MCB0204FR - PHOTO ALLERGY TEST: Assessment of The ... · PHOTO-ALLERGY TEST ... MCB 0204 FR LEO...

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CLINICAL STUDY REPORT

PHOTO-ALLERGY TEST

ASSESSMENT OF THE PHOTOSENSITISATION POTENTIAL

OF DAIVOBET / DOVOBET OINTMENT

(Calcipotriol 50 119/ 9 and Betamethasone (as Dipropionate} o.s m9/ 9 )

A Phase I, Single Centre, Randomised, Investigator Blinded Study with Intra-individual

Comparison of Treatments

The clinical study report has been redacted using the following principles: Wbere necessary,informationis anonymised to protect the priv acy o fstudy subjects and named persons a sso cia ted "'~th the trial as well as to retain commercial confidential information. Summary data are included but data on individual study subj ects, including data listings, are removed. This may result in page numbers not being consecutively numbered. Access to anonymised data on ind.iYidualstudy subject rna y be obtained up on approval of a rese.arch proposal by the Patient and Scientific Review Board. A.ppendices to the clinical study report are omitted. Further details and principles for anonymisationis available in the documentLEOPHARMA PRINCIPLES FOR ANONYMJSATION OF CLINICAL TRIALDATA

00002658

MCB 0204 FR

LEO Pharma

Medical Department

Final

3 June 2003

MCB 0204 FR 3 June 2003 Page 1 of 86

1 CLINICAL STUDY REPORT APPROVAL

[ ~ I LEO Pharm• ~ Media l Department

GCP I -SOP Dll

CLINICAL STUDY REPORT APPROVAL FORM PlloTOCOL Cooe NuNan: MCB 0204 FR

R!PORT T ITU:

Photo-allergy test

RII'ORT OAT! (DD-MMM·Y'IVY):

03 JUN 2003

By signing below I conform that I have read the Clinical Study Report and confirm that to the best of my knowledge It accurately describes the conduct and results of the study.

APPROVAL BY INTERNATIONAL Co-ORDINATING INVESTIGATOR

Date ~-'~~ S!GNAl\JAE

APPROVAL BY MEDICAL DIRECTOR, (MEDICAL DEPARTM!NT- CRITICAL CARE/ DERMATOLOGICAL MEDICAL DEPARTMENT] DEPARTMENT, LEO DK

PRtNTEO NAH! SlGN•l\JAE

APPROVAL BY [ HEAD OF MATHEMATICAL-STATISTICAL DEPARTMENT, LEO OK/ BIOMETRICS MANAGER, LEO UK]

StGN•TURf

APPROVAL BY VICI! PRESIDENT, MEDICAL DIRECTOR, LEO

PRtNTf:O NAHI! StGNATUAe

Distribution: Original - Trial Maste:r File (85 ~rt of Final Study Report)

Ve~ion : OI·Mav-2003

Date --:::-=:-:::::::::--OD-HMM·l"fn'

Printed: 03·Jun·2003

of86 3 June 2003 MCB 0204 FR

I ~ I LEO Pharma M Medical Dep~rtment GCP I·SOP DZ I

CLINICAL STUDY REPORT APPROVAL FORM PROTOCOL CODE NUMaiR:

MCB 0204 FR R IPDRT T ITLE:

Photo-allergy test

R ePORT Du • ( DD-MMM-YYYY):

03 JUN 2003 TF INDa No.: ;16.1; .

Sy signing below I confirm that I have read the Clinical Study Report and confirm that to the best of my knowledge It accurately describes the conduct and results of the study.

APPROVAL BY INTERNATIONAL CO.ORDINATlNG INVESTIGATOR

PAl~ NAME SIGNATVA.f Date --;;:00

;;:.-:::.,:;,.,::,.::wvv::::--

APPROVAL BY MEDICAL DIRECTOR, [MI!DICAL DEPARTMENT • CRITlCAL CARE/ DERMATOLOGICAL MEDICAL DI!PARTMEJIT] DEPARTMI!NT, LI!O DK

---- Date 03 -<}tw'-200?, StGHATU!le DO·MMM-'f'NY

APPROVAL BY [ HEAD Of MATHEMATICAL·STATISTICAL DEPARTMENT, LEO OK/ BIOMETRICS MANAGER, LEO UK]

APPROVAL BY VI CE PRESIDENT, MEDICAL DI RECTOR, LEO

PR:NTtD NAMf

Distribution: Original - Trio! Muter File ( .. part of Final Study Report)

Printed: 03·l un·2003 Vers<on: Ol·Mav· 2003

MCB 0204 FR 3 June 2003 Page 3 of86

2 REPORT STATEMENTS

2.1 CONFIDENTIALITY STATEMENT

This Clinical Study Report is the property of LEO Pharma and is a confidential document. It is not to be copied or distributed to other parties without written approval f rom LEO Pharma.

2.2 COMPLIANCE WITH GOOD CLINICAL PRACTICE

This Clinical Study Report is designed to comply with standards issued by the International Conference on Harmonization (ICH) (E3 St ructure and Content of Clinical Study Report; E6

Good Clinical Practice; E9 Statist ical Principles for Clinical Trials).

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2.3 STUDY AUTHENTICATION

I ~ I ~EO P~arma AA Medial D~rtment

PROTOCOL CODE NUMII!R: MCS 0204 FR RE.PORT T ITLE:

Photo-allergy test

AUTHENTICATION FORM ll!PORT DATE (DD-MI4M·YYYY) :

03-JUN-2003

GCP l·SOP 021

TF IHDEX No.: 16.1. . ·•·

This study was Performed in compliance with the Good Clinical Practice (GCP) standard issued by the International Conference on Harmonisation (ICH), the Declaration of Helsinki with SIJbseQuent amendments, and respecting national rules/regulations.

The study was performed in accordance with the approved Study Protocol and with LEO Pharma Standard Operating Procedures tor GCP. The report provides a true and accurate record of the results obtained.

Authorised by: PCPC

--- oate 0 ?l- 'JvN- :l..ooJ PR.1NTEO NAME 00·1'1MH•Y'f"Y't'

orstributlon: Original ~ Trial Master F<le (as part or Final Study Report)

Printed: 03-lun-2003 verSion: Ql .. Mav-2003 Paae 1 of!

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3 SUMMARY

Name of Sponsor/Manufacturer :

LEO PHARMA

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

Name of Finished Product, If Volume: available:

DAJVOBET I DOVOBET

Name of Active Substance:

Calcipotriol & betamethasone dipropionate

Title of Study/Protocol Code Number :

Page:

Pnt,tn-::~ll~>rr•v Test: Assessment of the photosensitisatlon potential of Daivobet/Dovobet i.Jg/g and betamethasone (as dipropionate) 0.5 mg/g) 1 MCB 0204

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:

19/08/2002 - 11/10/2002. 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 third 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 without product application/irradiation.

Challenge phase: 2 sets of the 2 products were applied on four new sites on the back, 24 hours under occlusive ons. Two untreated but occluded sites were used as well.

of86 3 June 2003 MCB 0204 FR

Name of Sponsor/Manufacturer:

LEO PHARMA

Location of study report in Regulatory (For National Authority Use only) Dossier tor authorities

Name of Finished Product, If Volume: available:

DAJVOBI!T I OOVOBET



Page:

one set of test sites was irradiated with 0. 75 MED full spectrum UV light followed by 4 J/cm2 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 discret ion.

