Ablation of Intestinal Metaplasia Containing Dysplasia

Barrett Esophagus Clinical Trial

Official title:

Ablation of Intestinal Metaplasia Containing Dysplasia (AIM Dysplasia Trial) A Multi-center, Randomized, Sham-Controlled Trial: Protocol Amendment to Extend Follow-up to 5 Years

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00282672
• Other study ID #: B-204
• Status: Completed
• Phase: N/A
• First received: January 25, 2006
• Last updated: October 5, 2017
• Start date: February 2006
• Est. completion date: August 2014

Study information

• Verified date: October 2017
• Source: Medtronic - MITG
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if the intervention of a 510(k)-cleared endoscopically-guided (Halo Ablation systems), ablation system plus anti-secretory therapy is better than anti-secretory therapy alone in clearing Barrett's Esophagus.

Description:

Barrett's esophagus or intestinal metaplasia (IM) is a change in the epithelial lining of the esophagus. Barrett's esophagus develops as a result of chronic exposure of the esophagus to refluxed stomach acid and enzymes, as well as bile, resulting in recurrent mucosal injury. Injury is accompanied by inflammation and, ultimately, a cellular change (metaplasia) to a specialized columnar epithelium (Spechler SJ. Barrett's Esophagus. N Engl J Med 2002;346(11):836-842.)

Patients who have a diagnosis of Barrett's esophagus typically undergo surveillance endoscopy every 1-3 years with multiple biopsy specimens obtained to facilitate early detection of progression of IM to dysplasia (more severe precancerous changes) and adenocarcinoma. (Sampliner RE. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am J Gastro 2002;97:1888-1895.) Progression of IM to low-grade dysplasia (LGD) indicates that cells exhibit more "cancer-like" architecture, thus warranting an accelerated surveillance endoscopy and biopsy program every 6 months rather than every 1-3 years as indicated for non-dysplastic IM. Progression to high-grade dysplasia (HGD) indicates that the cells are even more "cancer-like", thus warranting an even higher frequency surveillance endoscopy and biopsy program (every 3 months). Many HGD patients may undergo photodynamic therapy (PDT) or surgical esophagectomy, rather than remain in a frequent surveillance program. This more aggressive therapy is warranted because of the high rate of progression of HGD to adenocarcinoma.

Esophageal adenocarcinoma most commonly occurs after an insidious progression from IM to LGD to HGD. Therefore, surveillance is increased upon diagnosis of worsening grades of dysplasia. The incidence of esophageal adenocarcinoma is rapidly increasing as middle-aged and elderly demographic sub-groups expand (Peters JH, Hagen JA, DeMeester SR. Barrett's Esophagus. J Gastrointest Surg 2004;8(1):1-17.) In 2004, the American Cancer Society reported that there were 14,250 new cases of esophageal cancer, and 13,300 deaths attributable to esophageal cancer (www.cancer.org). The U.S. National Cancer Institute Surveillance, Epidemiology and End Results Program reported that the increasing incidence of esophageal adenocarcinoma was greater than for any other cancer in the United States (www.cancer.gov).

Elimination of the diseased epithelium containing IM with dysplasia is an intuitively favorable step for patients with this diagnosis. In other disease states, such as colon polyps or premalignant skin lesions, removal of the premalignant tissue results in a reduction in the risk of ultimately developing cancer. This is a logical conclusion when considering the premalignant lesion of Barrett's esophagus (particularly Barrett's esophagus with dysplasia), as the "tissue at risk" can be completely removed by ablation. This premise has been tested in the Barrett's dysplasia population in photoablative trials using PDT for patients with HGD, where PDT imparted a 50% reduction in risk over controls for the development of adenocarcinoma (Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett's esophagus: follow-up. Gastrointest Endosc 1999;49(1):1-7.) The AIM Dysplasia Trial primary endpoints are removal of all dysplasia and IM, rather than detection of a difference in progression to adenocarcinoma or higher grades of dysplasia.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 127
• Est. completion date: August 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:1.Subject is 18-80 years of age, inclusive. 2.Subject has documented diagnosis of IM, maximum endoscopic length of 8 cm (as measured endoscopically from the TGF to the most proximal extent of the IM; i.e. TGF-TIM containing dysplasia as follows:

1. For LGD:i.LGD documented on biopsy within previous 12 months from enrollment while subject on PPI therapy.

ii.Histology slides reviewed at central pathology service for trial confirm LGD on first confirmatory central pathology review or, if necessary, confirm LGD on a tie-breaker review by a second pathologist.

