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Sandborn W.J.,University of California at San Diego | Bosworth B.,Weill Cornell Medical Center | Zakko S.,Connecticut Gastroenterology Institute | Gordon G.L.,Center for Digestive and Liver Diseases Inc. | And 8 more authors.
Gastroenterology | Year: 2015

Background Aims Budesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis. Methods Two identically designed, randomized, double-blind, placebo-controlled trials evaluated the efficacy of budesonide foam for induction of remission in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis who received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo. Results Remission at week 6 occurred significantly more frequently among patients receiving budesonide foam than placebo (Study 1: 38.3% vs 25.8%; P =.0324; Study 2: 44.0% vs 22.4%; P <.0001). A significantly greater percentage of patients receiving budesonide foam vs placebo achieved rectal bleeding resolution (Study 1: 46.6% vs 28.0%; P =.0022; Study 2: 50.0% vs 28.6%; P =.0002) and endoscopic improvement (Study 1: 55.6% vs 43.2%; P =.0486; Study 2: 56.0% vs 36.7%; P =.0013) at week 6. Most adverse events occurred at similar frequencies between groups, although events related to changes in cortisol values were reported more frequently with budesonide foam. There were no cases of clinically symptomatic adrenal insufficiency. Conclusions Budesonide rectal foam was well tolerated and more efficacious than placebo in inducing remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. © 2015 by the AGA Institute.

Rubin D.T.,University of Chicago | Sandborn W.J.,University of California at San Diego | Bosworth B.,Jill Roberts Center for Inflammatory Bowel Disease | Zakko S.,Connecticut Gastroenterology Institute | And 7 more authors.
Digestive Diseases and Sciences | Year: 2015

Background: Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. Aim: The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. Methods: Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. Results: A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0 %, respectively). Adverse events occurred in 41.4 and 36.3 % of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic–pituitary–adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. Conclusions: This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic–pituitary–adrenal axis. © 2015, Springer Science+Business Media New York.

Panaccione R.,University of Calgary | Sandborn W.J.,University of California at San Diego | Gordon G.L.,Center for Digestive and Liver Diseases Inc. | Lee S.D.,University of Washington | And 8 more authors.
Inflammatory Bowel Diseases | Year: 2015

This study assessed the efficacy and safety of briakinumab, a human anti-IL-12/23p40 monoclonal antibody, compared with placebo for the induction and maintenance of remission in patients with moderately to severely active Crohn's disease. Methods: In this phase 2b, multicenter, double-blind, parallel group study, 246 patients stratified by prior tumor necrosis factor-antagonist use and response, were randomized (1:1:1:3) to 4 intravenous induction regimens: placebo, 200, 400, or 700 mg briakinumab, at weeks 0/4/8. At week 12, responders in the placebo or 400-mg induction groups entered the maintenance phase with the same regimen, whereas responders in the 700-mg induction group were rerandomized (1:1:1) to receive placebo, 200, or 700 mg briakinumab at weeks 12/16/20. At week 24, patients in remission stopped receiving study drug (withdrawal phase) until relapse. Patients experiencing relapse, nonresponders, and nonremitters could enter the open-label phase. Results: The primary end point of clinical remission at week 6 was not met. There were numerically greater rates of remission and response at 6, 12, or 24 weeks in patients treated with briakinumab. The safety and tolerability profile of briakinumab was similar in the induction and maintenance phases of the trial. Conclusions: Briakinumab showed a similar safety and tolerability profile to placebo in the induction and maintenance phases, and comparable rates of serious adverse events, adverse events leading to discontinuation, and malignancy. These data provide support for the potential efficacy of briakinumab and other IL-12/23 inhibitors in the treatment of moderate-to-severe Crohn's disease. © 2015 Crohn's and Colitis Foundation of America, Inc.

Gordon G.L.,Center for Digestive and Liver Diseases Inc. | Zakko S.,Connecticut Gastroenterology Institute | Murthy U.,Syracuse Medical Center | Sedghi S.,Gastroenterology Assoct. of Central Georgia LLC | And 6 more authors.
Journal of Clinical Gastroenterology | Year: 2016

Goals: To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis : A Randomized, Placebo-controlled Clinical Trial(UC) remission. Background: Mesalamine is a first-line treatment for induction and maintenance of UC remission. Study: A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. Results: A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function - potential concerns with long-term treatment - occurred at a rate similar to placebo. Conclusions: Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission. © 2015 Wolters Kluwer Health, Inc.

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