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 dipropionate)) 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~lcal 24-hour occlusive application. Fifty (SO) ~I applied per test site. Lot. no.:--


Name of Sponsor/M;muracturer:

LEO PHARMA

Location or study report In Regulatory (For National Authority Use only) Dossier for authorities

Name of Finished Product, if Volume: available:

DAIVOBI!T I DOVOBET


Calcipotrlol & betamethasone dipropionate

Criterill for evaluation

EffiCllcy :

N/A

Safety:

Induction Phase Evaluation

Page:

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

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Name of Sponsor/Manufacturer: Location of study report In Regulatory (For National Authority Use only) Dossier for authorities

LEO PHARMA

Name or Finished Product, If Volume: available:

DAIVOBET I DOVOBET



Adverse Event Evaluation

Page:

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 the 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 chal lenge 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•32 l

Number of subj ects \

30 100 . 0 0 0 0 0

30 100.0

Dai vobete vehicle Control (n•32l (n•32)

Number of Number of subjects ' 5\lbjects \

30 100 . 0 30 100.0 0 0 0 0 0 0 0 0

30 100.0 30 100 . 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.

MCB 0204 FR

Name of Sponsor/Manufllcturer:

LEO PHARMA

3 June 2003 Page 11 of86

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

Name ot Finished Product, if Volume: available:

DAIVOBET I DOVOBI!T



Page:

Global Clinical Score by treatment site and irradiated/non-irradiated side during the challenge phase (ITT analysis set)

Visit (Challenge phase) Daivobet'> Oaivobete vehicle Contro l Global (n=32 ) (n •32 ) (n•3 2) Clinical Score Irra- Non· irra - Irra· Non-irra - Irra- Non - irra-

diated diated diated diated d i&ted diate d 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 29 96.7 29 96.7 30 100.0 30 100.0 28 93 . 3 28 93.3 Equivocal reaction 1 3 . 3 1 3 .3 0 0 0 0 2 6 . 7 2 6 . 7 Total 30 100.0 30 100.0 30 100.0 30 100 . 0 30 100.0 30 100 . 0

Day 3 - Week 6 Normal skin aspect 11 36.7 13 43.3 23 76.7 28 93.3 24 so .o 27 90.0 Equivocal react ion 19 63.3 16 53 .3 7 23.3 2 6 . 7 6 20.0 3 10.0 ND* 0 0 1 3 .3 0 0 0 0 0 0 0 0 Total 30 100.0 30 100 .o 30 100 . o 30 100.0 30 100.0 30 100.0

Day 4 - Week 6 Normal skin aspect 28 93.3 28 93.3 30 100 . 0 30 100.0 30 100.0 30 100.0 Equivocal react ion 2 6. 7 2 6. 7 0 0 0 0 0 0 0 0 Total 30 100.0 30 100.0 30 100.0 30 100 .o 30 100 .o 30 100.0

Day S - Week 6 Normal skin aspect 30 100 .o 30 100 .0 30 100 . 0 30 100.0 30 100.0 30 100 . 0 Tota l 30 100 . 0 30 100.0 30 100.0 30 100.0 30 100.0 30 100.0

* 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.

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Name of Sponsor/Manufacturer:

LEO PHARMA

Location or study report In Regulatory (For NatiOnal Authority Use only) Dossier for authoritles

Name of Finished Product, if Volume: available:

DAI VOaET I DovoaET



Page:

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-irra-

d i ated diate d 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 2 7 90.0 2 7 90.0 27 90. 0 27 90 . o 25 83.3 25 83.3 Doubtful erythe ma 3 10. 0 3 10.0 3 10 .o 3 10 . 0 5 16.7 s 16 .7 Total 30 100.0 30 100.0 30 100.0 30 100.0 30 100.0 30 100.0

Day 3 - week 6 No reaction 4 13 . 3 13 43 . 3 12 40 . 0 28 93.3 l1 36.7 27 90.0 Doubtful erythema 17 56 . 7 10 33 . 3 18 60.0 2 6 .7 19 63.3 3 10. 0 Mild erythema 9 30 .o 7 23.3 0 0 0 0 0 0 0 0 Total 30 100 . o 30 100 . 0 30 100 .0 30 100.0 30 100.0 30 100.0

cay 4 - Weel< 6 No reaction 16 53.3 26 86.7 27 90 .o 29 96 .7 24 80 .o 29 96.7 Doubt.ful erythema 13 43. 3 3 10 . o 3 10.0 1 3.3 6 20.0 1 3.3 Mild erythema 1 3. 3 1 3. 3 0 0 0 0 0 0 0 0 Total 30 100.0 30 100 .o 30 100.0 30 100.0 30 100.0 30 100.0

Day s - week 6 No reaction 27 90 .o 29 96.7 30 100.0 29 96.7 30 100.0 30 100.0 Doubtful erythema 3 10.0 1 3. 3 0 0 1 3. 3 0 0 0 0 Total 30 100.0 30 100 . 0 30 100. 0 30 100.0 30 100 . 0 30 100.0

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), gastrit is (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

--- ·-----·


Name or Sponsor/Manufacturer: Location or study report In Regulatory (For National Authority Use only)

LEO PHARMA Dossier for authorities

Name or Finished Product, it Volume: available:

DAIVOBET I DOVOBET

Name of Active Substance: Page:


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

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3.1 SCHEDULE/CHART OF STUDY PROCEDURES

Screening Period (Day -14 to Day 0)

Informed Consent X

Medical History X

Demographics X Inclusion/Exclusion Criteria X

Pregnancy Test for Females X

INDUCTION PHASE ( Weeks 1, 2 and 3)

Day 1 Day 2 Day 3 Day4 Day 5

Inclusion/Exclusion Criteria Check X

UV Irradiation for MED (Week 1 only)

Assessment of Exposed Sites (22- MED 24 hours after irradiation) for MED (Week 1)

Determination

Products Application X X

Patches Removal X X

Site Evaluation X (except X X X week 1)

UV Irradiation X X

Adverse Event/Concomitant X X X X Medications

REST PHASE (WeekS 4-5)

Day 1 Day 2 Day 3 Day 4 Day 5

No Application/No Visits

CHALLENGE PHASE (Week 6 )


Products Application X

Patches Removal X

Site Evaluation X X X X

UV Irradiation (0.75 MED + 4 J/cm2 X UVA)

Adverse Events I Concomitant X X X X X Medications

FOLLOW-UP VISIT* ( Week 8 )

Adverse Events X

*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.

MCB 0204 FR 3 June 2003 Page 15 of 86

4 TABLE OF CONTENTS

1 CLINICAL STUDY REPORT APPROVAL. .. .......... ........... ..... ....................................... 1

2 REPORT STATEMENTS .............. ........ ... ..... ....... ........... .... ..... ............................... 3

2.1 Confidentiality Statement ......................... ...................................... ... ... .. .... 3 2.2 Compliance with Good Clinical Practice ... ............................................... ..... .. 3

2.3 Study Authentication ..... ......... ............................ ............... .... ........ ..... ..... .. 5

3 SUMMARY ......... ........... .. .. .................................. ... ..... ....... ........... ...... ... ....... ..... 7

3.1 Schedule/Chart of Study Procedures ................................... ........................ 14

4 TABLE OF CONTENTS ... ... ...... .... ...................... ....... ........... ................................ 15

5 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .. ....... ... ... .... ... .................... 17

5.1 List of Abbreviations ........ ...................... ........................... ........ ....... ..... .... 17 5.2 Definition of Terms .. ... ..... .. ....... ... .. ..... ....... .......... ..................................... 17

6 ETHICS ............. .................. ..... ................. ....................................... ................ 25

6.1 Independent Ethics Committee (IEC) or Institut ional Review Board (IRB) .... .... 25

6.2 Ethical Conduct of the Trial. .......... ... .. .. ... .. .................... ................... .. ........ 25 6.3 Patient Information and Informed Consent ........... ................. ... ................... 25

