The sponge is placed in fixative for 48 hours, then the cells are pelleted, and processed into paraffin blocks

Outcome Measures

Primary Outcome Measures

1. Cytosponge Acceptability by Number of Participants [7 days after Baseline]

   Acceptability will be measured the Impact of Events Scale (IES). This scale was developed to assess the distress associated with a specific life event. Respondents are asked to answer questions to indicate the amount of stress from the event. Scores are calculated with the following scale, (Not at all =0, Rarely =1, Sometimes =3, Often =5). Assessment yields a cumulative score that are calculated from each response, with a total final score ranging from (0-75). High scores represent high test induced distress and lower values represent low distress.

2. Mean Post Procedure Pain on the Visual Analog Scale [Immediately after Cytosponge removal]

   The visual analog scale (VAS) is a validated, subjective measure for acute and chronic pain. Scores are recorded by making a handwritten mark on a 100-mm line that represents a continuum between "no pain" and "worst pain." Higher scores are representative of worse pain.

3. Willingness to Repeat Cytosponge by Number of Participants [7 days after Baseline]

   Participants were asked if they would be willing to repeat the Cytosponge, yes/no.

4. Mean Procedure Preference Rating [7 days after Baseline]

   Participants were asked to rate both procedures (Cytosponge and esophagogastroduodenoscopy (EGD)) to indicate which procedure they preferred on a scale from 0-10. Higher scores represent greater preference.

Secondary Outcome Measures

1. Cytosponge™ Operating Characteristics [Baseline]

   The operating characteristics of the Cytosponge™ technique compared against a gold standard of upper endoscopy with biopsies for endoscopic surveillance was evaluated for sensitivity and specificity in the detection of BE in subjects with current (BE) or history of successful radiofrequency ablation for dysplastic BE. A true positive was considered when both the endoscopic biopsy and the Cytosponge detected the goblet cells characteristic of BE. A false positive was considered when the Cytosponge demonstrated these cells while the biopsies did not. A true negative occurred when neither the biopsies nor the Cytosponge showed goblet cells. A false negative was considered when the biopsies did demonstrate goblet cells while the Cytosponge did not. True Positives (TP) and False Negatives calculate sensitivity: (TP)/(TP + FN); True Negatives (TN) and False Positives (FP) are used to calculate specificity: (TN)/(TN + FP).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female subjects, age 18-80 years,

2. Meets the following:

2.1. Previous diagnosis of Barrett's Esophagus (BE) with dysplastic low grade dysplasia (LGD) or high grade dysplasia (HGD), as evidenced by both classical endoscopic appearance of salmon-colored mucosa in the tubular esophagus, as well as endoscopic biopsies from the involved areas demonstrating columnar metaplasia with goblet cells. The diagnosis of dysplasia must have been confirmed by a second expert pathologist. Previous endoscopic mucosal resection (EMR) of focal nodular high grade dysplasia (HGD) or superficial intramucosal cancer (IMC) is allowable, as long as the EMR specimen shows complete resection of any IMC with clear margins, and biopsies following ablation confirm excision of the lesion, AND 2.1.1. A history of complete eradication of both dysplasia and intestinal metaplasia by radiofrequency ablation. Complete eradication is defined as a normal endoscopic appearance of the tubular esophagus, and histologic confirmation by biopsies in 4 quadrants every cm from throughout the length of the previous BE (post-RFA cohort).OR 2.2. Current diagnosis of BE, presenting for routine care endoscopy (BE cohort).

1. Good general health, with no severely debilitating diseases, active malignancy, or condition that would interfere with study participation.

Exclusion Criteria:

1. Current use of blood thinners such as coumadin, warfarin, clopidogrel, heparin and/or low molecular weight heparin (requires discontinuation of medication 5 days prior to and 7 days after esophagogastroduodenoscopy (EGD) and Cytosponge administration, aspirin use is OK).

