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 noninferiority 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 >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(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. ClinicalTrials.gov Identifier: NCT00449722Aminosalicylates (mesalazine, sulfasalazine, olsalazine, balsalazide) have been the mainstay of inflammatory bowel disease treatment for over 60 years.1 These drugs are prescribed for active disease as well as for relapse prevention in both ulcerative colitis and in Crohn's disease. Aminosalicylates are the undisputed ''gold standard'' for maintaining remission in ulcerative colitis.2-4 Furthermore, they may have chemopreventive properties against colorectal cancer. 5Conventionally, a multiple daily dosing regimen of aminosalicylates is established. This is a demanding drug regimen, which can interfere with the everyday life of a patient, and can therefore reduce the quality of life. Moreover, the inconvenience of this dosing regimen can have a negative impact on adherence to the drugs, and thus, can lead to a poorer long-term prognosis. Adherence rates in prospective, community-based studies range from 40 to 60%, 6 7 and are particularly poor among patients in remission. [8][9][10][11] Three times per day (TID) dosing of mesalazine was the most significant risk factor for partial non-compliance. A total of 57% of patients who were prescribed mesalazine TID...

Prevalence, predictors, and clinical consequences of medical adherence in IBD: How to improve it?

“…Patient questionnaires showed significantly greater selfreported compliance (P < 0.05) and acceptability (P < 0.001) in the once-daily group. High compliance rates were reported for the once-daily MMX mesalazine and Salofalk ® granules [29,30] ; therefore the effect is likely to be generic rather than compound-specific. Thus, new mesalazine formulations offer a simplified dose regime, resulting in presumably improved long-term compliance that can be considered an important advantage in the management of UC patients.…”

Medical management of ulcerative colitis

“…Newer studies from the last years indicate that the total daily dose can be taken at one time (e.g. in the morning) -or even should be taken at one time, as in some studies there was even increased efficacy under these conditions [24][25][26] . The possibility to take the whole dose at one time is also likely to increase patient compliance and adherence to therapy.…”

Optimizing clinical use of mesalazine (5-aminosalicylic acid) in inflammatory bowel disease

“…Kruis and colleagues performed a noninferiority study comparing once daily dosing (3.0 g/day) to three times daily dosing (1.0 g three times daily) of Salofalk Õ granules in patients with mild to moderate active UC [Kruis et al 2009]. This was a positive trial, showing noninferiority of the 3.0 g once daily dosing, with 79.1% and 75.7% achieving clinical remission after 8 weeks of once or thrice daily dosing, respectively.…”