7 STUDY ADMINISTRATIVE STRUCTURE ... .... .. ......... ............... .... ... .... ...... ... .. ........ .. 27

7.1 Report Author(s) ... .. ........................ ......... .. ............................ .................. 27

7.2 Investigators and Trial Centres and CROs .......................... ... ....................... 28 7.3 Company Personnel ..... ........... ... ........... ........ ........... .... ............................. 29

8 INSURANCE AND UABILITY ....................................... ................................. ........ 33

9 INTRODUCTION AND RATIONALE ......................... ............................. ... ............... 33

9.1 Psoriasis .............................. ........ ..... ....... ... ..... ........... ..... ..... .................. 33

9.2 Investigational Product Description ..... .. ....... ..... ....... ... .. .............................. 33 9.3 Study Rationale .... ........................................ .................................. ......... 35

10 STUDY OBJECTIVES .. ............. .... ................... ................. ................................... 37

10.1 Primary Objective .. ...... ............ ......... ....................... ..................... ...... .... .. 37

11 INVESTIGATIONAL PLAN ...................................................... ..... .. ........ ................ 37

11.1 Study Design ............... ................................. .......... .. ................... ............ 37 11.2 Time Schedule ....................................... ......... .. ............ ... .......... .. ............ 38 11.3 Patient Numbers ...... ................................................................................ 38 11.4 Patients Selection (In- and Exclusion) .............. ..... ...................................... 39 11.5 Withdrawal Criteria ............ .. ........ ..................... .. ...................................... 40

11.6 I nvestigational Products .. ..... ....... ... ...... ............. .......... ........... .. ................. 41 11.7 Study Procedures ...................... ............................ .... ................. ........... ... 44 11.8 Efficacy Evaluation ....... .. ........... .. ... .................. ............. ........................... 53

11.9 Safety Evaluat ion .. ...... ................. ..... ... ................ ................... ..... ............ 53 11. 10 Quality Assurance/Audit .......... .... ....... .... ....... ............................................ 54 11.11 Data Handling .......................................................................................... 54 11.12 Statistical Analysis .................... ... ....... .. ................................... ........... .. ... 54

12 STUDY PERIOD ........... ... ................................................................................... 57

12.1 Study Dates ......... .. ... ........................... .... ... .............. ...... .................. ...... 57 12.2 Unblinding of the Study ................. .................... ....... .. ......................... ...... 57

13 STUDY POPULATION .. .. ............. ... .. ... ..... ......... ... .. .... ......... .. ............................... 59

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13.1 Patient Disposition .......... .... ..................................................................... 59 13.2 Protocol Deviations .................. ................................................................ 60

14 EFFICACY EVALUATION ..................................................................................... 61

14.1 Data Sets Analysed .................................................................................. 61

14.2 Demographic and Other Baseline Characteristics ......................................... 61 14.3 Treatment .............................................................................................. 66

14.4 Efficacy Results ....................................................................................... 67

15 SAFETY EVALUATION ........................................................................................ 69

15.1 Evaluation of Photosensitivity .................................................................... 69 15.2 Duration and Extent of Exposure to Trial Medication ..................................... 74

15.3 Adverse Events Reported .......................................................................... 75 15.4 Deaths, Other Serious Adverse Events and Other Significant Adverse Events .. 77 15.5 Laboratory Data ...................................................................................... 77

15.6 Vital Signs, Physical Findings and Other Observations Related to Safety ......... 78 15.7 Safety Results ......................................................................................... 78

16 DISCUSSION ................................................................................................... 79

16.1 Summary of Results ................................................................................. 79 16.2 Design and Conduct of the Study ................. .............................................. 79 16.3 Interpretation of Study Results .................................................................. 80

17 CONCLUSIONS .................... ....... ...................................................................... 81

18 REFERENCES ................................................................................................... 83

19 UST OF APPENDICES ........................................................................................ 85


5 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

5.1 liST OF ABBREVIATIONS

AE Adverse Event

CCPPRB Comite Consultatif de Protection des Personnes dans Ia Recherche Biomedicale

(Consultative Committee for the Protection of Persons in the Biomedical Research) -CRF

CRO

GCP

ICH

IEC

IRB

l /cm2

LCPC

MED

N/ A

SAE

UVA

UVB

Case Report Form

Contract Research Organisation

Good Clinical Practice

International Conference on Harmonization

Independent Ethics Committee (in this case CCPPRB)

Institutional Review Board (in this case CCPPRB)

Joules per square centimetre

local Clinical Project Co-ordinator

Minimum Erythema Dose

Not Applicable

Serious Adverse Event

Ultraviolet A (320-400 nm)

Ultraviolet B (280-320 nm)

5.2 DEFINITION OF TERMS

Adverse Drug Reaction (ADR)

In the pre-approval clinical experience with a new medicinal product or Its new usages,

particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug

reactions. The phrase responses to a medidnal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.

Regarding marketed medicinal products: a response to a drug which is noxious and

unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a

pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign

of86 3 June 2003 MCB 0204 FR

(including an abnormal laboratory finding), symptom, or disease temporally assodated with the use of a medicinal (investigational) product, whether or not related to the medicinal (Investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

Audit

A systematic and Independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were

recorded, analysed and accurately reported according to the protocol, Sponsor's standard

operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement( s).

Case Report Form

A printed, optical, or electronic document designed to record all of the protocol required Information to be reported to the sponsor on each trial subject.

The term Is synonymous for Case Record Form.

Concomitant Medication

Any medication taken by a subject apart from the investigational product(s).

Contr•ct Research Ofllan/SIItion (CRO)

A person or an organisation (commerdal, academic, or other) contracted by the Sponsor to perform one or more of a sponsor's trial-related duties and functions.

Direct Access

Permission to examine, analyse, verify, and reproduce any records and reports that are Important to evaluation of a dlnical trial. Any party (e.g., domestic and foreign regulatory

authorities, sponsor 's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the

confidentiality of subjects' identities and sponsor's proprietary information.

Enrolled Subject

A patient/subject who has signed an informed consent and been assigned a CRF number.

Essentl•l Documents

Documents which individually and collectively permit evaluation of the conduct of a study

and the quality of the data produced.

MCB 0204 FR 3June 2003 Page 19 of86

Fraud

Fabrication of data, selective and undisclosed rejection of undesired results, substitution with fictitious data, deliberately incorrect use of statistical methods for the purposes of reaching other conclusions than those ·warranted by the data, misinterpretation of results and

conclusions, plagiarism of results or entire articles from other researchers, misrepresentation of other researchers' results, unwarranted authorship, and misleading application for positions or funds.

Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

Informed Consent

A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the

subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.

Inspection

The act by a regulatory authority(ies) of conducting an official review of documents, facilit ies, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the Sponsor's and/or contract

research organisation's (CRO's) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).

Investlglltional Product

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorisation when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Investiglltor

A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted

by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Subinvestigator.

Investigator Agreement

A contract between LEO and an investigator specifying the conditions for the co-operation in

the clinical trial and the Investigators' responsibilities.


Investigator's Brochure

A compilation of the clinical and non-clinical data on the Investigational Product(s) which is relevant to the study of the Investigational Product(s) in human subjects.

Investigator Staff Signature Form

A form on which sub-investigators and other trial-related site staff sign and date and the

Investigator authorises their t rial -related tasks/duties.

Investigator Trial File

The collection of t rial documents required by LEO GCP SOPs, ICH Guidelines and/or regulatory requirements to be on file at the investigator site.

Local Clinical Project Co-ordinator (LCPC)

The person appointed by LEO to be the national representative responsible for all aspects of

a clinical trial within a country.

Monitor

A person appointed by LEO to carry out monitoring of a clinical trial.

Monitoring

The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted,

recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requ/rement(s).

Patient Identification List

A summary list kept in the Investigator Trial File that records all of that Investigative centre's enrolled patient's names, CRF book numbers and information to enable the patient to be

contacted .

