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.

Based on the following articles: Can J Gastroenterol 2007;21(12):827-34. Am J Gastroenterol 2005;100:2478-85.

May 2008

When the two ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) trials were designed, it was not known if initial therapy of delayed-release oral mesalamine 4.8 g/day would be more effective than 2.4 g/day in patients with mildly to moderately active ulcerative colitis (UC).

In ASCEND II (which was published before ASCEND I), Dr. Stephen B. Hanauer, Division of Gastroenterology, University of Chicago Medical Center, Illinois, and colleagues randomized each treatment group to six tablets a day, either with the 800-mg tablet for a total daily dose of 4.8 g or the 400-mg tablet for a total daily dose of 2.4 g. Of the 386 patients with mildly to moderately active UC randomized, 268 had moderate disease at baseline, defined as a Physician’s Global Assessment (PGA) score of 2.

The primary efficacy intention-to-treat (ITT) analysis included only patients with moderately active disease, 130 assigned to the lower dose and 124 assigned to the higher dose. At week 6, 59.2% of patients in the 2.4 g/day group and 71.8% of patients in the 4.8 g/day group were classified as having overall improvement (treatment success defined as either complete remission or a clinical response to therapy). The difference in overall improvement rates was 12.5% (P=0.036). Investigators reported that patients with moderate disease treated with the higher dose were 1.2 times more likely to experience complete remission or clinical response than those who received the lower dose with an absolute treatment difference of 13%. The median time to resolution of rectal bleeding was also significantly shorter in the higher-dose group at nine days vs. 16 days for the lower-dose group (P=0.035). Both regimens were well tolerated and adverse events were similar in both treatment groups.

Those with mild disease did not experience additional benefit from receiving the higher 4.8 mg/day dose.

As investigators pointed out, physicians generally initiate treatment in mildly to moderately active UC patients with delayed-release oral mesalamine at a dose of 2.4 g/day and then titrate up to a maximum of 4.8 g/day if they fail to respond to the lower dose after four to six weeks of treatment. Based on the results, the authors believe that clinical practice should be altered so that patients with mildly active UC are treated initially with delayed-release oral mesalamine 2.4 g/day and those with moderately active disease are treated initially with 4.8 g/day using the 800-mg tablet. The 800-mg tablet allows for 4.8 g/day mesalamine to be given in only six tablets a day.

ASCEND I

More recently, Hanauer et al. published results from ASCEND I, in which patients with mildly to moderately active UC were randomized to either the delayed-release oral mesalamine 400-mg or the 800-mg tablet for total daily doses of 2.4 g/day or 4.8 g/day, respectively.

Results of the primary efficacy ITT analysis for 286 patients with mildly to moderately active UC showed that 51% of those on the lower dose and 56% of those on the higher dose achieved treatment success at six weeks (P=0.441). Confining the analysis to 180 patients with moderately active disease at baseline, the authors found that 57% of patients (53 out of 93) on 2.4 g/day and 72% of those on 4.8 g/day (55 out of 76) achieved overall improvement at six weeks for a 15% difference in overall improvement between the two groups (P=0.0384).

As in ASCEND II, the incidence of adverse events in ASCEND I was similar in both treatment groups.

Investigators concluded that these results suggest that in patients with moderately active disease, initiating therapy at 4.8 g/day could improve response to initial therapy.

From the ASCEND trials, differentiating between mild and moderate disease may have important clinical implications, especially because approximately 70% of UC patients present with moderate disease. Historically, mildly and moderately active UC have been viewed clinically more as a continuum than as separate entities, and the appropriate dose for initial treatment of these patients has been expressed as a range (2.4 g/day to 4.8 g/day). The results of these trials demonstrate that patients with moderate disease benefit from an initial higher dose of 4.8 g/day.

Questions and Answers

This question-and-answer session is based on interviews with Dr. Hillary Steinhart, Head, Combined Division of Gastroenterology, UHN-Mount Sinai Hospital, Toronto, Ontario; and Dr. Pierre Paré, Professor of Medicine, Université Laval, Quebec City, Quebec.

Q: Now that an 800-mg tablet is available, do you think that a higher initial dose (and thus fewer tablets) will improve treatment outcomes?

Dr. Steinhart: For patients in acute flare-up, the number of pills they have to take is less of an issue than it is for maintenance therapy, when the disease is quiescent and taking many pills becomes more of a burden. Patients who have had a moderate to severe flare in the past should be on some form of maintenance therapy. If the total number of pills can be reduced in this setting, it may help with patient satisfaction and adherence.

Dr. Paré: Patients in an acute flare are sicker so the number of tablets they have to take is not of great concern; but for maintenance therapy, the number of tablets is much more of an issue, and certainly, it is more convenient to take fewer pills during the chronic phase of treatment, so that would be an advantage.

Q: Could findings from the ASCEND studies lead to a paradigm shift in the way patients with moderately active UC are treated?

Dr. Steinhart: The studies do support using the higher dose in moderately active UC because it provides a margin of benefit over the lower dose, and it does this without any increase in toxicity or side effects, so there isn’t really a down side to using the higher dose other than cost.

Dr. Paré: I initiate treatment early with high-dose agents in patients with moderate and severe disease. There are no data supporting the step-wise approach. It also makes sense that if you deliver a higher concentration of the drug to the mucosa, it may well result in better clinical outcomes, again in moderate to severe disease. Q: At what point in the disease or in which patients would you consider the use of biologicals?

Dr. Steinhart: I think the biologicals can be considered in patients who have failed or who cannot tolerate the conventional maintenance therapies from 5-ASA through to the steroids and the immunomodulators.

Dr. Paré: You need to consider the biologics first in fulminant disease—very severe disease where patients are admitted to hospital and it’s almost used as emergency treatment. I would also consider their use in patients who have poor control on all of the other drug classes, including the 5-ASAs, the steroids and the immunomodulators.