E. David Ballard

Once-Daily Budesonide MMX® Extended-Release Tablets Induce Remission in Patients With Mild to Moderate Ulcerative Colitis: Results From the CORE I Study

BACKGROUND & AIMS Budesonide is a corticosteroid with minimal systemic corticosteroid activity due to first-pass hepatic metabolism. Budesonide MMX® is a once-daily oral formulation of budesonide that extends budesonide release throughout the colon using multi-matrix system (MMX) technology. METHODS We performed a randomized, double-blind, double-dummy, placebo-controlled trial to evaluate the efficacy of budesonide MMX for induction of remission in 509 patients with active, mild to moderate ulcerative colitis (UC). Patients were randomly assigned to groups that were given budesonide MMX (9 mg or 6 mg), mesalamine (2.4 g, as reference), or placebo for 8 weeks. The primary end point was remission at week 8. RESULTS The rates of remission at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 17.9%, 13.2%, and 12.1%, respectively, compared with 7.4% for placebo (P = .0143, P = .1393, and P = .2200). The rates of clinical improvement at week 8 among patients given 9 mg or 6 mg budesonide MMX or mesalamine were 33.3%, 30.6%, and 33.9%, respectively, compared with 24.8% for placebo (P = .1420, P = .3146, and P = .1189). The rates of endoscopic improvement at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 41.5%, 35.5%, and 33.1%, respectively, compared with 33.1% for placebo. The rates of symptom resolution at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 28.5%, 28.9%, and 25.0%, respectively, compared with 16.5% for placebo (P = .0258, P = .0214, and P = .1025). Adverse events occurred at similar frequencies among groups. CONCLUSIONS Budesonide MMX (9 mg) was safe and more effective than placebo in inducing remission in patients with active, mild to moderate UC.

Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study

Objective Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). Design Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline. Results 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. Conclusion Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.

Induction of clinical and colonoscopic remission of mild-to-moderate ulcerative colitis with budesonide MMX 9 mg: pooled analysis of two phase 3 studies.

Conventional oral corticosteroids are effective at reducing inflammation associated with ulcerative colitis (UC); however, systemic adverse effects limit their use. Budesonide MMX is an extended‐release, second‐generation corticosteroid that targets delivery of budesonide to the entire colon.

Control of 24-hour intragastric acidity with morning dosing of immediate-release and delayed-release proton pump inhibitors in patients with GERD.

Goals To compare the effects of immediate-release omeprazole and 2 different delayed-release proton pump inhibitors on 24-hour intragastric acidity in gastroesophageal reflux disease patients. Background Because of its unique pharmacokinetic properties, immediate-release omeprazole does not need to be dosed before a meal to control intragastric acidity. Previous studies showed effectiveness of immediate-release omeprazole in controlling nocturnal intragastric acidity with bedtime dosing. This is the first study to compare the effects of prebreakfast dosing of immediate-release omeprazole and delayed-release lansoprazole and pantoprazole on 24-hour intragastric acidity. Aim To compare the effects of prebreakfast dosing of immediate-release omeprazole 40 mg capsules, lansoprazole 30 mg capsules, and pantoprazole 40 mg tablets on 24-hour intragastric acidity. Methods Fifty-five patients with gastroesophageal reflux disease received 7 consecutive once-daily morning doses of each drug in this open-label, randomized, 3-period crossover study. On day 7, intragastric pH was recorded for 24 hours. Results After 7 days, the percentage of time with intragastric pH >4 over 24 hours was 59.7% (14.3 hours) with immediate-release omeprazole, 48.8% (11.7 hours) with lansoprazole (P=0.005), and 41.8% (10.0 hours) with pantoprazole (P<0.001). Median intragastric pH was significantly higher with immediate-release omeprazole than with lansoprazole (P=0.003) or pantoprazole (P<0.001). All drugs were well tolerated. Conclusions When dosed in the morning, immediate-release omeprazole provided significantly better control of 24-hour intragastric acidity than lansoprazole and pantoprazole.

Budesonide MMX for the Induction of Remission of Mild to Moderate Ulcerative Colitis: A Pooled Safety Analysis

Background and aims: Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined. Methods: Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9mg, 6mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9mg or placebo for 4 weeks, then open-label budesonide MMX 9mg for 4 weeks]; and one open-label study [budesonide MMX 9mg for 8 weeks] were pooled. Results: Patients randomised to budesonide MMX 9mg [n = 288], 6mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects. Conclusions: Budesonide MMX 9mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis.

Tu1252 Effect of Budesonide MMx 6 mg on the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Patients With Ulcerative Colitis: Results From a Phase III, 12 Month Safety and Extended use Study

follow-up time from first biologic 4.5 years (IQR 1.4-7.6). 1751 IFX infusions were given, with increasing frequency over time reflecting the shift from episodic to maintenance therapy. Infusion number increased by 202.6% between 2004-5 and 143 patients commenced maintenance anti-TNF from 2005-11, in contrast with only 14 up to 2005. Median time from diagnosis to first anti-TNF was 97 months up to 2005, falling to 52 months from 200611. Of 72 CD patients treated with ADA, 37 required dose escalation to weekly, at a median interval of 6 months (median 29.5 months follow-up). No anti-TNF naive patients required dose escalation, but 12/18 patients starting ADA due to secondary loss of response to IFX required weekly therapy (66.7%). There were 238 hospital admissions (93 for disease flares) in the year preceding anti-TNF therapy, falling to 197 admissions (35 for disease flares) in the year after treatment initiation. Faecal calprotectin (FC) before and 3 months after starting anti-TNF was available for 22 patients; this fell by a median of 470.5 mcg/g. 39 infusion reactions were observed in 35 IFX-treated patients; 6 followed a treatment break of 1471568 days. 8 serum sickness-like reactions were observed following IFX, and 2 with ADA. Conclusion: Outcome of changes in treatment patterns will inform unanswered questions regarding patient selection and length of therapy. Drug holiday from IFX remains an indication for ADA. Innovations in monitoring response to anti-TNF therapy, notably recording of HBI and FC before every treatment (initiated in our centre during 2011) will further aid decision-making.