Patient Screening Log

A document which identifies patients/ subjects who entered pre-trial screening.

Pat ient Study Card

A card given to a patient by the investigative centre at the t ime a patient is enrolled into the clinical trial, t o identify that the patient is participating in a clinical t rial.


Principal Clinical Project Co-ordinator (PCPC)

The person appointed by LEO to be the main international representative responsible for all aspects of a clinical trial.

Protocol

A document that describes the objective(s), design, methodology, statistical considerations, and organisation of a trial. The protocol usually also gives the background and rationale for

the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments.

Protocol~endn1ent

A written description of a change(s) to or formal clarification of a protocol.

Quality Assurance (QA)

All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).

Quality Control (QC)

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.

Randonllsat/on

The process of assigning trial subjects to treatment or control groups using an element of

chance to determine the assignments in order to reduce bias.

Randomisation Code List

A list of (sequential) numbers to each of which a treatment is allocated (assigned) . Treatment may be revealed as a code letter (e.g., A, B, ... ) or by directly revealing the

specific treatment (Investigational Product, e.g. : Calcipotriol ointment).

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (S-ADR)

Any untoward medical occurrence that at any dose:

• results in death,

• is life-threatening,

• requires inpatient hospitalisation or prolongation of existing hospitalisation,

• results in persistent or significant disability/incapacity,

• is a congenital anomaly/birth defect,

- - - · - - ------ --- -------------

of86 3 June 2003 MCB 0204 FR

or

• other medically important condit ions.

Source Data

All information in original records and certified (dated and signed) copies of original records of clinical findings, observations, or other activities In a clinical trial necessary for the

reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

Source Documents

Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy dispensing

records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories

and at medico-technical departments involved in the clinical trial).

Sponsor's Medical Expert

A medically qualified person appointed by the Sponsor to be Sponsor's responsible on medical questions for a trial.

Statistical Analysis Plan

A document that contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data (ICH E9).

Study

A synonymous term for trial.

Subinvutlgator

Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also

Investigator.

Treatment Code Envelope

A sealed letter/envelope containing the direct information about an individual subject's treatment/Investigational Product.

MCB0204 FR 3 June 2003 Page 23 of86

Unexpected Adverse Drug Reaction (U·ADR)

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved Investigational Product

or package insert/summary of product characteristics for an approved product). (See the

Guideline for Cl inical Safety Data Management, Definit ions and Standards for Expedited Reporting).

of86 3 June2003 MCB 0204 FR


6 ETHICS

6.1 INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB)

• The protocol and any relevant amendments were approved by/received favourable opinion from relevant Institutional Review Boards (IRB)/Independent Ethics Committees (lEC) prior to enrolment of subjects.

• The appropriate Regulatory Authority(ies) approved or was notified about the t rial, as required.

6.2 ETHICAL CONDUCT OF THE TRIAL

• The t rial was conducted to conform with the principles of the Declaration of Helsinki as adopted by the 18th World Medical Assembly, 1964, and subsequent amendments.

• The trial was conducted in accordance with the principles of GCP.

Consent was obtained from the subjects to record, collect, process and transfer (to EU and

non-EU countries) data. Such data wi ll be handled in accordance with the EU Data Protection Directive (95/46/EC}.

6.3 PATIENT INFORMATION AND INFORMED CONSENT

All subjects received written and verbal information concerning the trial. This Information emphasised that participation in the trial was voluntary and that the patient could withdraw from the trial at any time and for any reason. All subj ects were given opportunity to ask

questions and were given sufficient time to consider before consenting.

• The subject's signed and dated informed consent to participate in the trial was obtained

prior t o any trial related procedure being carried out. A representative patient information and informed consent is provided in Appendix V.

The above was also included specifically in the individual "Investigator's Agreement " signed

by the investigators.

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MCB 0204 FR 3 June 2003

7 STUDY ADMINISTRATIVE STRUCTURE

7.1 REPORT AUTHOR(S)

LEO Pharma

Industriparken 55

DK-2750 Sallerup

Denmark

LEO Pharma

Industriparken 55

DK-2750 Sallerup

Denmark

MSc Pharm

Mathematical-Statistical Department

LEO Pharma

Industriparken 55

DK-2750 Sallerup

Denmark

Page 27 of86


7.2

7.2.1

7.2.2

Sub-I nvestigator

France

• •

MD

INVESTIGATORS AND TRIAL CENTRES AND CROS

INTERNATIONAL CO-ORDINATING INVE5nGATOR

The International Co-ordinating Investigator was responsible for approval of the study

protocol, CRF and report, on behalf of all investigators, and as agreed to in an International Co-ordinating Investigator Agreement.

France

• • NATIONAL CO-ORDINATING INVESTIGATOR

The National Co-ordinating Investigator was responsible for national issues relating to the study as agreed to in the National Co-ordinating Investigator Agreement.

France

• •


7.2.3

7.2.4

INVESTIGATOR

The Investigator was responsible for the complete trial conduct at his site, and as agreed to in an I nvestigator Agreement signed off prior to t rial initiation.

France

• . .... If Sub-investigators were delegated trial related dut ies, this was documented on the

"Investigator Staff Signature Form". The complete list of all participating (Sub)Invest.igators is provided in Appendix VIII.

CONTRACT RESEARCH 0RGANISATION(S)

Not applicable for this study.

7.3 COMPANY PERSONNEL

7.3.1

On behalf of LEO, only the Medical Director, LEO, the Medical Director, Dermatology and the Head of Mathematical-Statistical Department, LEO were authorised to approve the Protocol and any subsequent Protocol Amendments.

PRINCIPAL CUNICAL PROJECT CO-ORDINATOR (PCPC)

LEO Pharma

I ndust riparken 55

DK-2750 Ballerup

Denmark

of86 3 June 2003

7.3.2

7.3.3

7.3.4

LOCAL CUNICAL PROJECT Co-oRDINATOR (LCPC)

~,MD

Laboratoires LEO S.A.

BP 311

F-78054 St. Quentin Yvelines Cedex

France

SPONSOR'S MEDICAL EXPERT

-MD

, Dermatology

LEO Pharma

Industriparl<en 55

DK-2750 Ballerup

Denmark

STUDY STATISTICIAN

, MSc Stat

Statistical Department

LEO Pharma

Industriparken 55

DK-2750 Ballerup

Denmark

MCB 0204 FR

MCB 0204 FR 3 June 2003

7.3.5 MEDICAL DIRECTOR, PHARMACOVIGILANCE, LEO

, Pharmacovigilance

LEO Pharma

Industriparken 55

DK-2750 Ballerup

Denmark

Page 31 of86

of86 3 June 2003 MCB 0204 FR


8 INSURANCE AND LIABILITY

The patients in the present study were covered by the product and general liability Insurance

of LEO Pharma or LEO itself in the event of trial related injury or death, in accordance with applicable law and with the CPMP Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) of 17 July 1996.

9 INTRODUCTION AND RATIONALE

9 .1 PSORIASIS

Psoriasis is one of the most common chronic skin diseases, with a prevalence generally estimated at between 2-3% of the population [1,2]. It is characterised by sharply

marginated areas of affected skin which appear thickened, red and scaly, and may Itch. This appearance is produced by a greatly increased rate of epidermal proliferation with impaired

differentiation of keratinocytes. Denmal capillaries are dilated and there is infiltration of the skin with immunologically active cells [ 3,4]. The pathogenesis is not well understood, and controversy stil l exists as to whether the primary abnormality resides in the epidenmal

keratinocytes, dermal fibroblasts, cells of the immune system, blood vessels, or a combination of these [3,4).

