Safety of switching systemic steroids to budesonide modified-release capsules in steroid-dependent patients with inactive Crohn's disease

weeks. Safety included among other assessments the frequency and intensity (graded from 1 to 3) of possible glucocorticosteroid (GCS)-relatedadverse events (AEs) recorded at each visit and measurement of basal and stimulated plasma cortisol levels at study start and after the last intake of medication. Results: There was a positive correlation between initial prednisolone dose and baseline sum of GCS-relatedAEs intensities (p < 0.001). The sum of GCS-relatcdAEs intensities was reduced in both budesonide and placebo groups from 3.7 and 4.1, respectively, at the start of the tapering period, when patients were still receiving prednisolone, to 0.9 and 2.0, respectively, 13 weeks after cessation of prednisolone. There was a decrease in the intensity of AEs, particularly in moon face, acne, insomnia and mood swings. There were no differences in the sum of intensities of GCS-relatedAEs in both groups at 1 and 13 weeks after cessation of prednisolone. The mean unstimulated plasma cortisol increased by 139 nmol/I from first to last visit in the budesonide group (n = 37) (p = 0.007) and by 257 omol/l in the placebo group (n =30) (p
4023 Budesonide Foam vs. Hydrocodisone Foam in ProctosigmoidiUs S Bar-Meir, The Chaim Sheba Medical Ctr, Ramat Gan Israel; V Gross, Clin St Marien, Amberg Germany; G Bianchi Poro, L Sacco Univ Hosp, Milano Italy; R Greiwald, Dr Falk Pharma GmbH, Freiburg Germany Inflammatory bowel disease of the ano-rectum is best treated locally; foam being better tolerated. Hydrocortisone is efficacious either as an enema or as a foam. Budesonidc enemas were shown to be efficacious in patients with proctosigmoiditis. However, the efficacy and adverse effects of budesonide foam in comparison to hydrocortisone foam were never assessed. Therefore, a randomized, controlled trial was conducted comparing budesonide foam (2rag/d) with hydrocortisone foam (100 mg/d). Both medications were given for 8 weeks to patients with proctitis or proctosigmoiditis and disease activity index (DAI) of at least 4. Patients were excluded if their colitis was of less than 2 weeks duration, definitely if an infectious agent could be isolated. Patients who received either steroids within one month or immunosuppressant within 3 months prior to their enrollment were excluded. Patients were assessed at the beginning of the study and 2, 4 and 8 weeks later. Two hundred fifty one patients were enrolled in the study, 248 qualified for intention to treat analysis and 179 for per protocol analysis. Eighty-eight patients received budesonide foam (B) and 91 the hydrocortisone foam (H). Thirty-two B patients and 37 H patients were excluded because of major protocol violations Both groups were similar in their baseline characteristics. The OAI at enrollment for the g and the H was 7.2+1.9 and 7.0+2.0 respectively, Remission rate at the end of therapy was 55% and 51% for the B and the H respectively. A similar rate of improvement was noticed when endoscopic and histologic criteria were used. The rate of subjective improvement was higher, 66% and 70% for the B and H respectively. The rate of improvement was similar for both groups and by the end of 8 weeks the DAI decreasedfrom 7.2 and 7.0 to 3.5 and 4.1 in the B and H respectively. Most of the effect was achieved within 4 weeks and most probably already after 2 weeks. Side effects were negligible; acne occurred in 2 B patients and in 1 H patient. None developed hirsutism. Adrenal suppression was seen in 7% of the B and in 1% of the H, probably due to the direct absorption of budesonide into the systemic circulation. The patients equally tolerated both medications. It is concluded that budesonide foam for 8 weeks for patients with ulcerative proctosigmoiditis is of similar efficacy to hydrocortisone foam, safe and with minimal adrenal suppression. This study is supported by a grant from Dr Falk Pharma GmbH.

4026 Maintenance of Croh~'s Disease over 12 months: A Fixed versus Flexible Dosing Regimen using Budesceide Modified-Releace Capsules Jonathan Rb Green, Stoke City Gen Hosp, Stoke-on-Trent United Kingdom; Alan J. Lobo, Royal Hallamshire Hosp, Sheffield United Kingdom; Mustafa H. Giaffer, Hull Royal Infirmary, Hull United Kingdom; Simon Travis, Derriford Hosp, Plymouth United Kingdom; Hayley C. Watkins, AstraZeneca UK Ltd, Kings Langley United Kingdom Aim: To investigate the possibility to achieve more effective management of Crohn's disease (CO) by introducing a flexible dosage regimen sensitive to patients' needs by comparing the efficacy and tolerability of a fixed versus flexible budesonide modified-release capsules once daily (o.d.) treatment regimen for the prevention and management of relapse in CD patients. Methods: A randomized, double-blind comparison of a fixed dose of budesonide (6 mg o.d.) and a flexible dose of budesonide (3, 6, or 9 mg o.d.) for 12 months. The 143 patients had been in remission for a minimum of 1 month and a maximum of 12 months (mean time in remission: flexible group 117.0 days, fixed group 116.6 days) from Cmhn's disease of the ileum and/or ascending colon (CDAI<150). Patients began therapy on 6 mg o.d. and were stepped up and down to 6 mg (fixed group) or 3 mg (flexible group), and 6 mg (fixed dose) or 9 mg (flexible group) by the investigator, depending on the patients' clinical needs. Results: A very low rate of clinical relapse in CD was seen in both treatment groups. Neither was any significant difference seen between the groups with respect to treatment failures (flexible group 16%, fixed group 19%). Similar proportions of patients reported adverse events in the two groups. There were 33 serious adverse events (flexible 19, fixed t4) and 13 withdrawals due to adverse events (flexible 9, fixed 4). Conclusion: Crohn's disease patients receiving budesonide modified-release capsules, both the fixed and flexible dose, demonstrated a low rate of relapse. This complements and supports previous data showing that budesonide capsules prolongs remission in patients. Flexible dosing remains an option for individual patients with Crohn's disease.