2. For HGD:i.Regular, non-nodular, non-ulcerated mucosa. ii.HGD documented on biopsy within previous 6 months from enrollment. iii.Histology slides reviewed at central pathology service for Trial confirm HGD on first confirmatory review or, if necessary, confirm HGD on a tie-breaker review by a second pathologist.

iv.Baseline EUS within previous 12 months; 1.Catheter-based EUS excludes suspicious thickened Barrett's areas or, if suspicious areas found, prompts stacked biopsies of thickened area, the results of which do not render subject ineligible for enrollment.

3.For subjects with EMR history,the documented diagnosis of IM with dysplasia meets criterion #2 from biopsies collected either after the EMR procedure or during the EMR procedure but not from the EMR site.

4.Subject able to take oral proton pump inhibitor medication. 5.Subject able to discontinue aspirin and/or non-steroidal anti-inflammatory medications 7 days before and after all ablation procedures.

6.For female subjects of childbearing potential, a negative pregnancy test within 2 weeks of randomization.

7.Subject eligible for treatment and follow-up endoscopy and biopsy as required by the Protocol.

8.Subject willing to provide written, informed consent to participate in this clinical study and understands the responsibilities of trial participation.

Exclusion Criteria:1.The subject is pregnant or planning a pregnancy during the study period.

2.Esophageal stricture preventing passage of endoscope or catheter. 3.Active esophagitis described as erosions or ulcerations encompassing more than 10% of distal esophagus.

4.Any history of malignancy of the esophagus. 5.Prior radiation therapy to the esophagus,except head and neck region radiation therapy.

6.Any previous ablative therapy within the esophagus (PDT, MPEC, APC, laser treatment, other).

7.History of EMR that meets any of the following criteria:a.EMR performed less than 8 weeks prior to the randomization endoscopy encounter

b.EMR performed in a wide field manner (encompassing more than 90 degrees of any area of the esophagus.

8.Any previous esophageal surgery, including except fundoplication without complications (i.e. no slippage, dysphagia, etc).

9.Evidence of esophageal varices during treatment endoscopy. 10.Report of uncontrolled coagulopathy with international normalized ratio (INR) > 1.3 or platelet count <75,000 platelets per µL 11.Subject has a life-expectancy of less than two years due to an underlying medical condition.

12.Subject has a known history of unresolved drug or alcohol dependency that would limit ability to comprehend or follow instructions related to informed consent, post-treatment instructions, or follow-up guidelines.

13.Subject has an implantable pacing device (examples; AICD, neurostimulator, cardiac pacemaker)and has not received clearance for enrollment in this study by specialist responsible for the pacing device.

14.The subject is currently enrolled in an investigational drug or device trial that clinically interferes with the AIM Dysplasia Trial endpoints.

15.Subject suffers from psychiatric or other illness deemed by the investigator as an inability to comply with protocol.

For the 5 year extension, patient must have:1. Enrolled in the B-204 protocol. 2. Completed 1 year follow-up. 3. Completed 2 year follow-up.

Related Conditions & MeSH terms

• Barrett Esophagus
• Metaplasia

Intervention

Device:
• Ablation System plus anti-secretory medication
Treatment group subjects undergo up to 4 ablation procedures (circumferential or focal) plus standard anti-secretory drug therapy (proton pump inhibitor, PPI).
• Sham procedure plus anti-secretory medication
The Sham Control group undergo an upper endoscopy procedure with sizing of the esophageal diameter (a component of the ablation procedure steps, deemed the sham procedure) plus standard anti-secretory drug therapy (Proton pump inhibitor, PPI)

Locations

Country	Name	City	State
United States	UNC Center for Functional GI & Motility Disorders	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	VAMC Dallas	Dallas	Texas
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	University of Kansas School of Medicine - Veterans Affairs Medical Center	Kansas City	Missouri
United States	Gastrointestinal Associates	Knoxville	Tennessee
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Columbia University Medical Center	New York	New York
United States	UC Irvine Medical Center	Orange	California
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Oregon Health Sciences University	Portland	Oregon
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	Tacoma Digestive Disease Research Center	Tacoma	Washington
United States	University of Arizona, VAMC	Tucson	Arizona
United States	Harvard, VA Boston Healthcare W Roxbury	West Roxbury	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Medtronic - MITG	AstraZeneca

Country where clinical trial is conducted

United States, 

References & Publications (4)