Psoriasis can be managed by topical therapy, phototherapy, systemic therapy and/or any

combination of these options. Most patients receive topical therapy. The commonly used topical agents include calcipotriol, corticosteroids, tar products and dithranol, with the first two options predominating. Systemic treatments and phototherapy are generally reserved

for extensive disease. Such disease is very time-consuming and expensive to treat with topical therapies, and so warrants the extra toxicity risks associated with systemic treatment. The most commonly used are psoralen combined with UVA (PUVA), UVB, (broadband or narrow-band) methotrexate, vitamin A derivatives and cyclosporin A [5,6].

9 . 2 INVESTIGATIONAL PRODUCT DESCRIPTION

Calcjpotrjoi

Calcipotriol is a Vitamin D analogue manufactured by LEO Pharma.

A number of short term studies have been conducted with calcipotriol ointment SO 11g/g applied twice daily. Calcipotriol ointment has been shown to be more effective than short contact dithranol [7] and coal tar treatment [8) and at least as effective as betamethasone

17-valerate 0.1% ointment [9,10]. It is well tolerated, adverse events being mainly application-related lesional/perilesional irritation which tends to be mild and subside despite continuation of treatment. Calcipotriol ointment has been widely used for once or twice daily treatment of psoriasis since it was first approved in 1991.

Long term efficacy and safety has been confinmed in 4 studies using calcipotriol ointment for up to 1 year [11, 12, 13, 14).

In all trials, the most frequently reported treatment-related adverse events were burning, stinging and tingling, occurring in up to 20% of the patients. Laboratory test results showed no treatment-related changes.

of86 3 June 2003 MCB 0204 FR

Betamethasone

Betamethasone diproplonate is a synthet ic fluorinated corticosteroid classified as a WHO

Group III steroid. It is used topically to treat psoriasis vulgaris [ 15, 16, 17]. It has been available on prescript ion world-wide for many years for once or twice daily treatment of psoriasis.

Calcjpotrtol/betamethasone combinatjon ointment

The combination product Daivobet/ Dovobet ointment contains calcipotriol SO IJg/g and betamethasone 0.5 mg/ g (as dlpropionate). Daivobet/ Dovobet ointment is the result of

the development of a suitable vehicle in which calcipot riol and betamethasone dipropionate can be combined without compromising the action of the Individual components.

Based on existing preclinical data on calcipot riol and betamethasone, animal studies on the combination product (general toxicity studies in mice and mini-pigs and local tolerance

studies in rabbits) and 5 phase I studies in healthy volunteers Daivobet/ Dovobet ointment is considered to be a safe product [ 18].

I n the overall Daivobet/ Dovobet ointment trial programme including more than 2,500 patients, approximately 10% of patients experienced a non-serious adverse reaction. The

common adverse reactions were pruritus, various skin rashes and burning sensation of skin.

Only one serious adverse reaction has been reported in the total clinical trial programme [ 18].

Six phase III clinical studies have been conducted, including in total 6,050 patients with psoriasis vulgaris, to compare:

• Daivobet/ Dovobet ointment twice daily with each of the active constituents used alone in the Dalvobet/ Dovobet ointment vehicle twice daily.

• Daivobet/ Dovobet ointment twice daily with the marketed formulations of each

constituent twice daily.

• Daivobet/ Dovobet ointment once daily with Daivobet/ Dovobet ointment twice daily and Daivonex ointment twice daily.

• Daivobet/ Dovobet ointment once daily with tacalcttol ointment once dally.

• Different Daivobet/ Dovobet ointment once daily treatment regimens with Daivonex ointment twice daily.

• Dalvobet/ Dovobet ointment once daily with each of the active constituents used alone in the Daivobet/ Dovobet oint ment vehicle once dally.

The phase III studies consistently showed that up to 4 weeks' treatment with Daivobet/ Dovobet ointment applied once or twice daily is a more effective topical

t reatment for psoriasis vulgaris with a more rapid onset of action than either active constituent used alone in the same vehicle or In an already marketed formulation. Treatment with Daivobet/ Dovobet ointment was well tolerated in that a similar proportion of patients reported adverse events with Dalvobet/ Dovobet ointment and with betamethasone dipropionate, whereas more patients reported adverse events with calcipotriol or vehicle applied alone [ 18].


9.3 STUDY RATIONALE

The present study is part of the development programme for Daivobet/Dovobet ointment

in the treatment of psoriasis vulgaris. It was performed under an Investigational New Drug (IND) aiming at a US registration of Dalvobet/ Dovobet ointment in the treatment of psoriasis vulgaris.

The potential of Daivobet/Dovobet ointment to induce phototoxic reactions after a single exposure to the skin of healthy subjects was assessed in a previous study [19], using a

methodology adapted from the "Kaidbey and Kligman" method [ 20]. In that study no phototoxic reaction was observed at any evaluation time neither for Dalvobet/ Dovobet ointment (calcipotriol SO 1-1g/g and betamethasone 0.5 mg/g (as dipropionate)) nor for the

Dalvobet/ Dovobet ointment vehicle in the 32 subjects included in the study.

The aim of the present study was to assess the photosensitisation potential of Dalvobet/ Dovobet ointment in healthy subjects after repeated application and irradiat ion

to the skin using a methodology adapted from the method described by Kaidbey and Kligman [21].

The photosensitisation testing methodology, known as the Kaidbey & Kligman test [21], is typically divided into 3 phases: a 3-week induction phase, followed by a 2-week rest phase and a one application challenge phase. The schedule for application/irradiation and rest

phase is dictated by the photosensitisation reaction which is mediated by the immune system. The induction phase is therefore followed by a rest phase in order to allow any

sensitisation reaction to eventually take place during the challenge phase. Any potential photoreaction occurring upon challenge is also expected to be delayed; patch site examination is therefore required up to 72 hours after irradiation.

During the induction phase, in order to avoid severe photo-induced erythemal reactions, irradiation was performed with twice the subject's MED during the fi rst week, and three

times the subject's MED the second and third weeks.

During the challenge phase, treated but non-irradiated test sites were also included. They allowed to distinguish between a photosensitisation reaction and a sensitisation reaction.

One untreated but ·irradiated site was also included. It allowed to distinguish between a drug

related photosensitisation reaction and a non-drug related photo-induced reaction (photosensitive subject). The untreated and non-irradiated site served as control for a possible

reaction to the occlusive patch itself (irritation).

In this study, in addition to the combination product (calcipotriol SO !Jg/g and betamethasone

dipropionate 0.5 mg/g) ointment, the ointment vehicle was added as control.

No statistical comparisons were planned in this study.

of86 3 June 2003 MCB 0204 FR

MCB 0204 FR 3 June 2003 Page 37of86

10

10.1

STUDY OBJECTIVES

PRIMARY OBJECTIVE

The objective of this study was to determine the photosensitisat ion potential of a

combination product, Daivobet/ Dovobet ointment, containing calcipotriol SO J.lg/g and betamethasone O.S mg/g (as dipropionate) and its ointment vehicle after repeated applications and Irradiations to the skin of healthy subjects.

11 INVESTIGATIONAL PLAN

The entire Study Protocol is presented in Appendix I and t he unique pages of the CRF Book are presented in Appendix II.

11.1 STUDY DESIGN

Overall Study Design

This was a phase I, single-centre, randomised, Investigator-blinded, vehicle-controlled study

with intra-individual comparison of Daivobet/ Dovobet ointment (calcipotriol SO J.lg/g and

betamethasone O.S mg/g (as dipropionate) versus its ointment vehicle.

I ndividual Phases

Screening Period

The investigator evaluated subject eligibility at a screening visit, 0 to 14 days before start of the induction phase, after having given the subject written and verbal information and having obtained signed information consent.

