Sustained Remission With No Dose Escalation After Re-Induction With Certolizumab Pegol in Patients With Crohn's Disease Exacerbation Who Were NaïVE to Anti-TNF Treatment: 5-Year Results From Precise 4

292 Budesonide-MMx® 9 mg for Induction of Remission of Mild-to-Moderate Ulcerative Colitis (UC): Data From a Multicenter, Randomized, Double-Blind Placebo-Controlled Study in the Europe, Russia, Israel and Australia William J. Sandborn, Simon Travis, Silvio Danese, Limas Kupcinskas, Olga Alexeeva, Luigi Moro, E. David Ballard, William F. Bleker, David Kriesel, Philip Yeung

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Background: Corticosteroids (CS) are effective in inducing remission in active UC; however, side effects are frequent. Budesonide is a CS with high first-pass metabolism and low systemic bioavailability. MMX® technology is designed for targeted colonic delivery of active drugs. Pharmacoscintigraphic studies have shown that budesonide MMX® tablets deliver budesonide throughout the entire colon. Materials and methods: This study compared once daily budesonide MMX® (B-MMX) 9 mg and 6 mg tablets to placebo over an 8-week treatment period. An oral budesonide formulation designed for targeted delivery to the terminal ileum and the right colon (Entocort®EC 3x3mg administered once daily) was used as a reference comparator. The primary endpoint was the induction of remission as defined by a UCDAI score of ≤ 1 after 8 weeks with scores of 0 for rectal bleeding and stool frequency, and a ≥ 1-point reduction from baseline in the endoscopy score with no sign of mucosal friability. The proportion of patients achieving remission in both the 9 mg and 6 mg B-MMX groups after 8 weeks of treatment was compared with placebo. Results: A total of 511 patients were randomized and received at least 1 dose of study drug. In the modified intent to treat (ITT) population, [which excluded 101 patients with normal histology at baseline, GCP violations, randomization outside the IVRS or with major protocol violations], a significantly greater proportion of patients achieved remission in the B-MMX 9 mg group 17.4% compared with placebo 4.5% (p = 0.0047). Statistical significance was not achieved in the B-MMX 6 mg group. Analyses of all randomized patients (including patients excluded from the modified ITT population but set as non-responders) were also statistically significant for the B-MMX 9 mg group 15.0% (19/127) compared with placebo 3.8% (5/130) (p = 0.0022). There were no significant differences between the study groups in the frequency of treatmentrelated adverse events and serious adverse events, including potential glucocorticoid-related adverse events. Conclusion: Budesonide MMX® 9 mg administered once daily was found to be safe and effective at inducing remission in patients with mild-to-moderate UC.

