Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. Direct comparison of two different mesalamine formulations for the induction of remission in patients with ulcerative colitis: a double-blind, randomized study. Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group. Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial. An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. A randomized, placebo-controlled trial. The Mesalamine Study Group. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Interferon beta-1a in ulcerative colitis: a placebo controlled, randomised, dose escalating study. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Pentasa Study Group.
SPD476 (MMX mesalamine), a novel, once-daily mesalamine formulation, uses MMX Multi Matrix System (MMX) technology to delay and extend delivery of active drug throughout the colon. We performed a randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III study in patients with mild to moderately active ulcerative colitis.
                Two hundred eighty patients with mild to moderately active ulcerative colitis received MMX mesalamine 2.4 g/day given twice daily (n = 93), 4.8 g/day given once daily (n = 94), or placebo (n = 93) for 8 weeks. The primary end point was the percentage of patients in clinical and endoscopic remission (modified ulcerative colitis disease activity index score of < or =1, with a score of 0 for rectal bleeding and stool frequency, and at least a 1-point reduction in sigmoidoscopy score) at week 8. Patients with mucosal friability were not considered to have achieved this end point.
                Clinical and endoscopic remission at week 8 was achieved by 34.1% and 29.2% of patients receiving MMX mesalamine 2.4 g/day given twice daily and MMX mesalamine 4.8 g/day given once daily, respectively, versus 12.9% receiving placebo (P < .01). MMX mesalamine was generally well-tolerated.
                MMX mesalamine given once or twice daily is well-tolerated and, compared with placebo, demonstrated efficacy for the induction of clinical and endoscopic remission in mild to moderately active ulcerative colitis. Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases.
                We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization.
                Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable.
                In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis. Mesalamine is the first-line drug for the treatment of ulcerative colitis (UC). We directly compared the efficacy and safety of two mesalamine formulations for the induction of remission in patients with UC.
                In a multicenter, double-blind, randomized study, 229 patients with mild-to-moderate active UC were assigned to 4 groups: 66 and 65 received a pH-dependent release formulation of 2.4 g/day (pH-2.4 g) or 3.6 g/day (pH-3.6 g), respectively; 65 received a time-dependent release formulation of 2.25 g/day (Time-2.25 g), and 33 received placebo (Placebo). The drugs were administered three times daily for eight weeks. The primary endpoint was a decrease in the UC disease activity index (UC-DAI).
                In the full analysis set (n = 225) the decrease in UC-DAI in each group was 1.5 in pH-2.4 g, 2.9 in pH-3.6 g, 1.3 in Time-2.25 g and 0.3 in Placebo, respectively. These results demonstrate the superiority of pH-3.6 g over Time-2.25 g (P = 0.003) and the noninferiority of pH-2.4 g to Time-2.25 g. Among the patients with proctitis-type UC, a significant decrease in UC-DAI was observed in pH-2.4 g and pH-3.6 g as compared to Placebo, but not in Time-2.25 g. No differences were observed in the safety profiles.
                Higher dose of the pH-dependent release formulation was more effective for induction of remission in patients with mild-to-moderate active UC. Additionally, the pH-dependent release formulation was preferable to the time-dependent release formulation for patients with proctitis-type UC (UMIN Clinical Trials Registry, no. C000000288). This 12-month, double-blind, placebo-controlled study randomized 205 ulcerative colitis patients in remission to placebo or controlled-release mesalamine at 4 g/day for 12 months. Patients were stratified to either pancolitis or left-sided disease, based on previous diagnosis. Maintenance of remission was defined as a sigmoidoscopic index of < 5, less than five stools per day, and the absence of rectal bleeding. A significantly greater number of patients maintained remission on mesalamine 4 g/day than on placebo at each of five study visits, following the first one-month visit (P < 0.05). The estimated 12-month remission rates for the mesalamine group were 64% (38% for placebo, P = 0.0004). Baseline subgroups (disease location, time since last flare of active disease, and previous response to oral/rectal steroids or sulfasalazine) did not influence remission rates. Treatment-related adverse events were rare. Controlled-release mesalamine is a safe and efficacious single agent for maintaining remission of ulcerative colitis. Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder.
                To evaluate once-daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC.