Induction Phase

The minimal erythema dose (MED) was determined for each subject within Day 1 and Day 2

visits using full spectrum UV light. The 2 investigational products were applied under occlusive patches to 2 test sites on the subject's back during 24 hours, twice weekly for 3 weeks (one site remained unt reated). Twenty-four hours after product application the patches were removed and the test sites were irradiated. The irradiation dose was twice the subject's MED during the first week, and three times the subject's MED the second and the

third week, using a total spectrum of UV light (UVA + UVB solar simulated spectrum). According to the study visit schedule, skin reactions were assessed before application of invest igational products and before irradiation of the sites.

Rest Phase

Two weeks without product application/irradiation.

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11.2

11.3

Challenge Phase

Two sets of the 2 products were applied to 4 new sites on the mid back, 24 hours under

occlusive conditions. Two untreated but occluded sites were used as well. Only 1 set of test sites (left side of the back) was irradiated with 0. 75 MED full spectrum UV light followed by 4 J/cm2 UVA light. The non-irradiated sites served as a control for a possible contact sensitisation. Skin reactions (erythema score ± other local reactions) were scored after

product removal but before irradiation, and then 24, 48 and 72 hours after end of irradiation.

follow-uo Vjsjt

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 are 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 discretion.

Study Oyerv;ew

Phase Screening Induction Rest Phase Challenge Follow-up Period Phase Phase Visit (if

required*)

Days or -14 to 0 days Week 1, 2, 3 Week4, 5 Week6 Week 8 weeks

Visit 1 screening Visits on day No visits Visits on day follow-up

visit 1, 2, 4 and 5 1-5 visit

* Only 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 possibly probably related to trial drugs or not assessable. Telephone contact or visit

according to the Investigator's discretion.

TIME SCHEDULE

Planned date of inclusion of fi rst subject:

Planned date of inclusion of last subject:

Planned date of completion of last subject:

PATIENT NUMBERS

August 2002

September 2002

October 2002

A total of 32 subjects were enrolled In the study. The number was selected based on the recommended sample size of 30 subjects in guidance from the FDA on the photo-allergy test.


11.4

11.4.1

11.4.2

PATIENTS SELECTION (IN- AND EXCLUSION)

INCLUSION CRITERIA

1. Healthy male or female subjects, 18 to 65 years old inclusive.

2. Subjects without signs of irritation (erythema, dryness, roughness or scaling) on test areas.

3. Female subjects of childbearing potential had to use a reliable contraceptive method (oral contraceptive pill, intrauterine device, bilateral tubal ligation) for at least two months before the start of the study and had to accept to continue this method during

the study; or of non childbearing potential i.e., post-menopausal (one year without menstrual period, hysterectomy or bilateral ovariectomy).

4. Female subjects of chi ldbearing potential with a negative urinary pregnancy testing before enrolment into the study.

5. Subjects registered with Social Security in agreement with the French law (Huriet law; no 88.1138- 20.12.88) on biomedical research.

6. Subjects will ing to follow the study procedures and complete the study.

7. Subjects having understood and signed a written Informed consent.

EXCLUSION CRITERIA

1. Females who are pregnant, breast feeding or who are planning a pregnancy during the course of the trial.

2. Abnormal pigmentation of the skin, or skin type that could, in any way, confound interpretation of the study results (skin type V and VI on the Fitzpatrick scale} [22].

3. Any systemic or cutaneous disease that in any way could confound interpretation of the

study results (e.g. atopic dermatitis, eczema, psoriasis).

4. Known sensitivity related to any component of any of the formulations being tested (see ingredients listed in the Investigator's Brochure).

5. History of or active photo-induced or photo-aggravated disease (abnormal response to the sun light).

6 . Exposure to excessive or chronic UV radiation (i.e. sunbathing, tanning salon use, phototherapy) within 4 weeks prior to Inclusion, or planned during the study period.

7. Scars, moles, sunburn, or other blemishes in the test area which could interfere with grading.

8. Involvement in any investigational protocol (drug or device) within 3 months prior to the study.

9. Subjects who are In the exclusion period In the Healthy National Register of the French Ministry of Health.

10. Subjects protected by the Law (prisoners, guardian ships).

11. Use of:

* systemic drugs which may interfere with the inflammatory reaction such as

corticosteroids and other anti-inflammatory drugs, within 2 weeks prior to inclusion,

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11.4.3

11.5

*

*

systemic or topical medications suspected of causing photobiological reactions, such as tetracycline, thiazides and fluoroquinolones, within 1 month prior to Inclusion,

any other medication which would interfere with the study results, in particular topical drugs applied on the test site.

Unaythorjsed Treatments

Use of drugs listed under section 'Exclusion Criteria' point 11 may invalidate the subject's participation in the study.

Information on previous therapies that may have an Impact on inclusion/exclusion criteria should be recorded in the subject's medical record.

Information on concomitant therapy should be recorded on the Concomitant Therapy Form of the CRF. Any therapy used by the subject will be considered concomitant therapy; e.g.

aspirin, vitamins, etc. every attempt should be made to keep concomitant therapy dosing constant during the study. Any change to concomitant therapy should be noted on the Concomitant Therapy Form.

PATIENT REGISTRATION

At visit 1, each patient was assigned a "subject identification number", which was written by

the investigator on each copy of each page on the CRF used for that subject.

WITHDRAWAL CRITERIA

Patients could withdraw for any of the following reasons:

1) Voluntary withdrawal: Patients were free to withdraw from the study at any t ime and

for any reason.

2) Medical reasons: The investigator was free to withdraw the patient at any time for

medical reasons.

3) Adverse events: Any adverse event that the investigator or the patient considered

unacceptable.

4) Exduslon criteria: Any exclusion criteria that were emerging/becoming apparent during

the patient's participation in the study.

Reason(s) for withdrawal were to be recorded in the Case Report Form.

Patients withdrawn were not to be substituted.


11.6 INVESTIGATIONAL PRODUCTS

Brand name/Name Investigational Product

Formulat ion

Active Ingredient name and concent ration

Excipients

Pack Size(s)

Manufacturer's name

Supplier's name

Certifier's name

'[Brand name/Name Investigational Product]

Formulation

Active Ingredient name and concentrat ion

Excipients

Pack Slze(s)

Manufacturer's name

Supplier's name

Certifier's name

Lot number(s)/expiry date

Dalvobet/Dovobet

Dalvobet/ Dovobet vehicle

Ointment

NLA

Paraffin, Liquid Polyoxypropylene-15-Stearyl Ether a-Tocopherol White Soft Paraffin

50 g tubes

LEO Pharma

LEO Pharma

LEO Pharma

--2002.11

11.6.1 ADMINISTRATION OF INVESTIGATIONAL PRODUCTS

Route of Administration Topical occlusive (application under 12 mm diameter Finn Chambers®)

Dosing Range !lO IJI per test site, 24-hour application (twice

weekly for 3 weeks in induction phase and once in the challenge phase)

Daily Maximum 50 IJI (one test site per investigational

product) induction phase and 100 IJ I (two test sites per investigational product) challenge phase

Time of day for dosing N/A

Relation of time of dosing to dietary intake N/A

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11.6.2 TREATMENT AssiGNMENT

The "subject Identification number" assigned at screening corresponded to the chronological order of first application of investigational products.

The investigational products and the absence of treatment were coded, from A to C. Upon initiation, each of the 2 products was randomly applied on the back of two of the three zones

(Zl to Z3) according to a randomisation list. This randomisation list was generated by LEO Pharma using the Latin square design and provided to the designated personnel applying the investigational products.

The following diagram illustrates an example of product application randomisation and patch site location.

Induction Phase

8 8 8 No test site

(right side)

During the challenge phase, six previously untreated test sites were selected.

The three sites located on the left side of the spine received Irradiation. Those three located on the right side served as non-irradiated control sites.

Each product was symmetrically applied on each side of the back.

