One-year investigator-blind randomized multicenter trial comparing Asacol 2.4 g once daily with 800 mg three times daily for maintenance of remission in ulcerative colitis

Abstract

Background: Mesalazine (Asacol) is still widely prescribed in divided doses for ulcerative colitis (UC), despite evidence that adherence is improved by once-daily (OD) prescribing. We aimed to investigate whether OD Asacol was as effective as three times (TDS) daily dosing, and to evaluate the role of treatment adherence.

Methods: An investigator-blind randomized trial was undertaken comparing OD Asacol (three 800 mg tablets) versus one 800 mg TDS in maintenance of remission of UC over 1 year. The primary endpoint was relapse rate, and noninferiority would be concluded if the lower limit of the two-sided 95% confidence interval (CI) of the difference in proportions relapsing (TDS-OD) exceeded -10%. Adherence was measured by tablet counts and self-reported adherence. A subgroup of patients used a bottle cap that recorded all bottle opening events.

Results: In all, 213 patients were randomized. In the intention-to-treat (ITT) population, relapse rates were 31% (95% CI 22%-40%) in the OD and 45% (95% CI 35%-54%) in the TDS group. Primary analysis confirmed the noninferiority of OD dosing. Two of the study populations, ITT and per-protocol (PP), showed potential superiority of OD dosing. All measures of adherence showed that it was significantly better in the OD group. Multivariate analysis, however, showed OD dosing was associated with lower relapse risk independently of adherence.

Conclusions: OD dosing with Asacol 2.4 g is as safe and effective as TDS dosing, and secondary analysis confirmed significantly reduced relapse rates. The benefit, however, was clinically borderline and may relate in part to ease of adherence.

FIGURE 1

Patient disposition in trial.

FIGURE 2

Relapse rates in the ITT, CC, and PP populations. OD group given 2.4 g mesalazine once daily (three 800 mg Asacol tablets); TDS group given 800 mg tablet three times a day. Shown as percentage and 95% confidence intervals. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

FIGURE 3

Remission rate in the once daily group (blue line) versus the TDS group (green line). P = 0.211 (log rank, Mantel-Cox). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

FIGURE 4

(a) Frequency plot of number of cap openings in 1 day during trial (substudy population, ITT group). (b) Percentage days adherent as measured by MEMS data, plotted against mean daily tablets taken measured by tablet count. Line represents equivalence (substudy population, ITT group). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]