Dunkin BJ, Martinez J, Bejarano PA, Smith CD, Chang K, Livingstone AS, Melvin WS. Thin-layer ablation of human esophageal epithelium using a bipolar radiofrequency balloon device. Surg Endosc. 2006 Jan;20(1):125-30. Epub 2005 Dec 7. — View Citation

Ganz RA, Utley DS, Stern RA, Jackson J, Batts KP, Termin P. Complete ablation of esophageal epithelium with a balloon-based bipolar electrode: a phased evaluation in the porcine and in the human esophagus. Gastrointest Endosc. 2004 Dec;60(6):1002-10. — View Citation

Shaheen NJ, Overholt BF, Sampliner RE, Wolfsen HC, Wang KK, Fleischer DE, Sharma VK, Eisen GM, Fennerty MB, Hunter JG, Bronner MP, Goldblum JR, Bennett AE, Mashimo H, Rothstein RI, Gordon SR, Edmundowicz SA, Madanick RD, Peery AF, Muthusamy VR, Chang KJ, — View Citation

Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, Wang KK, Galanko JA, Bronner MP, Goldblum JR, Bennett AE, Jobe BA, Eisen GM, Fennerty MB, Hunter JG, Fleischer DE, Sharma VK, Hawes RH, Hoffman BJ, Rothstein RI, Gordon SR, Mashimo H, Chang KJ, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The % of Patients With Complete Eradication of Intestinal Metaplasia (IM) at 12 Month	% of patients with complete eradication of IM out of the number of participants analyzed at 12 month was calculated.	12 month
Primary	The % of Patients With Complete Eradication of Dysplasia at 12 Month	% of patients with complete eradication of Dysplasia out of the number of participants analyzed at 12 month was calculated.	12 month
Primary	The % of Patients With Complete Histological Clearance of Intestinal Metaplasia at 24 Months.	% of patients with complete eradication of IM out of the number of participants analyzed at 24 month was calculated.	24 Month
Primary	5 Year Extension: % of All Patients Enrolled in the Extension Protocol and Available for Analysis Demonstrating CR-IM at 5 Years	For patient who made it to the 5 year visit, % of patients demonstrating complete eradication of intestinal metaplasia (CE-IM) was calculated.	5 years
Primary	Durability of Eradication With no Additional Treatments		5 year
Primary	5 Year Extension: % of All Patients Enrolled in the Extension Protocol and Available for Analysis Demonstrating CR-D at 5 Years	For patient who made it to the 5 year visit, % of patients demonstrating complete eradication of dysplasia was calculated and all were free of dysplasia	5 years
Secondary	The % of Patients With Complete Histological Clearance of IM at 12 Months, Comparing Treatment Versus Sham Control Groups Within a Specific Dysplasia Subgroup		12 months
Secondary	Within the HGD Subgroup, the % of Patients With Complete Histological Clearance of HGD (CR-D) at 12 Months, Comparing Treatment Versus Sham Control Groups.		12 Month
Secondary	Histological Clearance of IM (% Biopsies)	% of patients with histological clearance of IM out of the number of participants analyzed at 12 month was calculated.	12 months
Secondary	Progression of Dysplasia (i.e., HGD to Adenocarcinoma, or LGD to HGD or Adenocarcinoma)		5 year
Secondary	Subject Discomfort : Chest Pain Score on Day 1	Chest pain score was measured on a visual analogue scale of 0 to 100, with higher scores indicating a greater severity of pain	Day 1 , if ablated
Secondary	Quality of Life Questionnaire (Baseline v. 12 and 24 Mos)		0, 12, and 24 months
Secondary	Adverse Event Incidence	Data reported in the adverse event section	12 months for Treatment and Sham Comparison
Secondary	For 5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension and Available for Analysis at 5 Years Demonstrating Any Adenocarcinoma in Any Biopsy Obtained From the Esophageal Body Since Primary RFA (0-5 Years)		5 years
Secondary	5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension and Available for Analysis at 5 Years Demonstrating Any Adenocarcinoma in Any Biopsy Obtained From the Esophageal Body After 2 Years and Inclusive of the 5 Year Visit		5 years
Secondary	5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-IM at 5 Year		5 years
Secondary	5 Year Extension:Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-D at 5 Year		5 years
Secondary	5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-IM at 4 Year		4 years
Secondary	5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-IM at 3 Year		3 years
Secondary	5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-D at 4 Year		4 years
Secondary	5 Year Extension: Serious Adverse Event Incidence		5 years
Secondary	5 Year Extension: All Cause Mortality of the Group From 2 to 5 Years.		5 years