4024 Targeted Delivery of Oral Budesonide(Entocort® Capsules) in Healthy Volunteers and Crohn's Disease Patients Pal Lundin, Staffan Edsbacker, Per Larsson, AZ R&D, Lund Sweden; Per Wollmer, Clin Physiology, University Hospital MAS, Malmoe Sweden Aim: Treatment of IBD with oral drugs should be targeted to ensure optimal effect. The gastrointestinal transport, release, and absorption of budesonide, a glucocorticosteroid with high topical anti-inflammatory effects, was investigated in healthy volunteers (HV) and in Crohn's disease (CD) patients. Methods: Budesonide (Entocort® pellets) 18 mg, mixed with ~l~ln pellets (3 Mgq), was administered to eight HV and six CD patients after a breakfast. Intestinal transit was recorded with a gamma camera, and blood samples collected simultaneously. The absorption of budesonide in different intestinal regions was estimated. As a reference, 2Hs-budesonide(0.5 rag) was given intravenously. Urine cortisol excretion was measured at baseline and 0-24 h after administration. Results: The average GI transit time was faster in CD than in HV. Despite this, the average amount absorbed (fraction of total absorbed dose) in ileum plus colon was about the same in HV and in CD (Table). Systemic availability was higher in CD patients than in HV but suppression of cortisol was similar. Pharmacokinetic data from i.v. administration did not distinguish between HV and CD. Conclusions: The fraction of budesonide absorbed in ileum and colon was similar in HV and CO. Despite a higher systemic exposure in Crohn's patients, the average cortisol suppression was similar for the two groups.

4027 Healthcare Cost Savings with BudesonideControlled Ileal Release Capsules (ClR) in Crohn's Disease Robert Lotberg, Karolinska Inst, Stockholm Sweden; Ake Danielsson, Umea Univ Hosp, Umea Sweden; Claes-Henrik Floren, Lund Univ Hosp, Lund Sweden; Sixten Borg, Karin Ericsson, AstraZeneca R&D Lund, Lund Sweden Background: Economic aspects are important when assessing the overall benefit of a treatment strategy. The number of investigations of these aspects are few within the field of Crohn's disease (CD). Objective: To assess the economic consequences, from a healthcare budget perspective, of treating CD patients with budesonide CIR (Entocort~ capsules) 6 mg per day as maintenance therapy compared to no maintenance treatment (NMT). Method: A validated decision-analytic model (Noble et al., 1998) on the treatment of CD in Sweden was used. The model uses pooled patient data from randomised, double blind trials of budesonide CIR capsules (n = 90) versus placebo (n = 90). in accordance with the clinical trials, the model covered a study period of one year and patients with CO in the ileum and/or the ascending colon and above 18 years of age. For events not investigated in the clinical trials, literature and panel data were used. Cost inputs for heaithcare resources were based on costs observed for 11 larger hospitals in Sweden in year 1996. The analysis took into account costs for heaithcare resources associated with managing inactive and active phases of CD e.g., diagnostic- and surgical procedures, physician visits, hospitalisations and drug consumption. Panel data and cost inputs were tested in a sensitivity analysis. Result: Average annual cost per patient was SEK 36,745 for budesonide CIR capsules patients compared to SEK 38,130 for NMT patients. With a Swedish prevalencebetween 13,000 to 18,000 patients this would mean annual savings of 18 to 25 million SEK (2-2.8 million USD). Stability of the results was confirmed when altering values on panel data and cost inputs. Conclusion: Budesonide CIR capsules, prolonging time in remission, is a cost-saving treatment strategy for the treatment of Crohn's disease in Sweden.

Pharmacokineticand-dynamicparameters(meanand min-max)

HV CD

GI transit (h)

Ileum-colon abs. (%)

F (%)

U-cortisol suppression (%)

30(16-44) 12 (3- 20)

75(55-97) 68 (39- 95)

12 (*lOto 14) 20/'13 to 33)

36(0-66) 33 (0- 76)

Ileum-colonabs = % of total absorbeddose F = Systemicavailability(*averageand 95% conf. limits)

4025 Safety of Switching Systemic Steroids to BudesonideModified-Release Capsules in Steroid-Dependent Patients with Inactive Crohn's Disease. Antoine Cortot, Jean-Frederic Colombel, Hosp Claude Huriez, Lille France; Paul Rutgeerts, Univ Hosp of Leuven, Leuven Belgium; Karsten Lauritsen, Univ Hosp of Odense, Odense Denmark; Helmuth Malchow, Stadisches Krankenhaus, Leverkusen Germany; Jens Hamling, KrankenhausTabea, Hamburg Germany; Trevor Winter, Groote Schuur Hosp, Cape Town South Africa; Andre Van Gossum, Hosp Erasme, Bruxelles Belgium; Eva Pettersson, AstraZeneca R&D Lund, Lund Sweden Aim: To compare the impact on safety of switching from prednisolone to a modified-release formulation of budesonide capsules or placebo for the maintenancec)f remission in steroiddependent Crohn's disease. Methods: 118 patients with Crohn's disease dependent on prednisolone for at least 8 months and with a Crohn's disease Activity Index (CDAI) of < 200 were randomised to receive placebo or budesonide 6 rag/day (n = 59 each). Prednisolonetreatment was tapered concomitantly from the start of budesonide or placebo treatment. After cessation of prednisolone therapy, patients were treated with placebo or budesonide for a further 13

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