Challenge Phase

8 8 8

Irradiated Side

(left side)

8 8 8 Non-irradiated side

(right side)

11.6.2.1 Randomisation Code List

During the t rial, the content of tubes A and B (Daivobet/Dovobet ointment or Dalvobet/Dovobet ointment vehicle) was only known by two parties: the Investigational Product Packaging Manager, LEO and the R&D, Quality Assurance Department, LEO. The t reatment code was kept inaccessible to all persons involved with conduct/administration of

the trial.


11.6.3 BLINDING OF STUDY

The Investigator evaluating the test sites was kept blind as to treatment assignment. Thus,

product application and product removal were made by a third person (the study assistant). In addition, access to the randomisation list was limited to the designated third person responsible for product application.

11.6.4 UNBUNOING OF THE STUDY

11.6.4.1 Unbllnding of Individual Patient Treatment During the Study

Two sealed treatment-code envelopes containing the product Identificat ion corresponding to the products coded A or B were supplied to the Investigator with the test materials.

The code was sm.lll to be broken in an emergency wherein Investigational Product ident ification was necessary. In such an event, it was important that the date and the reason for opening the envelope was recorded on the appropriate page in the CRF. Additionally, the following information should be recorded directly on the outside of the envelope:

1. Date of opening

2. Reason for opening

3. Opened by

4. Date of re-sealing.

An opened treatment code envelope was to be re-sealed as soon as possible after opening.

All treatment code envelopes originally delivered to the - from LEO Pharma were accounted for and collected by the study monitor at the end of the trial. All treatment code

envelopes were collected by LEO Pharma prior to unbllnding the study.

11.6.4.2 Unbllnding of the Study

11.6.5

The trial was fully unblinded only once a final validated database was available, all treatment

code envelopes were accounted for, the statistical analysis specified in this protocol was reviewed in relation to the blinded data actually obtained and the Statistical Analysis Plan had been approved.

This documentation was given to the R&D, Quality Assurance Department before the randomisation schedule was released from the R&D, QA Department to the study statistician.

DRUG ACCOUNTABIUTY AND COMPLIANCE CHECKS

Upon receipt of the clinical supplies, the designated study personnel performed a complete

inventory of all investigational products, completed and returned the I nvestigational Product Delivered Form together with the temperature records to LEO Pharma and assumed responsibility for storage and dispensing of investigational products. In accordance with ICH

GCP guideline, the Investigator or the designated study personnel kept all investigational products in a secure location with restricted access.

No investigational products were dispensed to the subjects. Product applications were performed at the study by the designated study personnel. All supplies sent to the Investigator were accounted for and in no case used In any unauthorised situation. All used

of86 3 June 2003 MCB 0204 FR

11.6.6

11.7

and unused supplies were appropriately inventoried, returned to LEO Pharma using the Investigational Product Returned Form (in collaboration with study monitor) and disposed by LEO Pharma or its designee.

PRIOR AND CONCOMITANT TREATMENT

Use of concomitant medication was recorded in the subject's medical record and in the CRF

{drug name, dose, indication and dates of start and stop). Any therapy used by the subject was considered concomitant medication (e.g . aspirins, vitamins) . Every attempt was made to keep concomitant medication dosing constant during the study. Any change in concomitant

medication was noted In the CRF.

Use of systemic drugs that might Interfere with the inflammatory reaction such as corticosteroids 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

applied on the test area, were not permitted.

STUDY PROCEDURES

Schedule of Study Procedures is shown on the next page.


11.7 .1 SCHEDULE OF STUDY PROCEDURES

Screening Period (Day -14 to Day 0)

Informed Consent X

Medical History X

Demographics X I nclusion/Exclusion Criteria X

Pregnancy Test for Females X

INDUCTION PHASE (Weeks 1, 2 and 3)


Inclusion/Exclusion Criteria Check X

UV Irradiation forMED ( Week 1 only)

Assessment of Exposed Sites (22- MED 24 hours after irradiation) for MED (Week 1)

Determination

Products Application X X

Patches Removal X X

Site Evaluation X (except X X X week 1)

UV Irradiation X X

Adverse Event/Concomitant X X X X Medications

REST PHASE ( Weeks 4-5)


No Application/No Visits

CHALLENGE PHASE {Week 6)


Products Application X

Patches Removal X

Site Evaluation X X X X

UV Irradiation (0.75 MED + 4 J/cm2 X UVA)

Adverse Events I Concomitant X X X X X Medications

FOLLOW-UP VISIT* (Week 8)

Adverse Events X

*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.

of86 3 June 2003 MCB 0204 FR

Screening Phase

The investigator evaluated el igibility at a screening visit 0 to 14 days before start of the

induction phase after having given the subject written and verbal information and having obtained signed informed consent.

Induction Phase

The Minimal Erythema Dose (MED) was determined for each subject within Day 1 and Day 2 visits using full spectrum UV light.

The 2 investigational products were applied under occlusive patches to 2 test sites on the subject's back during 24 hours, twice weekly for 3 weeks (1 site remained untreated). Twenty-four hours after product application the patches were removed and the test sites

were irradiated. Before removal of the patches, it was recorded whether they were in place.

The irradiation dose was twice the subject's MED during the first week, and 3 t imes the subject's MED the second and the third week, using a total spectrum of UV light (UVA+UVB

solar simulated spectrum). According to the study visit schedule, skin reactions were assessed before applicat ion of Investigational products and before irradiation of the sites.

Rest Phase

Two weeks without product application/irradiation.

Challenge Phase

Two sets of the 2 products were applied to 4 new sites on the mid back, 24 hours under occlusive conditions. Two untreated but occluded sites were used as well. Only 1 set of test sites (left side of the back) was irradiated with 0.75 MED full spectrum UV light followed by 4 J/ cm2 UVA light. The non-irradiated sites served as a control for a possible contact sensitlsation. Skin reactions (erythema score :1:: other local reactions) were scored after

product removal but before irradiation, and then 24, 48 and 72 hours after end of irradiation.

Follow-up Visjt

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 is 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.

Assessments

• Erythema reactions on each test site were assessed using a 5-point scale during induction and challenge phases. Skin reactions were assessed in the challenge phase using a Global Cl inical Score (5-point scale) .

• Other local reactions were reported .

• At the end of the study, the Investigator evaluated the occurrence of a possible photosensit isation reaction.


• Adverse events were reported individually.

Subjects Instructions

Each subject received instructions as to specific requirements or instructions to follow while participating in the study. All subjects were asked to refrain from wetting the test sites.

Showers on the front of the body were permitted. Swimming and vigorous exercises which

may result in excessive sweating were to be avoided, as well as sunlight or UV light exposure of the patched areas.

Light Irradiation Procedures

UV Radiation Source and Radiometer

The light source was produced by a solar simulator equipped with a high-pressure Xenon

vapor lamp which delivers a continuous spectrum from 240 to 1100 nm (Solar simulator IDEM 3000 [ . A set of filters allowed

the selection of the useful spectral bands (UVA, UVB, visible light) and a decrease of the infrared irradiation emission. The spectrum simulation was obtained with filter combination WG320/1.5 m and UGll/1 mm.

For the UVA irradiation, the UVB component of the spectrum was eliminated by using a WG 335 (3 mm) filter . The infrared filtration was reinforced with the UGll/1 mm filter placed in a water filter.

The lamp was switched on 15 minutes before the first irradiation. A light intensity check was

made prior to each irradiation with a UV-meter SOLAR UGHT ( ••••••••••• USA) with 2 photosensitive cells: 1 for UVA (320-400 nm) and 1 for UVB (280-320 nm).

MED Determination

The Minimal Erythema Dose (MED) was determined within Day 1 and Day 2 visits using the Solar simulator described above. A series of 6 UV irradiation exposures (expressed as Joules per square centimetre) was administered to an unprotected area of the back that was not designated as a patch area during evaluation of the Investigational Products. The doses selected were a geometric series of exposures wherein each exposure time interval was 25

percent greater than the previous time.

