Location of study report In Regulatory (For National Authority use only) Dossier for authorities

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1 MCB 0204FR 3 June 2003 Page 7 of86 3 SUMMARY Name of Sponsor/Manufacturer: Name Of Anished Product, If Volume: DAIVOBET /DOVOBET Title of Study/Protocol Code Number: Location of study report In Regulatory (For National Authority use only) Photo-allergy Test: Assessment of the photosensltisatlon potential of Daivobet/Dovobet oint~o I.JQ/9 and betamethasone (as ) 0.5 mg/g) 1 MCB 0204 FR/ International Co-ordinating Investigator Pmf. 0'-MD, IoWnotlonol Co-onll'"" France. Centre Details {number by country): One (1) centre in France. Publication References (Intended references): No publication planned. Study period details {date of first enrolment, date of last completed): Phase of development: 19/08/ /10/ Phase I. Objectives/hypothesis, If applicable: The objective of this study was to evaluate the photosensitisation potential of Daivobet/Dovobet ointment. Study Methodology (design, response variables, stratification): A phase I, single centre, randomised, Investigator blinded study with intra-individual comparison of Dalvobet/Dovobet ointment versus its vehicle in 32 healthy subjects. The test consisted of 3 phases: an induction phase, a rest phase, and a challenge phase. Induction phase: Day 1 and Day 2: assessment of minimal erythema dose (MED) by irradiation of six small test sites with UVA/B on upper back. The two investigational products were applied under occlusive conditions to two test sites on the back during 24 hours, twice weekly for 3 weeks (one site remained untreated). Twenty-four hours after each product application, irradiation was performed on the test site after patch removal. The irradiation dose was twice the subject's MED during the first week and three times the subject's MED the second and the t hird week, using a total spectrum of UV light. Skin reactions were assessed before application of investigational products and before irradiation of the sites. Rest phase: 2 weeks wit hout product application/irradiation. Challenge phase: 2 sets of the 2 products were applied on four new sites on the back, 24 hours under occlusive conditions. Two untreated but occluded sites were used as well. Only This document has been do\vnl.oaded from \vw w.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 informat1ona1 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 prescript1on or use.

2 Page 8 of86 3 June 2003 MCB 0204 FR Name of Sponsor/Manufacturer: Location of study report in Regulatory (For National Authority Use only) Dossier tor authorities Name of Finished Product, If Volume: DAJVOBI!T I OOVOBET one set of test sites was irradiated with MED full spectrum UV light followed by 4 J/cm 2 UVA light. The non-irradiated sites served as controls for a possible contact sensltlsation. All test sites were evaluated at 24, 48 and 72 hours after Irradiation. Skin reactions and erythema on the test sites were evaluated using a 5-point scale. At 72 hours after irradiation, the investigator assessed the occurrence of possible photosensitisation reactions. A follow-up visit was performed 2 weeks after the end of the treatment. This was only applicable In case of serious adverse events ongoing at last visit and non-serious adverse events ongoing at the last visit, which were classified as possibly/probably related to trial drug or not assessable. Follow-up was performed by means of telephone contact or visit according to the investigator's discretion. All subjects received both investigational products according to randomisation (two of three sites on the back). No stratification was applied. Number of Patients enrolled (according to treatment groups): Thirty-two (32) subjects. Diagnosis and Main Criteria tor patient selection: Healthy subjects of either sex between 18 and 65 years of age without signs of skin irritation on test areas, selected by specific inclusion/exclusion criteria. Subjects with abnormal pigmentation of the skin or skin type or any systemic or cutaneous disease that might confound interpretation of study results were excluded, as well as those with a history of or active photo-induced or photo-aggravated disease and those with scars, moles, sunburn or other blemishes in the test area. Exposure to excessive or chronic UV radiation within 4 weeks prior to Inclusion or during study period were not permitted, as well as the use of systemic drugs and other anti-inflammatory drugs within 2 weeks prior to inclusion, and use of any other medication that would interfere with the study results, in particular topical drugs on the test site. Investlgatlonal Product (name, dose [amount and frequency], dosage form, route or administration, lot numbers): Daivobet/Dovobet ointment (calclpotriol SO ~g/g and betamethasone (as )) 0.5 single topical 24-hour occlusive application. Fifty (50) ~ I applied per test site. Lot. no. : Treatment Duration (washout, treatment, follow-up as applicable): The investigational products were applied twice weekly for 3 weeks In the induction phase. There was no product application In the rest phase and product application only once in the challenge phase. The total duration of the 3 phases was 6 consecutive weeks, followed by 2 weeks' safety follow-up in case of unresolved serious adverse events or non serious adverse events with a possible, probable or not assessable relationship to study treatment. Reference Therapy (name, dose [amount and frequency], dosage form, route of administration, lot numbers): The control product was Daivobet/Dovobet ointment vehi~lca l occlusive application. Fifty (SO) ~I applied per test site. Lot. no.:-- 24-hour