Factors Which Impact Readmission in Those With Inflammatory Bowel Disease (IBD); A Retrospective Case Series Nyla Hazratjee, Rocio Lopez, Maged K. Rizk INTRODUCTION: Preventable hospital readmissions is a vitally imprortant issue in health care policy, and practice reform is vital to reducing cost, and improving quality of care. Care for patients with IBD is a substantial portion of hospital care in patients with gastrointestinal illnesses. The aim of this study was to explore factors associated with readmissions in IBD patients within an inpatient tertiary referral center. METHODS: 912 readmissions to CCF from September 1, 2008 to September 1, 2010, were extracted into a database from our Outcomes Review System. Index admissions were to the inpatient gastroenterology service, and readmission was defined as admission to any service within 30 days from index admission discharge date. Patients who carried a diagnosis of Irritable Bowel Disease were included (n=106) regardless of admission diagnosis. Chart review of all readmissions was inputted into a RedCap database. Variables included initial admission and readmission data (reason for hospitalization, length of stay, time to follow-up appointments in Gastroenterology clinic (FU), whether FU was scheduled and made, whether a nutrition plan or discharge care was provided to the patient). Student t-tests and Pearson's chi-square tests were used to analyze the data RESULTS: Of the 106 IBD patients, 78 had 1 readmission, and 28 had >1 readmission. Ninety-three patients (88%) were readmitted before FU. Of these 60% never had a scheduled appointment, 5% had a scheduled appointment within 7 days, 9% within 8-14 days, 7% within 15-21 days and 17% after 22 days. Contrarily, only 13 were readmitted after FU. 67% of patients where readmitted within 2 weeks of initial discharge. Subjects readmitted within 2 weeks were more likely to have not been given any plan for pain control (34% vs. 14%; p=0.034) and prescription of oral non-narcotic medications was significantly less common (44% vs. 69%; p=0.016).Use of central IV access during initial admission was less common in patients who were readmitted within 2-weeks (7% vs. 20%; p=0.058). Obstruction/SBO/pseudo-obstruction/Ogilvie's, and use of medications other than narcotics and benzodiazepines during initial admission were associated with multiple readmissions (p<0.05). Subjects readmitted because of surgery were more likely to only have 1 readmission. CONCLUSIONS: In our GI unit, important modifiable factors include scheduled FU, non-narcotic pain control, and nutrition management at time of discharge.Patients admitted with dehydration, obstruction or pseudo-obstruction should be stratified as high risk for readmission while those admitted for surgery should stratified as low-risk. 291

*Chi-square test for remission vs placebo

Once Daily Mesalazine as Maintenance Therapy for Ulcerative Colitis (UC): A One-Year Single-Blind Randomised Trial Antony B. Hawthorne, Rachel Stenson, David Gillespie, Edwin T. Swarbrick, Anjan Dhar, Kapil C. Kapur, Kerenza Hood, Christopher S. Probert

293 Sustained Remission With No Dose Escalation After Re-Induction With Certolizumab Pegol in Patients With Crohn's Disease Exacerbation Who Were NaïVE to Anti-TNF Treatment: 5-Year Results From Precise 4 William J. Sandborn, Stefan Schreiber, Jean-Frederic Colombel, David L. Sen, Gary R. Lichtenstein

Background Mesalazine has traditionally been administered in divided doses, but there is emerging evidence that once daily dosing is no less effective, and may improve treatment adherence. Methods The Colitis Once Daily Asacol® (CODA) study was designed to assess the efficacy and safety of once daily dosing with Asacol® 2.4g given as 3 x 800mg tablets (OD) in comparison with three times daily dosing (one 800mg tablet three times daily) (TDS). Adult UC patients taking mesalazine or sulphasalazine in remission for >4 weeks, and <2 years, were randomised (investigator-blind) to OD or TDS dosing. The primary endpoint was the difference between groups in relapse rates over one year. Relapse was defined as typical symptoms of relapse with a Baron sigmoidoscopy score of 2 or 3. With estimated relapse rate of 20-30%, and a meaningful difference of 10% between groups, 250 patients were required to demonstrate non-inferiority with one-sided α of 5% and 1-β of 80%. Noninferiority would be concluded if the upper limit of the 95% confidence interval (CI) for the difference between treatments was <10% for both per protocol (PP) and intention to treat (ITT) population. (For ITT analysis, missing data was imputed as relapse.) Results 213 patients were recruited in 32 UK centres. Groups were well matched. There was no difference in adverse events between OD and TDS groups. Primary analysis confirmed non-inferiority of once-daily dosing. In a secondary analysis, (table) both ITT and per protocol (PP) populations demonstrated superiority of OD vs TDS dosing which was statistically significant. A multivariable analysis of baseline factors predicting relapse will be presented. Self-reported adherence at 12 months or relapse was >90% in 97% of patients (OD group) and 85% (TDS group). When asked how easy it was to remember to take tablets, it was reported to be very or fairly easy in 98% (OD group) versus 73% (TDS group). Conclusions Once daily dosing with AsacolTM 2.4g is as safe and effective as three times daily dosing, and secondary analysis confirmed significantly reduced relapse rates. The benefit was however clinically borderline and may relate to ease of adherence.