                Randomized, double-blind, placebo-controlled trial of patients (n=209 MG, n=96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding=0, mucosal appearance <2] who took MG 1.5 g or placebo once-daily for up to 6 months. Primary efficacy endpoint: the percentage of patients who remained relapse-free at month 6/end of treatment. Relapse was defined as SDAI rectal bleeding score ≥1 and a mucosal appearance score ≥2, a UC flare, or initiation of medication to treat a UC flare.
                The percentage of relapse-free patients at month 6/end of treatment was higher with MG than placebo (78.9% vs. 58.3%, P < 0.001) in the intent-to-treat analysis. Significant differences (P ≤ 0.025) favouring MG were observed for most secondary endpoints including improvement in rectal bleeding, physician's disease activity rating, stool frequency, the SDAI at month 6/end of treatment, patients classified as a treatment success and relapse-free duration. The incidence of adverse events was similar between groups.
                Once-daily mesalamine (mesalazine) was effective in maintaining remission of UC for 6 months.
                © 2010 Salix Pharmaceuticals. To compare the safety and efficacy of a pH-sensitive, polymer-coated oral formulation of mesalamine (Asacol, Procter & Gamble Pharmaceuticals, Cincinnati, Ohio) with those of placebo in maintaining remission in patients with ulcerative colitis.
                Multicenter, double-blind, placebo-controlled, randomized clinical trial.
                Eight private practices, five university-based medical centers, and four hospitals or clinics.
                264 patients with ulcerative colitis that had been maintained in remission for at least 1 month while the patients were receiving stable doses of sulfasalazine or any oral mesalamine product.
                Coated mesalamine at oral dosages of 0.8 g/d or 1.6 g/d or matching placebo for 6 months.
                Treatment success, defined as maintenance of remission after 6 months, and treatment failure, defined as relapse during the study (as indicated by proctosigmoidoscopy at 1, 3, or 6 months of treatment) or withdrawal due to adverse events. Safety was assessed on the basis of laboratory analyses and patient- and investigator-noted adverse events.
                189 patients were compliant with the protocol for 6 months or stopped receiving therapy because of relapse or adverse events. Of these 189 patients, 25 of the 63 patients (39.7%) in the placebo group had treatment success compared with 40 of the 68 patients (58.8% [95% CI, 46.4% to 71.3%]) in the group receiving mesalamine, 0.8 g/d (P = 0.036) and 38 of the 58 patients (65.5% [CI, 52.4% to 78.6%]) in the group receiving mesalamine, 1.6 g/d (P = 0.006). In the intention-to-treat analysis of all patients, 42 of the 87 patients (48.3%) in the placebo group had treatment success compared with 57 of the 90 patients (63.3% [CI, 52.8% to 73.8%]) in the group receiving mesalamine, 0.8 g/d (P = 0.050) and 61 of the 87 patients (70.1% [CI, 59.9% to 80.3%]) in the group receiving mesalamine, 1.6 g/d (P = 0.005). Age, sex, and race were not found to predict treatment success or failure. The mesalamine tablet was well tolerated, and no clinically significant changes were seen in hematologic, hepatic, or renal laboratory profiles.
                Coated mesalamine at oral dosages of 0.8 g/d and 1.6 g/d is safe and effective in maintaining remission in patients with quiescent ulcerative colitis. SPD476 (LIALDA in the US; MEZAVANT in the EU; otherwise known as MMX mesalamine; Shire Pharmaceuticals Inc., Wayne, PA, under license from Giuliani SpA, Milan, Italy) is a novel, once-daily, high-strength (1.2 g/tablet) formulation of mesalamine, utilizing MMX Multi Matrix System (MMX) technology designed to deliver the active drug throughout the colon. We performed a double-blind, multicenter study, comparing MMX mesalamine vs placebo for the treatment of active ulcerative colitis. A delayed-release oral mesalamine (ASACOL; Procter & Gamble, Cincinnati, OH) reference arm was included.
                Three hundred forty-three patients with active, mild-to-moderate ulcerative colitis received MMX mesalamine 2.4 g/day or 4.8 g/day given once daily, ASACOL 2.4 g/day given in 3 divided doses, or placebo for 8 weeks. The primary end point was the proportion of patients in clinical and endoscopic remission (modified ulcerative colitis disease activity index of < or =1 with rectal bleeding and stool frequency scores of 0, no mucosal friability, and a > or =1-point reduction in sigmoidoscopy score from baseline).