3 MCB 0204 FR 3 June 2003 Page 9 of86 Name of Sponsor/M;muracturer: Location or study report In Regulatory (For National Authority Use only) Name of Finished Product, if Volume: DAIVOBI!T I DOVOBET Calcipotrlol & betamethasone Criterill for evaluation EffiCllcy : N/A Safety: Induction Phase Evaluation Skin reactions were assessed before application of investigational products and prior to irradiation of the sites, using the following grading scale of erythema: 0 No reaction 0.5 Doubtful erythema 1 Mild erythema 2 Moderate erythema 3 Severe erythema Other signs of skin reactions such as papules (Pa), vesicles (V), blisters (B), dryness (D), cracking (C), peeling (Pe) and others were recorded as well as immediate pigmentation and pigmentation induced by UV irradiation. Challenge Phase Evaluation Skin reactions were assessed 24, 48 and 72 hours after irradiation, using the same scale as during induction phase as well as a Global Clinical Score: 0 Normal skin aspect 0.5 Equivocal reaction 1 Slight erythema with small papules and/or slight oedema 2 Moderate eryt hema with papules and/or vesicles and/or oedema 3 Intense erythema, oedema, confluent vesicles forming blisters Other signs of skin reactions such as spreading of reaction beyond the patch area (5), dryness (D), cracking C), peeling (Pe) and others were recorded as well as immediate pigmentation and pigmentation induced by UV irradiation. Any positive or equivocal photosensitisation reaction as well as any unexpected and/or severe skin reaction was photographed. Each photograph was identified with the study number, subject number and initials, visit day and test site. The investigator assessed the occurrence of a possible photosensitisation reaction, by evaluation of each area in comparison to the corresponding non-irradiated test site and the untreated irradiated test site, 72 hours after irradiation in the challenge phase by using the following categories: 0 Negative 1 Equivocal 2 Positive

4 Page 10 of86 3 June 2003 MCB 0204 FR Name of Sponsor/Manufacturer: Name or Finished Product, If Volume: DAIVOBET I DOVOBET Location of study report In Regulatory (For National Authority Use only) Adverse Event Evaluation Adverse events were reported on an ongoing basis. Statistical Methodology (as In protocol, or, especially, If dltferent than originally presented in protocol): The statistical analysis was performed in accordance with the protocol. The assessment of possible photosensitive reactions 72 hours following irradiation in the challenge phase were tabulated by treatment site. The assessments of signs in the two score systems (Global Clinical Score and grading scale of erythema) were tabulated by t reatment site during t he induction phase and by treatment site and irradiated/non-irradiated site during the challenge phase. All other adverse events were described individually. Summary/Discussion A total of 32 subjects (7 males and 25 females) were enrolled and 30 subjects completed the study as planned. The age ranged from 19 to 61 with a mean of 38 years. No significant medical history or physical examination findings were reported at baseline. Efficacy Results (for primary and secondary endpoints, with tables): N/A Safety Results The occurrence of photosensitive reactions at 72 hours following radiation on the first day in the challenge phases was tabulated by treatment site. Occurrence of photosensitive reactions by treatment site 72 hours following radiation on the first day in the challenge phase (lit analysis set) Occurrence of photosensitive reactions Negative Equi vocal Positive Total Daivobet (n 32l Number of subj ects \ Dai vobete vehicle (n 32l Number of subjects ' Control (n 32) Number of 5\lbjects \ o All test sites were evaluated as negative with respect to occurrence of photosensitive reactions. Thus, there were no differences between treated sites and control sites. The Global Clinical Score assessments were tabulated by treatment site and irradiated side during the challenge phase.

5 MCB 0204 FR 3 June 2003 Page 11 of86 Name of Sponsor/Manufllcturer: Location ot study report In Regulatory (For National Authority use only) Name ot Finished Product, if Volume: DAIVOBET I DOVOBI!T Global Clinical Score by treatment site and irradiated/non-irradiated side during the challenge phase (ITT analysis set) Visit (Challenge phase) Daivobet'> Oaivobete vehicle Control Global (n=32 ) (n 32) (n 32) Clinical Score Irra- Non irra- Irra Non-irra - Irra- Non -irradiated diated diated diated d i&ted diated s i de side aide side aide aide ISbj = Number of subjects sbi \ WSbj \ WSb j t sbj \ #Sbj t isbj Day 2 - Week 6 Normal ski n as-pect Equivocal reaction Total Day 3 - Week 6 Normal skin aspect so.o Equivocal react ion ND* Total o o Day 4 - Week 6 Normal skin aspect Equivocal reaction Total o o Day S - Week 6 Normal skin aspect o Total ' * ND: not done. During the challenge period, only normal aspect or equivocal reactions were observed after irradiation. On Day 3 (24 hours after irradiation), a higher number of equivocal reactions were observed on both Irradiated and non-irradiated Daivobet/ Dovobet-treated sites compared to vehicle-treated or control sites. However, already on Day 4 almost all sites showed normal skin aspect.

