Ablation of Intestinal Metaplasia Containing Dysplasia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Barrett Esophagus

Intervention / Treatment
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* Device: Ablation System plus anti-secretory medication
* Device: Sham procedure plus anti-secretory medication


Participation Criteria
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Eligibility Criteria
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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: 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: LGD Sham Procedure first then LGD Radiofrequency Ablation<br>Sham procedure plus anti-secretory medication. Subjects with Low Grade Dysplasia (LGD) receive proton pump inhibitor (PPI) with dose of Esomeprazole 40 mg BID. At 12 month, subjects crossover to receive radiofrequency ablation. | Device: Sham procedure plus anti-secretory medication<br>* 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)<br>|
| Active Comparator: LGD:Radiofrequency ablation<br>Ablation System plus anti-secretory medication. Subjects with Low Grade Dysplasia (LGD) undergo an upper endoscopy with sizing of the esophageal diameter followed by radiofrequency ablation plus standard anti-secretory therapy (proton pump inhibitor, PPI-dose: Esomeprazole 40 mg BID.) | Device: Ablation System plus anti-secretory medication<br>* Treatment group subjects undergo up to 4 ablation procedures (circumferential or focal) plus standard anti-secretory drug therapy (proton pump inhibitor, PPI).<br>* Other names: HALO 90;|
| Sham Comparator: HGD Sham Procedure first then HGD Radiofrequency Ablation<br>Sham procedure plus anti-secretory medication. Subjects with High Grade Dysplasia (HGD) with proton pump inhibitor (PPI) dose: Esomeprazole 40 mg BID. At 12 month, subjects crossover to receive radiofrequency ablation. | Device: Sham procedure plus anti-secretory medication<br>* 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)<br>|
| Active Comparator: HGD:Radiofrequency ablation<br>Ablation System plus anti-secretory medication. Subjects with High Grade Dysplasia (HGD) undergo an upper endoscopy with sizing of the esophageal diameter followed by radiofrequency ablation plus standard anti-secretory therapy (proton pump inhibitor, PPI-dose: Esomeprazole 40 mg BID.) | Device: Ablation System plus anti-secretory medication<br>* Treatment group subjects undergo up to 4 ablation procedures (circumferential or focal) plus standard anti-secretory drug therapy (proton pump inhibitor, PPI).<br>* Other names: HALO 90;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Durability of Eradication With no Additional Treatments |  | 5 year | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Progression of Dysplasia (i.e., HGD to Adenocarcinoma, or LGD to HGD or Adenocarcinoma) |  | 5 year | 
| 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 | 
| Quality of Life Questionnaire (Baseline v. 12 and 24 Mos) |  | 0, 12, and 24 months | 
| Adverse Event Incidence | Data reported in the adverse event section | 12 months for Treatment and Sham Comparison | 
| 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 | 
| 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 | 
| 5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-IM at 5 Year |  | 5 years | 
| 5 Year Extension:Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-D at 5 Year |  | 5 years | 
| 5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-IM at 4 Year |  | 4 years | 
| 5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-IM at 3 Year |  | 3 years | 
| 5 Year Extension: Proportion (%) of All Patients Enrolled in This Extension Protocol and Available for Analysis Demonstrating CR-D at 4 Year |  | 4 years | 
| 5 Year Extension: Serious Adverse Event Incidence |  | 5 years | 
| 5 Year Extension: All Cause Mortality of the Group From 2 to 5 Years. |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysplasia, Barrett's Esophagus, Radiofrequency Ablation