Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial

Abstract

Objectives: To determine the therapeutic equivalence and safety of once daily (OD) versus three times daily (TID) dosing of a total daily dose of 3 g Salofalk (mesalazine) granules in patients with active ulcerative colitis.

Design: A randomised, double-blind, double-dummy, parallel group, multicentre, international, phase III non-inferiority study.

Setting: 54 centres in 13 countries.

Patients: 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis (clinical activity index (CAI)>4 and endoscopic index > or =4 at baseline) were randomised and treated.

Interventions: 8-week treatment with either 3 g OD or 1 g TID mesalazine granules.

Main outcome measures: Clinical remission (CAI< or =4) at study end.

Results: 380 patients were evaluable for efficacy and safety by intention-to-treat (ITT); 345 for per protocol (PP) analysis. In the ITT population, 79.1% in the OD group (n = 191) and 75.7% in the TID group (n = 189) achieved clinical remission (p<0.0001 for non-inferiority). Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group (86%; n = 97) versus the TID group (73%; n = 100; p = 0.0298). About 70% of patients in both treatment groups achieved endoscopic remission, and 35% in the OD group and 41% in the TID group achieved histological remission. About 80% of all patients preferred OD dosing. Similar numbers of adverse events occurred in 55 patients (28.8%) in the OD group and in 61 patients (32.3%) in the TID group, indicating that the two dosing regimens were equally safe and well tolerated.

Conclusions: OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule. With respect to the best possible adherence of patients to the treatment, OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis.

Trial registration: ClinicalTrials.gov NCT00449722.

Figure 1. Patient disposition. One patient was excluded from the intention-to-treat population because he did not receive study medication. Patients were excluded from the per-protocol population because of protocol deviations. AEs, adverse events; ITT, intention-to-treat; OD, once daily; PP, per protocol; SAE, serious adverse event; TID, three times daily.

Figure 2. Clinical remission rates (CAI⩽4) at week 8 (LOCF). χ² test (one-sided) for proving non-inferiority of OD vs TID treatment, with a pre-defined non-inferiority margin of −15% for the difference of the remission rates between treatments. CAI, clinical activity index; CI, confidence interval; ITT, intention-to-treat; LOCF, last observation carried forward; OD, once daily; PP, per protocol; TID, three times daily.

Figure 3. Course of the mean clinical activity index during the study (ITT). CAI, clinical activity index; ITT, intention-to-treat; LOCF, last observation carried forward; OD, once daily; SD, standard deviation; TID, three times daily.