This document has been downloaded from www.leo-pharma.com subject to the terms of use state on the website. It contains data and results regarding approved and non-approved uses, formulations or treatment regimens, and it is provided for transparency and informational purposes only. The content does not reflect the complete results from all studies related to a product. As a document of scientific nature it is not to be seen as a recommendation or advice regarding the use of any products and you must always consult the specific prescribing information approved for the product prior to any prescription or use. MBL 0501 FR 11-JUL-2007 Page 1 of 5 SYNOPSIS Title of study/protocol Code Number: In vivo bioequivalence study of betamethasone in and DIPROSONE lotion according to FDA Guideline for vasoconstrictor bioassay/mbl 0501 FR Centre details: The trial was conducted in France Publication references: No publication planned Study period details: Pilot Phase: First subject enrolled on 16 June 2005 Last subject completed on 01 July 2005 Not Applicable Phase of development: Phase I/IIa (pharmacodynamic study) Objectives/hypothesis, if applicable: This study was planned to be comprised of two parts: The pilot phase of this study was intended to determine the dose duration response curve for the commercially available reference product, DIPROSONE lotion (betamethasone 0.5mg/g, Schering Plough) in order to estimate the dose duration ED 50 to be used in the pivotal study (part II of this study) and the proportion of subjects expected to meet an a posteriori detector criterion based on the D 2 /D 1 ratio. The pivotal phase of this study was cancelled by the Sponsor. The pivotal phase was intended to compare the pharmacodynamic activity (skin blanching effect due to vasoconstriction) of (formulation containing betamethasone 0.5mg/ml and calcipotriol 50mcg/g) to the commercially available reference product 00076090
MBL 0501 FR 11-JUL-2007 Page 2 of 5 DIPROSONE lotion in order to document the in vivo bioequivalence of the formulation to the reference product. Study methodology: Design The study was a single centre, randomised, controlled, investigator blinded, dose duration response study with randomisation of dose duration skin sites and intra-individual comparison of treatments. The study was conducted as an unoccluded Mc Kenzie-Stoughton s test (human skin blanching assay) with staggered application and synchronised removal, colorimetric measurements and visual scoring to evaluate skin blanching. Pilot Phase Within 15 days prior to the test all enrolled subjects attended a screening visit to select responder subjects meeting a predefined minimum vasoconstrictor response to DIPROSONE lotion. On the day of the test a baseline colorimetric measurement was performed. Eight dose durations of DIPROSONE lotion (0.25, 0.5, 0.75, 1, 1.5, 2, 4 and 6 hours) were applied to test sites on the forearms. Colorimetric measurements and visual scorings were performed 10 min, 2, 4, 6, 19 and 24 hours after product removal. Pivotal Phase Evaluation criteria Primary criterion Colorimetric measurements: At each time, two successive series of measurements were performed on each test site. The primary efficacy variable was the a* value, which represents the red/green balance. Secondary criterion
MBL 0501 FR 11-JUL-2007 Page 3 of 5 Visual skin blanching assessment (visual score) was performed, using the following scale: 0 no change in skin colour 1 slight (barely visible) blanching 2 obvious blanching 3 intense blanching 4 blanching judged to be maximal Intermediate scores (of half units) could be used when needed. Safety criteria Clinical assessment of local irritation signs and adverse events were reported on an ongoing basis. Number of patients enrolled: Pilot phase: Sixteen (16) subjects were enrolled and twelve (12) healthy subjects who met the "responder" criterion defined in the FDA guideline were randomised. Pivotal phase: Diagnosis and main criteria for patient selection: Subjects of either sex, 18 to 45 years old (both inclusive), with skin type I to IV and demonstrating adequate vasoconstriction to DIPROSONE lotion (unoccluded application of the reference for 4-6 hours screening pre-test showing a visual score of at least one unit (visual scale (0-4)). Investigational product, dose, method of administration, lot numbers: Pilot Phase: DIPROSONE lotion, Batch number 4009/Exp. 11/2006 10 mcl single applications of the reference product, DIPROSONE lotion were applied under non-occluded conditions on eight different test sites (eight different dose durations, from 0.25 hour to a maximum of 6 hours were tested).
MBL 0501 FR 11-JUL-2007 Page 4 of 5 Reference product, dose, method of administration, lot numbers: Duration of treatment: Pilot Phase: 10 mcl single application under non-occluded conditions on eight different test sites with eight different dose durations. The maximum dose duration was 6 hours. Statistical methodology Population to be analysed: All subjects in the Safety Analysis Set for safety. Per Protocol Analysis set for pharmacodynamics. Variables to be analysed: - Primary criterion: Colorimetric parameter a*. The analysed variable was the mean of the two successive measurements performed on each site. For each time, colorimetric variables were adjusted to baseline and to untreated controls on the same forearm (Δa*) - Secondary criterion : Visual score of skin blanching (from 0 to 4). The analysed variable was the mean of visual blanching scores between the two readers, for each time. Methods: The area under the effect curve (AUEC 0-24 ) over 24 hours was to be calculated for Δa* (adjusted values) using the trapezoidal method for each individual test site.
MBL 0501 FR 11-JUL-2007 Page 5 of 5 Summary Pilot part: Sixteen (16) subjects attended the screening visit and were enrolled in the pilot part. Four (4) were not responders and were discarded. Twelve (12) positive responder subjects (x xxxxxxx, x xxxxx) aged 20-42 years (mean: 27.6 ± 7.8) were randomised and completed the study. Primary criterion (a*): The parameter estimates from the Emax model fitted by non-linear least squares regression were Emax =-10.38; ED 50 =0.20 h (12 min); D 1 =0.10 h (6 min); D 2 =0.40h (24 min). Secondary criterion (visual score): The parameter estimates from the Emax model fitted by non-linear least squares regression were Emax = 36.07; ED 50 =0.19 h (11 min); D 1 =0.09 h (6 min); D 2 =0.38 h (23 min). No serious adverse events were reported. Under the conditions of the study, DIPROSONE lotion was safe and well tolerated. Pivotal part: Conclusions The results of the present study are in accordance with the results of the previous study MBL 0403 FR, and confirm that potent corticosteroid formulations, such as betamethasone formulations, generate short ED 50. As the pivotal study was cancelled by the sponsor, no conclusion about the bioequivalence of betamethasone in and DIPROSONE lotion can be drawn. Report date: 11-JUL-2007