Ablation of Intestinal Metaplasia Containing Dysplasia

• The % of patients with complete histological clearance of dysplasia within the HGD subgroup (n=63) at 12 months, comparing treatment versus sham control groups. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• The % of patients with complete histological clearance of IM at 12 months, comparing treatment versus sham control groups (n=127) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• The % of patients with complete histological clearance of dysplasia within the LGD subgroup (n=64) at 12 months, comparing treatment versus sham control groups. [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
  
• 5 year extension: % of all patients enrolled in the extension protocol and available for analysis demonstrating CR-IM at 5 years, and demonstrating CR-dysplasia at 5 years. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  

• The % of patients with complete histological clearance of dysplasia at 12 months, comparing treatment versus sham control groups (n=127). [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• The % of patients with complete histological clearance of IM at 12 months, comparing treatment versus sham control groups within a specific dysplasia subgroup (LGD [n=64] and HGD [n=63] ) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• Within the HGD subgroup (n=63), the % of patients with complete histological clearance of HGD at 12 months, comparing treatment versus sham control groups. [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
  
• Histological clearance of IM (% biopsies) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• Progression of dysplasia (i.e., HGD to adenocarcinoma, or LGD to HGD or adenocarcinoma) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• Regression of dysplasia (i.e., HGD to LGD for HGD group only) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• Subject discomfort at baseline and 0-14 days post-procedure [ Time Frame: 0 and 6 Months for all subjects; 2, 4, 9, and 15 months, if ablated ] [ Designated as safety issue: No ]
  
• Quality of Life questionnaire (baseline v. 12 and 24 mos) [ Time Frame: 0, 12, and 24 months ] [ Designated as safety issue: No ]
  
• Adverse event incidence [ Time Frame: 12 months for Treatment and Sham Comparison ] [ Designated as safety issue: Yes ]
  
• 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) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• 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 [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• 5 year extension: Proportion (%) of all patients enrolled in this extension protocol and available for analysis demonstrating CR-IM at 3 and 4 years, analyzed separately [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• 5 year extension:Proportion (%) of all patients enrolled in this extension protocol and available for analysis demonstrating CR-D at 3 and 4 years, analyzed separately [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• 5 year extension: Proportion (%) of all patients enrolled in this extension protocol and available for analysis demonstrating CR-IM and CR-D (analyzed separately) at 3, 4, and 5 years subgrouped according to entry pathology (LGD, HGD) at randomization [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• 5 year extension: Proportion of patient-years of trial follow-up spent in CR-IM, calculation commencing after the 2 year interval [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• 5 year extension: Proportion of all esophageal biopsies collected at 3, 4, 5 years that are free of IM, and separately, free of dysplasia [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  
• 5 year extension: Adverse event incidence [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
  
• 5 year extension: All cause mortality of the group from 2 to 5 years. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  

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.