This was a randomised, double-blind, vehicle-controlled, with intra-individual comparison, single centre study.

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1 Final Reort No. MCB 0202 FRI October , SYNOPSIS Study title: Reeat insult atch test with Daivobet!Dovobet Ointment - A Protocol number: Studied eriod: First subject in (inclusion): First study-drug administration: Last study-drug administration: Last subject out (comletion): March II'\ 2003 March 17"', 2003 June 16'\ 2003 June , 2003 Objectives: The objective of this study was to determine the otential of reeated alications ofdaivobet/dovobet ointment and the ointment vehicle to induce sensitisation to the skin of healthy volunteers. Methods: This was a randomised, double-blind, vehicle-controlled, with intra-individual comarison, single centre study. Two hundred and twenty () subjects were included, in order to fulftl the criteria of 200 subjects to comlete the study. Comleters were subjects who comleted the entire study or those who droed out because of adverse events. The duration of the study for each subject was 6 to 9 weeks, comrising of a 2 week run-in eriod followed by a 3- week induction hase and a 1-week challenge hase, searated by a 2-week rest hase. A comletion visit was erformed during the last day of assessment or within the week after. In case of serious adverse events ongoing at last visit and non-serious adverse events ongoing at the last visit which were classified as ossibly/robably related to trial drug or not assessable, a follow-u visit was erformed 2 weeks after the last visit. All subjects received both Daivobet!Dovobet ointment and its vehicle in a randomised manner. According to randomisation, one test site er subject was allocated to Daivobet!Dovobet ointment containing 50 j!g/g of calciotriol (as hydrate) and 0.5 mg/g ofbetamethasone (as diroionate) and one test site to the Daivobet!Dovobet ointment vehicle for the whole induction hase. This document has been dovmloaded from 'vw w.teo-hanna.c-om subject to the terms of use state on the website. It contains data and results regarding aroved and non-aroved uses, formulations or treatment regimens, and it is rovided for transarency and informational uroses only. The content does not reflect the comlete results from all studies related to a roduct. As a document of scientific nature it is not to be seen as a rec-ommendation or advice regarding the use of any roducts and you must always consult the secific rescribing information aroved for the roduct rior to any rescrition or use. 4/69 c

2 Final Reon No. MCB 0202 FRI October 24'11, 2003 l..aboratoires LEO S.A. Location of study reort in Regulatory Daivobet/Dovobet Ointment betamethasone didrodionate Methods (continued) All toical alications were erformed on the skin of the back using occlusive dressings (Large Finn Chambers~. For each alication of each investigational roduct was delivered directly into a Finn Chambe~ atch-test using a microiette (Eendone). The Finn Chambe~ constitutes an isolated volume with a food occlusion: it is ail aluminium scaula which is 12 mm in diameter. Finn Chambers were stuck on SCANPOR adhesive tae and fixed on the back. During the induction hase, the investigational roducts were alied to the same designated sites on the left an of the back according to the randomisation list. During the challenge hase, investigational roducts were alied to 2 new sites on the right art of the back. - Induction hase A total of 9 alications was erformed over a 21-day eriod, on Mo.ndays, Wednesdays and Fridays (s 1, 3, 5, 8, 10, 12, 15, 17, 19). Products alied on Mondays, Wednesdays and Fridays were removed on Wednesdays, Fridays and Mondays, resectively. After removal and scoring, a new alication was erformed. -Rest hase The induction hase was followed by a 2-week eriod during which no alication was made. - Challenge hase The investigational roducts were alied on 36 and remained on skin for 48 hours. They were removed on 38 and the test sites scored. The sites were scored again on s 39 and 40 after a funher 24- and 48-hour eriod, resectively. Sensitisation otential was based on an assessment using a visual scoring of the skin reaction. The first evaluations were done aroximately 30 minutes after removal of the atches. In addition, in the challenge hase, clinical scoring was reeated aroximately 24 and 48 hours after removal of the atches. In case of serious adverse events ongoing at the last visit and non-serious adverse events ongoing at the last visit which were classified as ossibly/robably related to trial drug or not assessable, a follow-u visit was erformed after 2 weeks. Number of subjects: Planned: Screened: Included: Comleted trial: In local tolerability analysis: In safety analysis: c

