Clinical Newswire, January 11, 2010-Mesalamine for the treatment of ulcerative colitis (UC) has historically been administered in multiple daily doses due to toxicity and efficacy assumptions, however, comparison with once daily treatment has not been explored in depth. A study led by WJ Sandborn and published online in the January edition of Gastroenterology, has shown that once daily dosing of delayed release oral mesalamine (Asacol) at doses of 1.6-2.4 g/day is just as effective and safe as twice daily dosing for maintenance of clinical remission in patients with a history of mild to moderate UC.
This was a randomized investigator-blinded 12 month trial with a total of 1023 patients. All patients had mild to moderate UC and had been in clinical remission (Simple Clinical Colitis Activity Index (SCCAI) score of 2 or less points) for at least 3 months on Asacol (dose range 1.6-2.4g/day). Patients were randomized to receive a once-daily (n=512) or twice-daily (n=511) regimen of Asacol (400mg tablet) at the same total daily dose that the patients were receiving at baseline. Patients were assessed for disease severity and efficacy with the SCCAI score at months 0 (baseline), 3,6,9 and 12. Relapse was defined as a SCCAI score of 5 or higher. Primary end point was maintenance of clinical remission at month 6 in the primary efficacy analysis population (intent to treat population). Primary efficacy analysis attempted to determine non-inferiority of the once-daily dosing regimen at month 6. Secondary end points included time to relapse measured from the first dosing date to diagnosis of relapse, maintenance of clinical remission at months 3 and 12, patient-defined remission at months 6 and 12, Medication Adherence Report Scale (MARS) assessment at months 3, 6 and 12, and patient satisfaction and preference with treatment regimen at months 6 and 12.
At baseline, most patients (70%) received 2.4g/day Asacol, and 28% 1.6g/day. Four percent of patients at baseline were receiving a once-daily dosing regimen, 62% were receiving a twice-daily regimen, 33% a 3 times daily regimen, and 1% were receiving an “other” regimen. The primary objective of noninferiority was met. Of those patients that received dosing once-daily, 90.5% (428/473 patients) maintained clinical remission, compared to 91.8% in the twice-daily group (95% CI for twice-daily ― once-daily、-2.3 to -4.9). No significant difference in dosing regimens was observed at 3 and 12 months as well. Time to relapse was also similar between dosing regimens at month 6 (hazard ratio, 1.17; 95% CI, 0.76 –1.80) and month 12 (hazard ratio, 1.01; 95% CI, 0.71–1.42; Figure 1B and C). No significant differences in patient-defined remission were seen between regimens at months 6 and 12. Patient satisfaction was not statistically different at month 6 (P=0.08), however, at month 12 a significantly higher proportion of patients were more satisfied with the once-daily dosing regimen (P=0.01). Overall at months 6 and 12, patients preferred taking medication fewer times a day, with once-daily preferred over twice daily (P<0.0001) and thrice daily (P<0.0001). Adherence to medication was high in both treatment groups.
Incidence of withdrawals resulting from adverse events (AEs) were slightly but not significantly higher in the twice-daily dosing regimen vs. once-daily There were slightly but not significantly more serious AEs in the twice-daily compared to once-daily regimens (3.5% (n=18) vs. 1.8%(n=9), respectively), although nearly all were judged unrelated to the study drug.
The researchers concluded that delayed release Asacol administered once daily at doses of 1.6 –2.4 g/day was noninferior to twice-daily dosing for maintenance of clinical remission in patients with a history of mild-to-moderate UC. Other effective once-daily mesalamine formulatons such as Lialda, Apriso, and Pentasa prolong, extend or sustain release throughout the colon in contrast to Asacol, which releases mesalamine in the terminal ilum and right colon only. The authors remarked that the results indicated that precise delivery of mesalamine throughout the colon is not required for successful once-daily dosing. The success of these compounds is likely the result of the pharmacodynamic properties of mesalamine and not the specific formulation determining drug delivery.
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