                A significantly greater proportion of patients receiving MMX mesalamine 2.4 g/day given once daily (40.5%; P = .01) and 4.8 g/day given once daily (41.2%; P = .007) achieved clinical and endoscopic remission at week 8, vs placebo (22.1%). The clinical and endoscopic remission rate for ASACOL (32.6%; P = .124) was not significantly superior to placebo. All active treatments were well-tolerated.
                Once-daily MMX mesalamine was efficacious and well-tolerated for the induction of clinical and endoscopic remission. MMX mesalamine offers effective and convenient mesalamine therapy, potentially improving treatment compliance. and aims: Administration of interferon (IFN)-beta may represent a rational approach to the treatment of ulcerative colitis through its immunomodulatory and anti-inflammatory effects. The present study was performed to evaluate the efficacy and tolerability of IFN-beta-1a.
                Patients (n=18) with moderately active ulcerative colitis were randomised to receive IFN-beta-1a or placebo. IFN-beta-1a was started at a dose of 22 micro g three times a week subcutaneously, and the dose was increased at two week intervals to 44 micro g and then to 88 micro g if no response was observed. The maximum duration of treatment was eight weeks. End points were clinical treatment response, defined as a decrease of at least 3 points from baseline in the ulcerative colitis scoring system (UCSS) symptoms score and induction of endoscopically confirmed remission.
                Baseline characteristics and disease severity were similar in both groups. Data from 17 patients are included in this report (10 patients in the IFN-beta-1a group and seven patients in the placebo group). Clinical response was achieved in five patients (50%) in the IFN-beta-1a group and in one (14%) in the placebo group (P=0.14). Remission was achieved in three patients in the IFN-beta-1a group and in none in the placebo group (p=0.02). Most adverse reactions associated with IFN-beta-1a were influenza-like symptoms or injection site reactions, and were mild or moderate in severity.
                IFN-beta-1a may represent a promising novel treatment approach in ulcerative colitis. The efficacy of a capsule formulation of mesalamine was assessed in 374 patients with mild to moderately active ulcerative colitis. Patients, stratified to pancolitis or left-sided disease, received either placebo or mesalamine at 1, 2, or 4 g daily for 8 wk. Efficacy was assessed using clinical improvement--physician global assessment, sigmoidoscopic index, biopsy score, trips to the toilet, and clinical symptoms (abdominal pain, urgency, stool consistency, and rectal bleeding)--and induction of remission (more stringent criteria for physician global assessment, sigmoidoscopic index, and biopsy score). For physician global assessment of treatment benefit, 79% and 84% of patients on the 2-g and 4-g doses of mesalamine, respectively, received treatment benefit, compared with 54% on placebo (p < or = 0.0002). For the physician global assessment of treatment success, both the 2-g and 4-g doses of mesalamine were superior to placebo (57% and 59% of patients, p = 0.0021 and 0.0012, respectively), compared with 36% on placebo. Both the 2-g and 4-g doses produced statistically significant macroscopic (endoscopic) improvement compared with placebo (p < 0.004). The 4-g dose also produced a statistically significant microscopic (histologic) improvement compared to placebo (p < 0.002). Significant improvement compared to placebo was also observed at 2 g and 4 g for the four clinical symptoms and trips to the toilet (p < or = 0.003). Oral mesalamine capsules were significantly superior to placebo for inducing remission, with 29% of patients at 2 g and 29% at 4 g achieving remission by physician global assessment, compared with 12% on placebo. Forty-four percent and 48% of patients receiving 2 g and 4 g of mesalamine, respectively, achieved remission by sigmoidoscopic index (p < 0.05), compared with 31% on placebo. Thirty-nine percent of patients at 4 g daily achieved microscopic remission, compared with 23% on placebo (p < 0.03). Treatment response was not affected by extent of disease or prior steroid or sulfasalazine therapy. These data suggest that controlled-release mesalamine capsules are a safe and effective monotherapy in doses of 2-4 g daily for treating mild to moderately active ulcerative colitis, as well as for inducing remission, regardless of prior oral steroid or sulfasalazine therapy or extent of disease.
Data from one trial suggests that MLN-02 may be effective for induction of clinical response and remission in patients with moderately severe ulcerative colitis. Adverse events appear to be similar to placebo, although immunogenicity may be an issue. Further trials are needed to confirm the results of this study and to define the optimal dose and frequency of administration of MLN-02.