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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.


Zakko S.,Connecticut Gastroenterology Institute | Barton G.,Arkansas Gastroenterology | Weber E.,Novartis | Dunger-Baldauf C.,Novartis | Ruhl A.,Novartis
Alimentary Pharmacology and Therapeutics | Year: 2011

Background Neurokinin receptors may play an important role in the visceral hypersensitivity and exaggerated motor/secretory activity associated with diarrhoea-predominant irritable bowel syndrome (IBS-D). Aim To evaluate the effects of DNK333, a novel neurokinin antagonist, in women with IBS-D. Methods In two consecutive phase II studies, women with IBS-D were randomised to twice-daily (b.d.) DNK333 25 mg, DNK333 100 mg or placebo for 2 weeks (Trial 1), or DNK333 25 mg b.d. or placebo for 4 weeks (Trial 2). Primary efficacy variables studied were change from baseline of stool form at week 2, and satisfactory relief of IBS-related abdominal pain/discomfort and global IBS-D symptoms. Secondary efficacy variables, pharmacokinetics and safety were also evaluated. Results In total, 315 subjects were randomised. There were no statistically significant differences between treatment groups for the primary efficacy variables. However, analysis of combined data from both trials revealed significant differences favouring DNK333 25 mg over placebo for satisfactory relief of IBS-related abdominal pain/discomfort and global IBS-D symptoms. Trends favouring improvement with DNK333 25 mg vs. placebo were seen for all secondary efficacy variables. DNK333 had a safety profile similar to placebo. Conclusions DNK333 25 mg b.d. appears to be effective and well tolerated in women with IBS-D. Further studies with neurokinin antagonists are warranted. © 2011 Blackwell Publishing Ltd.


Pimentel M.,Cedars Sinai Medical Center | Lembo A.,Beth Israel Deaconess Medical Center | Lembo A.,Harvard University | Chey W.D.,University of Michigan | And 7 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS. METHODS: In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study. RESULTS: Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P = 0.01, in TARGET 1; 40.6% vs. 32.2%, P = 0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P = 0.005, in TARGET 1; 41.0% vs. 31.9%, P = 0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among patients who had IBS without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools. (Funded by Salix Pharmaceuticals; ClinicalTrials.gov numbers, NCT00731679 and NCT00724126.). Copyright © 2011 Massachusetts Medical Society.


Lichtenstein G.R.,University of Pennsylvania | Zakko S.,Connecticut Gastroenterology Institute | Gordon G.L.,Center for Digestive and Liver Diseases | Murthy U.,Syracuse Medical Center | And 5 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2012

Background Mesalazine (mesalamine) granules (MG) were shown to be effective for the maintenance of remission of ulcerative colitis (UC) in two double-blind placebo-controlled trials. Aim To evaluate the efficacy of once-daily MG for maintenance of remission in patients with UC who switched from other 5-aminosalicylic acid (5-ASA) formulations. Methods Data from two independent multicenter, randomised, double-blind, placebo-controlled, 6-month trials evaluating patients with UC in remission were combined for analysis of a subpopulation of patients who switched from other 5-ASA formulations to MG 1.5 g or placebo upon randomisation. The primary endpoint was the percentage of patients who remained relapse-free at Month 6 or end of treatment. Relapse was defined as a Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, a UC flare or medication used to treat a UC flare. Results Of the 487 patients who received 5-ASA maintenance therapy at enrolment, 322 were in the MG group and 165 were in the placebo group. The percentage of patients who remained relapse-free (based on Sutherland Disease Activity Index scores) after 6 months was significantly higher with MG than placebo (78.3% vs. 58.8%, P < 0.001). Rectal bleeding, stool frequency and the physician's rating of disease activity remained unchanged after 6 months in a higher percentage of patients using MG compared with those on placebo (P < 0.004 for each endpoint). Conclusion Mesalazine granules 1.5 g once-daily is effective for maintenance of remission in UC patients who switch from other 5-ASA formulations. identifiers NCT00744016, NCT00767728. © 2012 Blackwell Publishing Ltd.


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.

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