Purpose Patients who experienced disease exacerbation on either active or placebo maintenance therapy in PRECiSE 2 were re-induced with certolizumab pegol in PRECiSE 4. The purpose of this analysis was to evaluate the long-term (5-year) safety and sustainability of remission (total Harvey-Bradshaw Index [HBI] score of ≤4 points) of certolizumab pegol in anti-tumor necrosis factor (TNF) naïve vs non-naïve patients who were in remission at Week 4 of PRECiSE 4. Methods In PRECiSE 2 (NCT00152425), patients (n=428) who responded to induction therapy with certolizumab pegol at Week 6 were randomized to continuous therapy with certolizumab pegol or placebo (drug interruption) during Weeks 6-26. Patients who had an exacerbation of symptoms before Week 26 could enter PRECiSE 4 (NCT00160706), an open-label extension study. In PRECiSE 4, patients received certolizumab pegol 400 mg at Weeks 0, 2, and 4 followed by every-4-week maintenance therapy with certolizumab pegol 400 mg through Week 256 (5 years). Thus, patients receiving active treatment in PRECiSE 2 were given one single extra dose, and then continued with every-4-week maintenance therapy in PRECiSE 4. Results A total of 124 patients entered PRECiSE 4 from PRECiSE 2: 49 patients who had been randomized to certolizumab pegol and 75 patients who had been randomized to placebo. Among these patients, 84 were antiTNF naïve and 40 were non-naïve. By Week 4, 38% (47/124) achieved HBI remission. After 5 years of every-4-week certolizumab pegol 400 mg maintenance therapy in naïve vs nonnaïve patients, remission was maintained in 73% vs 40% patients, respectively (observed case) and 10% vs 5% patients, respectively (nonresponder imputation; Table). No new safety concerns were identified. Conclusion Among patients with disease exacerbation who were naïve to anti-TNF treatment and remained in PRECiSE 4, certolizumab pegol 400 mg reinduction successfully recaptured and maintained remission. These data suggest that a longterm benefit can be achieved with a re-induction strategy in anti-TNF-naïve patients with Crohn's disease who lost response due to drug interruption or loss of initial response to active therapy without resorting to dose escalation.

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AGA Abstracts

AGA Abstracts

Conclusions: Our meta-analysis of population-based studies suggests 5-ASA is not associated with reduced risk of colorectal cancer in IBD patients in stark contrast to a previous metaanalysis. 5-ASA should not be routinely offered solely as a chemopreventive measure against colorectal cancer.

AGA Abstracts

Ninety minutes after administration of 30 mg AZD1386, there was a 23% (95% confidence interval [CI]: 10 to 38%) increase in the pain detection threshold to heat stimulation of the esophagus. For the 95 mg dose, the equivalent increase was 28% ([CI]: 14 to 43%). An increased tolerance to heat stimulation of the skin was also demonstrated. Following the 30 mg dose of AZD1386, the pain detection threshold to heat stimulation was increased by 3.0°C ([CI]: 1.7 to 4.4°C), and for 95 mg AZD1386 the increase was 5.0°C ([CI]: 3.7 to 6.4°C). The analgesic effect to heat stimulation persisted in the esophagus and skin for 2.5 hours. No effect of AZD1386 was found on the sensation of pain induced by the other stimuli studied. ‘Feeling cold’ was the main adverse event reported by volunteers exposed to AZD1386 (50% of individuals). A mean increase in body temperature was observed in those exposed to 30 mg AZD1386 (0.4°C ± 0.3°C) and in those exposed to 95 mg AZD1386 (0.7°C ± 0.3°C; p < 0.05). Conclusions. The TRPV1 antagonist AZD1386 increased the heat pain threshold in the esophagus and skin, and had a favorable safety profile. This drug class may provide therapeutic benefit for patients with GERD. 318 Effect of a Novel Metabotropic Glutamate Receptor 5 Antagonist (AZD2066) on Transient Lower Esophageal Sphincter Relaxations and Reflux Episodes in Healthy Males Wout O. Rohof, Aaltje Lei, David Hirsch, Magnus Åstrand, Lars Ny, Mark Berner Hansen, Guy E. Boeckxstaens

