Sporadic adenomatous polyp regression with Exisulind is effective but toxic: a randomized, double-blind, placebo- controlled, dose-response study

Nadir Arber ^1*, Scott Kuwada ², Moshe Leshno ¹, Rune Sjodahl ³, Rolf Hultcrantz ⁴ and Douglas Rex ⁵

¹ Tel-Aviv Medical Center and Tel Aviv University, Israel
² University of Utah Health Sciences Center, Salt Lake City, United States
³ University Hospital, Linkoping, Sweden
⁴ Karolinska University Hospital, Stockholm, Sweden
⁵ Indiana University Medical Center, Indianapolis, United States

^* To whom correspondence should be addressed. E-mail: narber{at}post.tau.ac.il.

Accepted 30 August 2005

Abstract

Background: Exisulind inhibits tumor growth by induction of apoptosis.

Aim: Exisulind will induce the regression of sporadic colonic adenomas.

Patients and Methods: At baseline colonoscopy, left-sided polyps (3-10 mm) were tattooed, measured and left in place. Subjects received exisulind 200 or 400 mg, or placebo daily. Follow-up sigmoidoscopy was performed on month-6, and removal of any remaining polyps at month-12 colonoscopy. A 12-month, multi-center, randomized, double blind, placebo-controlled, phase 3, dose-response study. The primary efficacy variable was change in polyp size from baseline.

Results: 281 patients were enrolled and randomized. 155 (55%) fulfilled the criteria for the intention-to-treat (ITT) analysis, and 114 (41%) fulfilled the criteria for the efficacy evaluation analysis (patients who underwent month-12 colonoscopy). The decrease in median polyp size was significantly greater (p=0.03) in patients receiving exisulind 400 mg (- 10mm2) as compared to those receiving placebo (-4 mm2). Complete or partial response was significantly higher in the exisulind 400 mg group (54.6%) compared to the placebo group (30.2%), and disease progression was significantly lower (6.1% vs. 27.9%) (p = 0.04 and 0.02, respectively). Increased liver enzymes (8.4%) and abdominal pain (14.7%) were also reported at a greater frequency in the exisulind 400mg group.

Conclusion: Exisulind caused a significant regression of sporadic adenomatous polyps, but was associated with more toxicity. This model of polyp regression, short in its term and involving a comparatively small patient sample size, may be the best available tool to assess a therapeutic regimen before launching into large preventive clinical studies.

Keywords: Exisulind, adenoma regression, polyps, randomized trial, sulindac sulfone

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