6 Page 12 of86 3June 2003 MCB 0204 FR Name of Sponsor/Manufacturer: Location or study report In Regulatory (For NatiOnal Authority Use only) Dossier for authoritles Name of Finished Product, if Volume: DAI VOaET I DovoaET Grading scale of erythema by treatment site and irradiated/non-irradiated side during the challenge phase (ITT analysis set) Visit (Challenge phase) Daivobet Daivobet vehicle COntrol Grading (n 32 ) (n 32) <n=32l scale of erythema Irra Non - irra Irra- Non- irra- Irra- Non-irrad i ated diated diated diated diateo diated s i de side side side a ide side net Nu~r of subjects #Ptt ' 8Ptt ' #Ptt ' #Ptt ' MPtt ' #Ptt Day2 - Week 6 No reaction o Doubtful erythe ma o s 16.7 Total Day 3 - week 6 No reaction l Doubtful erythema Mild erythema 9 30.o Total o cay 4 - Weel< 6 No reaction o o Doubt.ful erythema o Mild erythema Total o Day s - week 6 No reaction o Doubtful erythema Total ' Also when considering erythema, there were more cases of doubtful or mild erythema on Daivobet / Dovobet sites than on vehicle-treated sites on Day 3 (24 hours after irradiation), but on Day 5 almost all irradiated sites and non-irradiated sit es had no reaction, and only four of the Dalvobet/ Dovobet-treated sites had doubtful erythema. During the induction phase, the occurrence of erythema and other reactions was similar for all the treatments. Ten out of the 32 subjects reported a total of 13 adverse events. Five of the 13 adverse events were classified as possibly related to the study drug by the investigator and thus classified as adverse drug reactions. Of these, all five were systemic adverse events: back pain (1), gastritis (1), headache (2) and nasopharyngitis (1). Given that all subjects received both investigational products concomitantly, it may be questioned whether the assessment of a causal relationship of a systemic adverse event to a specific or individual investigational product is of relevance. Also the amount of approximately 368 mg of each of the investigational products during the study period is regarded to be so low that a systemic effect is considered to be unlikely. Two subjects left the study due to unacceptable adverse events, not related to study medication. No deaths or other serious adverse events were reported. Conclusion (relationship of risks and benefits) The results observed in this study indicated that no photosensitisation reaction was

7 MCB 0204 FR 3 June 2003 Page 13 of86 Name or Sponsor/Manufacturer: Location or study report In Regulatory (For National Authority Use only) Name or Finished Product, it Volume: DAIVOBET I DOVOBET observed neither for Daivobet/ Dovobet nor for its ointment vehicle at any of the evaluation visits. Furthermore, no sign of sensitisation was observed on the test sites on the non-irradiated side. The study did not show any unexpected or significant safety issues arising during the study period. Report date: 3 June 2003

8 Page 14 of86 3 June 2003 MCB 0204 FR 3.1 SCHEDULE/CHART OF STUDY PROCEDURES Informed Consent Medical History Demographics Inclusion/Exclusion Criteria Pregnancy Test for Females Scree ning Period (Day -14 to Day 0) Inclusion/Exclusion Criteria Check UV Irradiation for MED INDUCTION PHASE ( Weeks 1, 2 and 3) Day 1 Day 2 Day 3 Day4 Day 5 (Week 1 only) Assessment of Exposed Sites (22- MED 24 hours after irradiation) for MED (Week 1) Determination Products Application Patches Removal Site Evaluation (except week 1) UV Irradiation Adverse Event/Concomitant Medications REST PHASE (WeekS 4-5) Day 1 Day 2 Day 3 Day 4 Day 5 No Application/No Visits CHALLENGE PHASE (Week 6 ) Day 1 Day 2 Day 3 Day 4 Day 5 Products Application Patches Removal Site Evaluation UV Irradiation (0.75 MED + 4 J/cm 2 UVA) Adverse Events I Concomitant Medications FOLLOW-UP VISIT* ( Week 8 ) Adverse Events *This was only applicable in case of serious adverse events ongoing at last visit and non-serious adverse events ongoing at the last visit which were classified as possibly/probably related to trial drug or not assessable. Telephone contact or visit according to the investigator's discretion.