2. Known bleeding disorder

3. For the post-RFA cohort, prior ablative therapy of the esophagus other than radiofrequency ablation (RFA), including photodynamic therapy (PDT), more than one session of spray cryotherapy, and any other ablation therapies is exclusionary. However, prior endoscopic mucosal resection (EMR) is acceptable and up to two prior treatments of thermal/coagulation therapy (other than RFA) for focal residual disease following otherwise successful RFA therapy is acceptable.

4. History of esophageal stricture precluding passage of the endoscope or sponge,

5. Pregnancy, or planned pregnancy during the course of the study,

6. Any history of esophageal varices, liver impairment of moderate or worse severity (Child's- Pugh class B & C) or evidence of varices noted on any past endoscopy,

7. Any history of esophageal surgery, except for uncomplicated fundoplication, and,

8. History of coagulopathy, with international normalized ratio (INR) >1.3 and/or platelet count of <75,000.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• University of Cambridge
• National Institutes of Health (NIH)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Medtronic

Investigators

• Principal Investigator: Nicholas Shaheen, MD, MPH, UNC-Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 8, 2015

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT02106910
• Other Study ID Numbers: 13-2618; 1K24DK100548-01
• First Posted: Apr 8, 2014
• Last Update Posted: Nov 20, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by University of North Carolina, Chapel Hill: Barrett's Esophagus; Radiofrequency Ablation
• Additional relevant MeSH terms: Barrett Esophagus

Study Results

Participant Flow

Arm/Group Title	Participants With Barrett's and no History of Ablation	Participants With Barrett's After Ablation
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.
Period Title: Overall Study
STARTED	49	89
COMPLETED	48	88
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Participants With Barrett's and no History of Ablation	Participants With Barrett's After Ablation	Total
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Total of all reporting groups
Overall Participants	49	89	138
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.0 (10.6)	66.3 (8.8)	65.2 (9.6)
Sex: Female, Male (Count of Participants)
Female	13 26.5%	18 20.2%	31 22.5%
Male	36 73.5%	71 79.8%	107 77.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	49 100%	88 98.9%	137 99.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 1.1%	1 0.7%
Region of Enrollment (Count of Participants)
United States	49 100%	89 100%	138 100%

Outcome Measures

1. Primary Outcome

Title	Cytosponge Acceptability by Number of Participants
Description	Acceptability will be measured the Impact of Events Scale (IES). This scale was developed to assess the distress associated with a specific life event. Respondents are asked to answer questions to indicate the amount of stress from the event. Scores are calculated with the following scale, (Not at all =0, Rarely =1, Sometimes =3, Often =5). Assessment yields a cumulative score that are calculated from each response, with a total final score ranging from (0-75). High scores represent high test induced distress and lower values represent low distress.
Time Frame	7 days after Baseline

Outcome Measure Data

Analysis Population Description

Data unavailable for 2 participants who did not complete assessment.

Arm/Group Title	Participants With Barrett's and no History of Ablation	Participants With Barrett's After Ablation
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus. Period Title: Overall Study
Measure Participants	48	88
No meaningful impact (Scores 0-8)	46 93.9%	81 91%
Impact Event (Scores 9-25)	2 4.1%	6 6.7%
Powerful Impact Event (Scores 26-43)	0 0%	1 1.1%
Severe Impact Event (Scores 44-75)	0 0%	0 0%

2. Primary Outcome

Title	Mean Post Procedure Pain on the Visual Analog Scale
Description	The visual analog scale (VAS) is a validated, subjective measure for acute and chronic pain. Scores are recorded by making a handwritten mark on a 100-mm line that represents a continuum between "no pain" and "worst pain." Higher scores are representative of worse pain.
Time Frame	Immediately after Cytosponge removal

Outcome Measure Data

Analysis Population Description

Data unavailable for 2 participants who did not complete assessment.

