Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

44th Annual Meeting of the Canadian Association of Gastroenterology

Banff, Alberta / February 24-27, 2006

As ulcerative colitis (UC) is a debilitating disease afflicting patients often in the busy years of early adulthood (Rioux et al. Am J Hum Genet 2000;66(6):1863-70) and requires lifelong treatment even in the absence of symptoms, there is a demand for therapies that can accommodate patients’ needs. Dr. Sunanda Kane, Associate Professor of Medicine, University of Chicago, Illinois, told delegates that typical formulations of 5-aminosalicylic acid (5-ASA or mesalamine) might be “inconvenient and require multiple daily dosing” that could “interfere with normal life and reduce the overall quality of life” (Kase SV. Aliment Pharmacol Ther 2006;23(5):577-85).

Adherence is an important issue to be considered by physicians who are treating patients suffering from UC. The burden on patients is changing with newer, higher-dose 5-ASA formulations designed to be more convenient for them (Hanauer et al. Am J Gastroenterol 2005;100(11):2478-85). A strategy that is being used amongst many physicians is to reduce pill burden and dosing frequency. Emphasizing the need for ease of use, Dr. Kane and her colleagues have found that patients who were not compliant with medication had more than a fivefold greater risk of recurrence than adherent patients (Kane et al. Am J Med 2003;114(1):39-43). Subsequently, tolerability becomes an equally important aspect for UC patients, who would understandably wish to avoid additional adverse events.

Addressing Adherence

To address these concerns, Dr. Gary Lichtenstein, Director, Inflammatory Bowel Disease Program and Professor of Medicine, University of Pennsylvania, Philadelphia, and colleagues conducted a multicentre, phase III, prospective, double-blind study (Table 1) to assess the efficacy and tolerability of SPD476, a new high-strength 5-ASA (1.2 g/tablet) multimatrix (MMX) formulation using a delayed- and extended-release technology. This agent is developed to slowly dissolve itself throughout the colon, which may prolong its therapeutic activity. The purpose of the study was to determine if the new regimen would increase therapeutic compliance and regimen adherence.

In study 301, 280 patients with mild-to-moderate UC were randomized into three cohorts (Table 1). The primary end point of this study was the percentage of patients in remission at eight weeks. For the purposes of this study, remission was defined as having a UC disease activity index (UC-DAI) £1, a score of 0 for rectal bleeding and stool frequency, as well as a ³1-point reduction in sigmoidoscopy score from baseline. Criteria used to enrol patients in the study included but were not limited to a sigmoidoscopy score ³1. End point data included information from the 79 participants who withdrew from the study (17 from the 1.2 g b.i.d. cohort, 21 from the 4.8 g q.d. cohort and 41 from the placebo cohort). Dr. Michael Kamm, Professor of Gastroenterology, Chairman of Medicine and Director, Physiology Unit, St. Mark’s Hospital, London, UK, noted that the once-daily higher dose was associated with greater clinical improvement, as well as a reduction in stool frequency and rectal bleeding when compared with the 1.2 g b.i.d. dose. Overall, the once-daily higher dose was well tolerated by patients who had mild-to-moderate UC.

Table 1. Results from Study 301

Improving Delivery

Dr. Kamm and colleagues studied the effects of new 5-ASA formulations designed for more effective delivery with larger dosages, thereby decreasing dosing frequency. A phase III, double-blind, multicentre study assessed the efficacy and tolerability of once-daily mesalamine (1.2 g 5-ASA/tablet). The eight-week study monitored 341 patients with mild-to-moderate UC randomized to one of four cohorts (Table 2). The primary end point of this study was the percentage of patients in remission at eight weeks. For the purposes of this study, remission was defined as having a UC-DAI £1, a score of 0 for rectal bleeding and stool frequency, as well as a ³1-point reduction in sigmoidoscopy score from baseline. In the end results, when compared to placebo, a statistically greater proportion of patients in both cohorts of SPD476 achieved both remission and clinical remission. The delayed-release formulation given three times daily was not statistically superior to placebo for either end point. There were more patients from the placebo arm who withdrew from the study due to disease-related adverse events than in the active comparator
esults from Study 302

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The improvement in outcomes may be attributed to the well-profiled effectiveness of 5-ASA in general as a treatment for UC, as well as to the newer high-strength formulations (1.2 g/tablet). The new MMX technology allows both delayed and extended drug release, thereby reducing dosage frequency. Dr. Kamm noted that achieving effective lumenal concentrations of 5-ASA requires the use of special release formulations (Kamm MA. Aliment Pharmacol Ther 2002;16(4):21-4).

Summary

Among the many cutting-edge presentations given here at the Canadian Digestive Diseases Week were novel treatment strategies for UC, expanding the options available for patients dealing with this condition to help optimize overall compliance. By providing more convenient higher dosages given once daily, these new formulations have the potential to be more effective in inducing and maintaining remission in UC patients. This may help physicians to optimize overall compliance and thus improve the quality of life for these patients.