LOCF, last observation carried forward. 294

Introduction. Selective metabotropic glutamate receptor 5 (mGluR5) antagonists have been shown to inhibit transient lower esophageal sphincter relaxations (TLESRs) in animal studies, and to reduce acid reflux and improve clinical symptoms in patients with gastroesophageal reflux disease (GERD). The primary objective of this study was to assess the effect of AZD2066, a novel mGluR5 antagonist, on the frequency of postprandial TLESRs and reflux episodes in healthy males (ClinicalTrials.gov: NCT00813306). Methods. In this doubleblind, randomized, single-center, two-way crossover study, healthy male volunteers were administered a single 13 mg dose of oral AZD2066 solution and a single dose of oral placebo solution, each on different study days separated by a 7-28 day washout period. Participants received food 30 minutes after dose administration (consumed within 15 minutes). Manometry and pH impedance measurements were taken for 3 hours and 45 minutes after each dose. Results. Of 16 individuals enrolled in the study, three did not fulfill pre-entry screening criteria. The remaining 13 were randomized to the dose regimens and all completed the study. The pharmacodynamic effects of AZD2066 compared with placebo are given in the Table. During the 3-hour postprandial period, there was a significant 27% reduction in the mean number of TLESRs in subjects who received AZD2066 compared with those who received placebo. This was accompanied by a significant 51% reduction in the mean number of reflux episodes. Compared with placebo, the mean number of acid reflux episodes was significantly reduced in participants receiving AZD2066. No significant differences in the mean number of weak acid reflux episodes or mean number of swallows, or in the mean lower esophageal sphincter pressure were observed between AZD2066 and placebo groups. Most adverse events in subjects taking AZD2066 were nervous system related, most commonly dizziness (3/13) and disturbance in attention (3/13). No adverse events reported in those taking placebo were nervous system related (0/13). There were no serious adverse events. Conclusions. The large reduction in the number of reflux episodes associated with mGluR5-mediated inhibition of TLESRs confirms the potential of mGluR5 antagonists as reflux inhibitors for the treatment of GERD. Table. AZD2066 13 mg and placebo: pharmacodynamic effects

Prevalence and Risk of Avascular Osteonecrosis in Inflammatory Bowel Disease Christian D. Stone, Jiajing Chen, Paula Buchanan, Glenn L. Gordon, Thomas Burroughs Background: Avascular necrosis (AVN) of bone is a dreaded complication thought to result from prolonged steroid use. Case series have reported an association between steroids and AVN of the hip/neck of femur and other sites, though the incidence of AVN has not been studied in depth in large patient populations. Given that patients with inflammatory bowel disease (IBD) often receive treatment with steroids and may develop steroid-dependent disease, we sought to investigate the prevalence of AVN in IBD and to determine whether its risk is related to length of steroid exposure. Methods: Using a large administrative health claims database, we conducted a retrospective cohort analysis to determine the prevalence AVN in IBD and identify factors associated with AVN occurrence. ICD-9 codes were used to identify subjects with IBD and diagnosis of AVN. We excluded subjects who also had diagnoses of lupus and other disorders for which steroids are used frequently. Treatment with steroids was documented and categorized into four exposure groups based on duration of use. All subjects were followed forward in time until the occurrence of AVN, end of capture period (Dec 2006) or end of enrollment. The prevalence of AVN in IBD was compared to that in a non-IBD population (1:5 ratio). Logistic regression was used to calculate independent risk (expressed as odds ratio [OR]) for AVN stratified by steroid exposure. Results: 53,434 IBD subjects were included and mean follow-up time was 2.4 years. The overall prevalence of AVN was 0.3% in IBD and 0.2% in non-IBD subjects. The rates were similar for Crohn's disease (CD) and ulcerative colitis (UC) but the steroid exposure overall was greater in CD. The risk of AVN with any steroid exposure compared to none was greater in CD (OR = 2.1, P = 0.0019) than in UC (OR = 1.1, P = 0.74). In the multivariate analysis, risk of AVN increased with longer steroid exposure, after adjustment for age and gender (Table). Conclusions: Among IBD patients, risk of AVN increases significantly with greater duration of steroid use. The prevalence is higher in CD than in UC but this difference may be due to lower steroid exposure in UC. There does not appear to be an increased risk for AVN due to IBD alone. Odds ratios for avascular osteonecrosis