Arm/Group Title	Participants With Barrett's and no History of Ablation	Participants With Barrett's After Ablation
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.
Measure Participants	48	88
Mean (Standard Deviation) [units on a scale]	19.1 (17.7)	17.0 (17.5)

3. Primary Outcome

Title	Willingness to Repeat Cytosponge by Number of Participants
Description	Participants were asked if they would be willing to repeat the Cytosponge, yes/no.
Time Frame	7 days after Baseline

Outcome Measure Data

Analysis Population Description

Data unavailable for 3 participants who did not complete assessment.

Arm/Group Title	Participants With Barrett's and no History of Ablation	Participants With Barrett's After Ablation
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.
Measure Participants	47	88
Yes	44 89.8%	86 96.6%
No	3 6.1%	2 2.2%

4. Primary Outcome

Title	Mean Procedure Preference Rating
Description	Participants were asked to rate both procedures (Cytosponge and esophagogastroduodenoscopy (EGD)) to indicate which procedure they preferred on a scale from 0-10. Higher scores represent greater preference.
Time Frame	7 days after Baseline

Outcome Measure Data

Analysis Population Description

Data unavailable for 2 participants who did not complete assessment.

Arm/Group Title	Participants With Barrett's and no History of Ablation	Participants With Barrett's After Ablation
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.
Measure Participants	48	88
Cytosponge Rating, On scale of 1-10	7.8 (2.3)	7.9 (2.0)
EGD Rating, On scale of 1-10	9.2 (1.4)	9.1 (1.5)

5. Secondary Outcome

Title	Cytosponge™ Operating Characteristics
Description	The operating characteristics of the Cytosponge™ technique compared against a gold standard of upper endoscopy with biopsies for endoscopic surveillance was evaluated for sensitivity and specificity in the detection of BE in subjects with current (BE) or history of successful radiofrequency ablation for dysplastic BE. A true positive was considered when both the endoscopic biopsy and the Cytosponge detected the goblet cells characteristic of BE. A false positive was considered when the Cytosponge demonstrated these cells while the biopsies did not. A true negative occurred when neither the biopsies nor the Cytosponge showed goblet cells. A false negative was considered when the biopsies did demonstrate goblet cells while the Cytosponge did not. True Positives (TP) and False Negatives calculate sensitivity: (TP)/(TP + FN); True Negatives (TN) and False Positives (FP) are used to calculate specificity: (TN)/(TN + FP).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Data unavailable for 2 participants who did not complete assessment.

Arm/Group Title	Participants With Barrett's and no History of Ablation	Participants With Barrett's After Ablation
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.
Measure Participants	48	88
Specificity to detect BE	92.00 187.8%	85.00 95.5%
Sensitivity to detect BE	80.00 163.3%	74.00 83.1%
Assay Accuracy	NA NaN	84.00 94.4%

Adverse Events

Time Frame	From Baseline until approximately 30 days after completion of biomarker panel, an overall approximate total of 45 days.
Adverse Event Reporting Description	Per study protocol section 7.2, only those events that are potentially related to participation in this research study must be reported.
Arm/Group Title	Participants With Barrett's and no History of Ablation		Participants With Barrett's After Ablation
Arm/Group Description	Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations with no history of ablation. Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.		Participants presenting with Barrett's Esophagus (BE) for routine endoscopic examinations after history of at least one session of Endoscopic Eradiation Therapy (EET). Cytosponge Cell Collection Device is indicated for use in the collection and retrieval of surface cells in the esophagus.
All Cause Mortality
	Participants With Barrett's and no History of Ablation		Participants With Barrett's After Ablation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/89 (0%)
Serious Adverse Events
	Participants With Barrett's and no History of Ablation		Participants With Barrett's After Ablation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/89 (0%)
Other (Not Including Serious) Adverse Events
	Participants With Barrett's and no History of Ablation		Participants With Barrett's After Ablation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/49 (14.3%)		14/89 (15.7%)
Gastrointestinal disorders
Sore Throat	7/49 (14.3%)	7	14/89 (15.7%)	14

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.