Glenn L. Gordon

Budesonide Foam Induces Remission in Patients With Mild to Moderate Ulcerative Proctitis and Ulcerative Proctosigmoiditis

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. ClinicalTrials.gov ID: NCT01008410 and NCT01008423.

Briakinumab for treatment of Crohn's disease: Results of a randomized trial

Background: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 Crohns 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 Crohns disease.

Safety and Efficacy of a New 3.3 g b.i.d. Tablet Formulation in Patients With Mild-to-Moderately-Active Ulcerative Colitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVES:To evaluate the safety and efficacy of a new twice-daily balsalazide disodium 1.1 g tablet dosing regimen (6.6 g/day, three tablets twice daily) for the treatment of mild-to-moderately-active ulcerative colitis (UC).METHODS:In a double-blind, multicenter study patients with symptoms of acute UC and a baseline Modified Mayo Disease Activity Index (MMDAI) score between 6 and 10, inclusive, with a subscale rating of ≥2 for both rectal bleeding and mucosal appearance were randomized to receive 3.3 g of balsalazide or placebo tablets twice daily for 8 weeks. The primary end point was the proportion of patients achieving clinical improvement (≥3 point improvement in MMDAI) and improvement in rectal bleeding (≥1 point improvement) at 8 weeks. Safety assessments were conducted from baseline through 2-weeks post-treatment.RESULTS:A total of 249 patients (166 balsalazide, 83 placebo) received at least 1 dose of study medication. The mean MMDAI score at baseline was 7.9; 62% of patients had a score ≥8.0 (moderate disease). A significantly larger proportion of patients achieved clinical improvement and improvement in rectal bleeding in the balsalazide group vs. the placebo group (55 vs. 40%, P=0.02). The most common adverse events reported were worsening of UC and headache; both were reported more often in the placebo group.CONCLUSIONS:Balsalazide disodium 1.1 g tablets administered as 3.3 g twice daily are effective, well tolerated and significantly better than placebo for improving signs and symptoms of mild-to-moderately-active UC. This new formulation with a reduced pill and dosing burden offers the potential to improve convenience and compliance in patients with active UC.

Once-daily Mesalamine Formulation for Maintenance of Remission in Ulcerative Colitis: A Randomized, Placebo-controlled Clinical Trial.

Goals: To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (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.

Once-daily mesalamine granules for maintaining remission of ulcerative colitis: pooled analysis of efficacy, safety, and prognostic factors

ABSTRACT Objectives: A capsule formulation of mesalamine granules (MG) was developed for once-daily dosing and better compliance. The study aim was to evaluate MG efficacy and tolerability in maintaining ulcerative colitis (UC) remission. Methods: Pooled analysis of 2 identical phase 3, randomized, double-blind trials of once-daily MG 1.5 g or placebo for up to 6 months. The primary endpoint was percentage of patients remaining relapse-free at month 6 versus placebo. Relapse was defined as revised Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, UC flare, or UC–related adverse event (AE). Results: Data were pooled for patients receiving MG (n = 373) and placebo (n = 189). Significantly more patients were relapse-free at 6 months with MG (79.4%) than placebo (62.4%; P < 0.001) and across subgroups based on select demographic and baseline characteristics (P < 0.05). Secondary outcome measures including rectal bleeding, physician rating of disease activity, stool frequency, total SDAI score, and relapse-free duration favored MG (P < 0.01). Common AEs with MG and placebo, respectively, were headache (10.9% and 7.6%), diarrhea (7.9% and 7.0%), and abdominal pain (6.3% and 6.5%). Conclusion: Once-daily MG was more efficacious than and as well tolerated as placebo in maintaining UC remission. ClinicalTrials.gov identifiers: NCT00744016 and NCT00767728.

T1202 Once-Daily Mesalamine Granules Effectively Maintain Remission from Ulcerative Colitis: Data from 2 Phase 3 Trials

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.

T1200 Long-Term Safety of Once-Daily 1.5-G Mesalamine Granules in Patients in Remission from Ulcerative Colitis

Mesalamine granules (MG) are the first 5-aminosalicylate (5-ASA) formulation to use an innovative delivery system that combines delayedand extended-release mechanisms to release mesalamine directly in the ileum and colon. Agents with a low pill burden and favorable safety profile are more likely to enhance patient compliance in the long-term maintenance of UC remission. Two similarly designed multicenter, randomized, doubleblind, placebo-controlled, phase 3 trials (RCTs) have individually demonstrated significant efficacy of MG (1.5 g, q. d.) for the long-term maintenance of ulcerative colitis (UC). Additionally, an open-label extension trial (OLT) with new and rollover subjects from the two phase 3 trials was conducted to study the long term safety of MG for maintenance of UC remission. The integrated safety data in the expanded population of subjects who received MG from all three trials are presented here (All MG population). Methods: Data for the All MG analyses (n=557) included subjects who received MG in the two RCTs (n=367) and the OLT. The OLT included 197 MGtreated patients who rolled over from the RCTs; and 190 MG naive patients (83 placebo-treated patients from the RCTs, and 107 new patients) all in UC remission. Results: Of 557 patients included in the analysis, 250 patients were exposed for >1 year and 354 were exposed to MG (1.5 g, q.d.) for >6 months. Incidence of treatment-emergent adverse events (TEAEs) was 69.7% in the All MG group. Majority of TEAEs were mild or moderate in intensity, with a profile similar to that during the 6month RCTs. The notably lower incidence of UC flare observed in the RCTs for MG (10.9%) versus placebo (24.3%) was maintained (10.4%) in the OLT. Other common TEAEs in the All MG group were headache (13.8%), diarrhea (9.7%), nasopharyngitis (8.8%), abdominal pain (7.7%), sinusitis (5.4%), and nausea (5.2%). Incidences of serious adverse events and TEAEs leading to study discontinuation were comparable between the 6-month RCT group and the All MG population in the open label study. Occurrences of renal, hepatic, and pancreatic adverse events in patients in the open-label study were ≤1%. Long term compliance for the once-daily treatment regimen was high: mean compliance was ≥ 95% in each treatment group in the RCT population, and 88% for the All MG population. Conclusions: The favorable safety profile of MG when combined with a high compliance of once-daily dosing may support its dispensation as first-line therapy for long-term maintenance of UC remission.