3 Daivobe,t/Dovobet Final No. MCB 0202 October Location of study re on in Regulatory Daivobet!Dovobet Ointment Name of active ingrecuent betamethasone diorooionate Diagnosis and main criteria for Inclusion: The subjects to be included in this study were to be healthy as defined by medical history and a hysical examination (including blood ressure and urine regnancy test for the women) made rior to inclusion. Subjects were to be 18 to 55 years old and willing to give written informed consent. Test roduct: DAIVOBET/DOVOBET OINTMENT- Calciotriol (SO J.Lg/g) and betamethasone diroionate (0.5 mglg) Manufacturer: Unit dose: Batch number I Exiry date: LEOPhanna 50 J.Ll Placebo: DAIVOBET/DOVOBET OINTMENT VEHICLE Manufacturer. Unit dose: / Ari12004 LEOPhanna so J1l Batch number/ Exiry date: / February 2005 DoWReglmeniRoute: Test Product: Regimen: Ten alications in total. During the induction hase: three alications er week for 3 weeks (6 reeated 48-hour toical alications and three 72-hour alications were erformed on the same sites). During the challenge hase: one 48-hour toical alication at a different site. Mode/route: Placebo: Regimen: Mode/route: Toical, occlusive As for the Test Product Toical, occlusive Duration of treatment: 21 days lus a final 48-hour alication after a rest eriod of 2 weeks. Criteria for Evaluation : Local tolerabllity: Visual scoring of skin rea.ctions from 0 (no erythema) to 4 (severe erythema, oedema, vesicles or blisters). Investigator's assessment of sensitisation otential of each roduct. Safety: Monitoring for the occurrence of adverse events (AEs) and changes in hysical examination, vital signs (blood ressure and ulse rate). f.lf.o

4 Final No. MCB 0202 October 24"', 2003 Lcx:ation of study reort in Regulatory Daivobel/Dovobet Ointment betamethasone diroionate Statistical Methods: Descritive statistics accomany all analyses if not otherwise indicated. These statistics include n, mean, standard deviation, standard error of the mean, minimum, median and maximum for continuous arameters. Categorical and ordinal scale arameters were summarized with frequencies and treatment ercentages. The visual scoring and the sensitisation otential analysis was erformed on the Per ProtocOl oulation. Visual scoring data were resented using descritive statistics and grahically dislayed. Results for sensitisation otential assessment were listed by subject and treatment. A frequency table resenting the count and frequency of subjects by category of sensitisation (negative/ositive) and treatment was rovided. Proortion of each sensitisation category was resented grahically er treatment using bar charts. Results and Conclusion: The mean ::1: standard error of the mean (SEM) values of visual scoring of skin reactions after alication of either Daivobet/Dovobet ointment or its vehicle were low. For the sites treated with Daivobet!Dovobet ointment, the mean score increased slightly from 10 to 22 during the induction hase while for the sites treated with the Daivobet/Dovobet ointment vehicle, the mean scores were almost unchanged from 3 to 22 as shown in the following figure: 0.6 o l T ~l l 1 i \ 0. 1 I.,z....t ::-. ---f -----f ---r t / ~ l: \\ I 3 bay e bay u u 38 3a39<0 I Treat ment: Dal ob t (lot slto) Voblolo ( ltllllo) I I

5 Final Reort No. MCB 0202 FRJ October 24~~>, 2003 Location of study reort in Regulatory Name offi11lshed roduct Daivobet/Dovobet Ointment Calcioaiol and betamethasone diroionate Individual values of visual scoring of the site treated with Daivobet!Dovobet ointment or vehicle were for a majority of subjects equal or below I thus indicating no erythema or a barely ercetible erythema for most of the subjects. Only three subjects (one at the site ofdaivobe.t/dovobet ointment alication, and two at the site of vehicle alication) had a noticeable skin reaction which was assessed to be due to fomculitis. The results indicate that the investigational roducts have low skin irritation otential. During the challenge hase, mean values of visual scoring were lower than the maximum values observed during the induction hase for Daivobet/Dovobet ointment while for the Daivobet/Dovobet ointment vehicle a slight increase in mean values of visual scoring was observed. Indeed, considering individual data, there were 27 subjects for Daivobet/Dovobet ointment and 41 subjects for Daivobet/Dovobet ointment vehicle who showed higher maximum scores during the challenge hase than during the induction hase. However, theses increases were small and were not considered to indicate any sensitisation. The result of the visual scoring was conftnned by the investigator's assessment of sensitisation otential on 40, which was negative for all subjects. Overall, no sensitisation reaction was observed for any subject during the whole duration of the study including the induction hase. One subject reorted local mild adverse event (folliculitis) on the Daivobet/Dovobet ointment site, and 2 subjects reorted mild folliculitis on the vehicle site. These AEs were judged robably related to the investigational drugs. In addition, 9 subjects reorted systemic adverse events that were considered as not related to the study roducts. Overall, no clinically relevant changes in vital signs and hysical examinations were seen during the study. It can be concluded from these results that, under the conditions of the study, Daivobet/Dovobet ointment had no sensitisation otential and that reeated alications of Daivobet/Dovobet ointment were safe and well tolerated. P: 8169 c