Dose finding study of the efficacy and safety of newly developed 5-ASA containing pellets in patients with active ulcerative colitis

Abstract

Only few dose finding trials exist testing the optimum dosis of mesalazine in inducing remission of patients with active ulcerative colitis (UC). In addition, pharmakokinetic characteristics of currently used mesalazine preparations are not ideal. Therefore, the therapeutic effects of newly developed 5-ASA containing coated pellets of small size « 2 rom) were studied. This new preparation of mesalazine pellets (mespel) was developed to provide pH-dependent delayed release after pyloric passage independently of the respective motor phase (Dr. FalkPharma GmbH, Germany). 321 patients with mildly to moderately active UC were randomized to receive either 0.5 g tid of mespel (group I; n = 104), or 1.0 g tid (group 2; n = 108), or 1.5 g tid (group 3; n = 109) in a double-blind fashion. The trial lasted for 8 weeks. Clinical activity index (CAl) as well as endoscopic index (EI), both according to Rachmilewitz and histology were used to describe UC activity. Primary endpoint of the study was the number of patients achieving remission (CAl < 4). For intention-to-treat analysis 316 patients were included. 52/103 (50 %) with mespel 0.5 g tid achieved remission, 71/107 (66 %) with 1.0 g tid (p = 0.01) and 58/106 (55 %) with 1.5 g tid (n.s. to both other groups). The mean time to response in group 1-3 was 27.5 days, 26.5 days and 21.5 days respectively (n.s.). The rates of endoscopic remission were 28 %, 48 % and 49 % respectively. Histologic improvement occurred in 42 %, 56 %, and 63 % of the three patient groups. Acceptability of the new mespel was rated better (44 %), no difference (29 %), and worse (28 %) by patients experienced in other 5-ASA preparations. Adverse events were similar among the 3 groups (63 %, 61 %, and 58 % respectively). Discontinuation of the study medication because of adverse events occurred in 11, 7, and 9 patients, respectively. No drug related serious adverse events were reported. Our dose finding study demonstrates an optimum threshold like dosis of 1.0 g tid. This dose was significantly superior to a lower but not inferior to a higher dosis in inducing remission of patients with active UC. This newly developed pellet preparation showed high acceptability and safety.