*P < 0.001 315 Efficacy of a Transient Receptor Potential Vanilloid 1 Antagonist (AZD1386) in Human Esophageal Pain: A Two-Centre, Randomized, Placebo-Controlled, Cross-Over Study Anne L. Krarup, Lars Ny, Magnus Åstrand, Antal Bajor, Frederk Hvid-Jensen, Mark Berner Hansen, Magnus Simren, Peter Funch-Jensen, Asbjørn M. Drewes

319 Preliminary Report: Comparing Omeprazole With Fluoxetine for Treatment of Non Erosive Reflux Disease and Its Subgroups: A Six-ARM, Double-Blind, Placebo-Controlled Clinical Trial Seyed Amir Mirbagheri, Mohammad Reza Ostovaneh, Yasin Farrokhi Khajeh Pasha, Behtash Saeidi, Kaveh Hajifathalian, Arash Etemadi, Seyed mahmoud Eshagh hosseini

Introduction. Patients with gastroesophageal reflux disease (GERD) can be hypersensitive to heat or acid and many patients experience residual symptoms despite proton pump inhibitor (PPI) therapy. The transient receptor potential vanilloid 1 (TRPV1) receptor is activated by heat or acid stimuli. TRPV1 antagonists may therefore have therapeutic potential in hypersensitive GERD patients. The aim of this study was to investigate the effect of the TRPV1 antagonist AZD1386 on experimentally induced esophageal pain (ClinicalTrials.gov: NCT00711048). Methods. The study was conducted at teaching hospitals in Denmark and Sweden. Twenty-two healthy male volunteers (aged 20-31 years) participated in this twocenter randomized, placebo-controlled, double-blinded, crossover study examining the effects of a single oral dose of AZD1386 (30 mg or 95 mg) on esophageal pain. Subjects were block-randomized and, on treatment days, were subjected to painful heat, mechanical, and electrical stimuli, as well as acid-induced hyperalgesia in the esophagus. Painful heat stimulation of the skin and deep pressure pain were used as somatic controls. Data were analyzed on an intention-to-treat basis. Results. In total, 21 participants completed the protocol and one voluntarily discontinued after treatment with placebo and 95 mg AZD1386.

AGA Abstracts

Background: It has been documented that rate of symptomatic response to proton pump inhibitors (PPIs) in patients with non-erosive reflux disease (NERD) is lower than those with erosive esophagitis. There are a growing number of evidences implicating the impact of psychological comorbidities on increasing the risk of developing reflux symptoms. Furthermore, Pain modulators have been shown to improve symptoms in patients with functional gastrointestinal disorders. Aim: The aim of the study was to compare the efficacy of fluoxetine(FX), omeprazole(OM) and placebo(PL) on symptoms of NERD patients. Methods: In a double blind, placebo controlled clinical trial, 82 NERD patients were enrolled. All cases had normal endoscopic findings and none of them administered any PPI or other anti acid medications during at least 30 days before enrollment. The patients were classified into pHpositive and pH-negative groups based on 24-hour pH monitoring study. Each group randomly received FX, OM or PL for 6 weeks (totally 6 arms). Symptom severity was

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