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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.

SummaryBackground The Crohn's Disease Activity Index (CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes (PROs) should be the primary outcome in randomised controlled trials for Crohn's disease (CD). Aim As no validated PRO exists for CD, to investigate whether CDAI diary card items could be modified for this purpose. Methods Data from a trial of rifaximin-extended intestinal release were used to identify cut-points for stool frequency, pain and general well-being using receiver operating characteristic curves with CDAI

of life, little is known about their satisfaction with clinical management, or with associated drug treatment. Knowing the perception and satisfaction that patients have about the management of their disease, it will allow designing strategies aimed to improve patients’ quality of life and promoting adherence and treatment effectiveness. The aim of this study is to understand perceptions, attitudes, experiences, and satisfaction with clinical management of UC patients, particularly in aspects related to treatment. Methods: A discussion group was performed with eight UC patients in remission who had not received biologics or corticosteroids during the previous year. The heterogeneity was ensured by selecting different UC profiles using the following variables: severity, time since onset, follow-up level of care, currently on treatment, managed by a UC care unit, patients belonging to any patient association and gender. Following qualitative methodology a descriptive-interpretative content analysis was performed to detect emerging categories, building an explanatory framework. Results: The most frequent mentions are related to diagnostic process, follow-up and treatment. Diagnostic delay was detected due to lack of clinical suspicion from primary care (PC) and delayed diagnostic tests. Patients prefer to receive care on demand, channeled through remote care, which helps to resolve questions about UC, issues with treatment, or when a relapse occurs, and minimizes visits to the hospital. Patients with moderate UC diagnosis perceive some training lacks in PC physicians about management of symptoms, although, in general, they declare their satisfaction with follow-up both in PC and specialist care. When forced to go to the emergency room, they are quite dissatisfied with management, due to the delay in providing symptoms resolution, mainly related to inadequate knowledge of UC management. To avoid this, patients suggest the possibility of receiving care on demand from a specialist in UC. In relation to treatment, patients expect it to be effective, reducing symptoms. Secondly, treatment should be safe, minimizing short and long-term side effects. Regarding to treatment characteristics that patients would like to improve, they mention a reduction in the number of doses and tablets per day, and an increased number of tablets per box. Conclusions: These results suggest the importance of developing strategies to facilitate care on demand, remote care, and to investigate on effective and safe treatments to improve patients’ quality of life. P176 Patient reported outcome measures derived from the Crohn’s Disease Activity Index: Correlation between PRO2 and PRO3 scores and CDAI-defined clinical thresholds R. Khanna1, G. D’Haens1,2, B.G. Feagan1,3, W.J. Sandborn1,4, M.K. Vandervoort1, G. Zou1, R.L. Rolleri5, E. Bortey5, B.G. Levesque1,4 *. 1Robarts Clinical Trials Inc., Robarts Research Institute, Western University, London, Ontario, Canada, 2University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 3Western University, Department of Epidemiology and Biostatistics, Department of Medicine, London Ontario, Canada, 4University of California, San Diego, Division of Gastroenterology, La Jolla, United States, 5Salix Pharmaceuticals Inc., Clinical Development, Raleigh North Carolina, United States

Lynn R Webster,1 Robert L Rolleri,2,3 Glenn C Pixton,3 Kenneth W Sommerville31Lifetree Clinical Research, Salt Lake City, UT, USA; 2Salix Pharmaceuticals, Inc., Raleigh, NC, USA; 3Pfizer Inc, Cary, NC, USABackground: Abuse-deterrent formulations attempt to address public health and societal concerns regarding opioid abuse. Oxycodone HCl-niacin tablets combine oxycodone HCl with niacin and functional inactive excipients to create potential barriers to oral, intranasal, and intravenous abuse. This study compared the relative abuse potential of oral immediate-release oxycodone HCl-niacin with that of oral immediate-release oxycodone HCl and placebo in nondependent, recreational opioid users.Methods: Forty-nine participants received oxycodone HCl-niacin 40/240 mg and 80/480 mg, oxycodone 40 mg and 80 mg, and placebo in a randomized, double-blind, placebo-controlled and active-controlled, five-way crossover study. Primary endpoints based on a bipolar 100 mm visual analog scale for drug liking were area under effect curve (AUE0–1h, AUE0–2h, AUE0–3h), peak disliking, and effect at 0.5 hours post-dose (E0.5h). Other endpoints included take drug again assessment, overall drug liking, and pupillometry.Results: There were statistically significant differences between oxycodone HCl-niacin and oxycodone HCl doses for all primary endpoints (P < 0.0001, all comparisons), suggesting reduced abuse potential with oxycodone HCl-niacin. Take drug again and overall drug liking showed greater liking of oxycodone alone. Oxycodone HCl-niacin 80/480 mg had consistently lower liking assessments than oxycodone HCl-niacin 40/240 mg, suggesting a dose-response to the aversive effects of niacin. Opioid-related adverse events were similar for equivalent oxycodone doses. The treatment-emergent adverse events most specifically associated with oxycodone HCl-niacin (ie, skin-burning sensation, warmth, and flushing) were consistent with the expected vasocutaneous effects of niacin. No serious adverse events were reported.Conclusion: Oxycodone HCl-niacin tablets may, in a dose-dependent manner, decrease the potential for oral abuse of oxycodone without unexpected adverse events or clinically significant differences in safety parameters compared with oxycodone alone. Although statistically powered, the small size of the study sample and the characteristics of its participants may not be generalizable to the population that abuses prescription opioid medications.Keywords: drug abuse, opioid, oxycodone, niacin

Objective To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(lH)-quinolinone hydrochloride], in healthy male subjects. Methods This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. Results Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration—time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses. Clinical Pharmacology and Therapeutics (1994) 55, 55–63; doi:10.1038/clpt.1994.10

Background & AimsBudesonide 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.MethodsTwo 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.ResultsRemission 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.ConclusionsBudesonide 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.