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BACKGROUND: Budesonide MMX® (B-MMX) is a once-daily, extended release oral formulation designed to provide targeted delivery of budesonide throughout the colon. Previous post-hoc analyses of randomized, controlled studies of B-MMX monotherapy suggested that it was effective for induction of remission of mildly to moderately active UC in patients with or without prior 5-ASA use. Here we present data from a prospectively designed, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-MMX in patients experiencing an active UC flare despite treatment with an oral 5-ASA. METHODS: Patients with mildly to moderately active UC (UCDAI ≥4 and #10) inadequately controlled with oral 5-ASA monotherapy were randomized 1:1 to add once-daily B-MMX 9 mg or placebo (PBO) for 8 weeks to their existing 5-ASA. Patients were required to be on a stable, therapeutic dose of an oral 5-ASA (e.g., mesalamine ≥2.4 g/day or equivalent dose of another 5-ASA) throughout the study. Patients who increased their 5-ASA dose or administered other UC therapies were considered non-responders. The primary efficacy endpoint was combined clinical and endoscopic remission at Week 8, as defined by a UCDAI score of #1, with subscores of 0 for rectal bleeding, stool frequency and mucosal appearance. Secondary and exploratory endpoints assessed clinical remission (rectal bleeding and stool frequency subscores ¼ 0), endoscopic remission (mucosal appearance subscore ¼ 0) and histological healing (histological activity grade ¼ 0, as assessed via central reading). Missing data were handled using a worst case imputation scheme, in which patients with missing data were considered non-responders. Adverse events (AEs) were assessed throughout the study. RESULTS: Of 510 patients enrolled, 458 (230 B-MMX, 228 PBO) were included in the intent-to-treat population (46% female, mean age: 44.5), which excluded patients with normal baseline mucosal histology or infectious colitis. Combined clinical and endoscopic remission was achieved in a greater percentage of B-MMX-treated patients than PBO-treated patients (13% versus 7.5%, P ¼ 0.0488, worst case analysis). This treatment effect was driven primarily by the mucosal appearance subscore. On this measure, a greater percentage of B-MMX-treated patients than PBOtreated patients achieved a score of 0 (20% versus 12.3%, P ¼ 0.0248), indicative of endoscopic remission. B-MMX also induced histological healing in a greater percentage of patients than placebo (27% versus 17.5%, P ¼ 0.0155). Overall, 31.8% and 27.1% of patients treated with B-MMX or placebo reported an AE, and the majority were mild or moderate in severity. Study discontinuation due to AEs occurred in 4.7% and 3.5% of the B-MMX and placebo groups, respectively. CONCLUSIONS: In patients experiencing an active flare of UC despite baseline oral 5-ASA therapy, adding B-MMX 9 mg was significantly more effective than placebo at inducing combined clinical and endoscopic remission as well as histological healing. B-MMX was generally wel...