The MED was determined 22 to 24 hours after irradiation. The subject was graded in a prone

position. The MED was determined as the smallest dose of energy that produced a perceptible redness reaching the borders of the exposure site (patch) at 22 to 24 hours postexposure for each series of exposures.

UVA/UVB Irradiation

The irradiation of the subject was done with the same simulator as that used for MED determination. Prior to irradiation, excess Investigational Product was removed with a dry

gauze pad.

The left set of 3 patch areas was irradiated with 20 J/cm2 UVA. Following irradiation with UVA, the fi lter was removed from the light source and the irradiated patch sites were further

of86 3 June 2003 MCB 0204 FR

11.7.2

exposed to 0.75 t imes the MED of UVA/UVB radiation determined for each subject. The set of test areas on the right side served as a non-irradiated control.

PAnENT ELIGIBILITY

At screening, the patient's eligibility for the study was determined by visual examination of the skin and confirmation of all inclusion and exclusion criteria. The skin type was

determined and a general physical examination was performed. Patients' demographic details (date of birth, sex, height and weight), medical history, concomitant diagnoses and medication were recorded.

The Investigator confirmed the eligibility of the subject by signing the CRF.

11.7.3 CUNICALAssESSMENT

11.7.3.1 Inve•tlgator Msessments

The (sub)lnvestigator was to make the following clinical assessments:

Induction Phase Eyaluatjon

Skin reactions were assessed before application of Investigational products and prior to

irradiation of the test sites, using the following scale:

Grading scale of erythema

0 No reaction


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 In the CRF book, 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 following two

scales:

Global Clinical Score

0 Normal skin aspect

0.5 Equivocal reaction

1 Slight erythema with small papules and/or slight oedema

2 Moderate erythema with papules and/or vesicles and/or oedema

3 Intense erythema, oedema, confluent vesicles forming blisters

MCB 0204 FR 3 June 2003 Page49 of86

11.7.4

Challenge grading scale of erythema

0 No reaction


1 Mild erythema

2 Moderate erythema

3 Severe erythema

Other signs of skin reactions such as spreading of reaction beyond the patch area (S), dryness (D), cracking C), peeling (Pe) and others were recorded in the CRF book, 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 zone number.

Photosensitisation reaction

The investigator assessed the occurrence of a possible photosensltisation reaction 72 hours after Irradiation by evaluating each test site in comparison with the corresponding non

irradiated test site and the untreated irradiated test site, using the following categories:

0 Negative

1 Equivocal

2 Positive

ADVERSE EVENTS

Adverse Event (AE): any untoward medical occurrence in a patient or clinical Investigation subject administered a pharmaceutical product and which does not necessarily have a causal

relationship with the treatment. An adverse event (AE) can therefore be any unfavourable

and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

Adverse Drug Reaction (ADR): in the pre-approval clinical experience with a new

medicinal product or Its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product

means that a causal relationship between a medicinal product and an adverse event is at

least a reasonable possibility, i.e., the relationship cannot be ru led out.

Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or

therapy of diseases or modification of physiological function (see the ICH Guideline for Clinical Safety Data Management : Definitions and Standards for Expedited Reporting).

At all visits after treatment start, the subject was asked a non-leading question by the

investigator: "Since I last saw you, have you had any problems?".

No specific symptoms was asked for.

of 86 3 June 2003 MCB 0204 FR

If the answer was "NO", no further questions were asked. If the answer was "YES", the investigator recorded the event's nature, intensity, duration, location for cutaneous adverse

events, suspected causal relationship to the Investigational Product and outcome.

It was important t hat the investigator also observed the subject for any changes not reported by the patient and recorded these changes.

11.7.4.1 Reporting of Adverse Events

Events either reported by the subject, or observed by the investigator, that fall Into any of

the above definitions were to be recorded on the adverse event page of the CRF book and described in the following manner:

The NATURE of the event was to be described in precise, standard medical terminology (i.e., not necessarily the exact words used by the subject). If known, a specific diagnosis should

be stated (e.g., allergic contact dermatitis).

The INTENSITY of the event was described in terms of mild, moderate or severe according to the investigator's clinical judgement.

mild. The adverse event does not interfere in a significant manner with the subj ect's normal functioning level. It may be an annoyance.

moderate. The adverse event produces some impairment of functioning but is not hazardous to health. It is uncomfortable and/or an embarrassment .

severe. The adverse event produces significant impairment of functioning or incapacitation and/or it is a hazard to the subject.

The DURATION of the event was described by the start date and end date.

The LOCATION for cutaneous adverse events may be described as either the face, scalp or trunk/limbs. Furthermore, it was Indicated in terms of lesional/perilesional (.:2 em from the border of lesion(s) treated with invest igational product) or distant (>2 em from the lesional border).

The CAUSAL RELATIONSHIP of the event to the use of the Investigational Product was described in terms of probable, possible, not related or not assessable according to the

investigator's clinical judgement .

Probable

follows a reasonable temporal sequence from administration of the invest igational product

could not be reasonably explained by t he subject's clinical state, environmental or toxic factors or other therapies administrated to the subject

disappears or decreases on cessation or reduction in dose of the invest igational product

follows a known pattern of response to the Investigat ional product

reappears or worsens upon rechallenge

Possible

follows a reasonable temporal sequence from administration of the Investigational product


11.7.5

could be reasonably explained by the subject's clinical state, environmental or toxic factors or other therapies administ rated to the subject

follows a known pattern of response to the investigational product

Not related

does D..Q! follow a reasonable temporal sequence from administration of the investigational product

could be reasonably explained by the subject's clinical state, environmental or toxic factors or other therapies administrated to the subject

does DQJ; follow a known pattern of response to the investigational product

does nsn reappear or worsen upon rechallenge

Not asseS8able

the adverse event cannot be judged otherwise yet because present Information is

insufficient or contradictory. A final judgement should be made as more information becomes available.

The OUTCOME of the event was described In terms of:

Recovered/ resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Unknown

Fatal

During the trial, all serious and non-serious adverse events were to be followed-up to

determine the final outcome.

Once a subject had completed the trial, the investigator should follow-up for outcome on ali adverse events classified as possibly/probably related to trial drug or not assessable for 2 weeks or until final outcome was determined whichever came first.

Pregnancy

Pregnancy, which occurs during a clinical trial with an investigational product, must be reported to LEO by use of the Serious Adverse Event (SAE) Form • Clinical Trial, and handled

as an SAE with regard to reporting time frame. All pregnancies must be followed-up until conclusion.

SERIOUS ADVERSE EvENTS

Serious Adverse Event (SAE) or Serious Adverse Drug Re.ctlon (Serious ADR) : any

untoward medical occurrence that at any dose:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability/incapacity or

of86 3 June 2003

is a congenital anomaly/birth defect, and

other medically important condition.

MCB 0204 FR

(see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

11.7.5.1 Reporting of Serious Adverse Events

Any serious adverse event, related or unrelated to the Investigational Product occurring during the course of the study was reported to LEO Pharma within .QM working day after first knowledge by the investigator.

Note: Hospitalisation or prolonged hospitalisation for logistic/convenience reasons or

hospitalisation solely for study-related purposes do not fulfi l the criteria for being an untoward medical occurrence and are therefore not a Serious Adverse Event.

The Serious Adverse Event Report was to be sent/faxed to the local LEO company.

Reports were made using the SERIOUS ADVERSE EVENT (SAE) FORM - CLINICAL TRIAL, supplied by LEO. The information provided on the form included a description of the

clinical course of the serious adverse event and an assessment of the intensity, relationship to the Investigational Product(s), the action taken and the outcome to date.

The initial report was followed by a detailed description later which may include copies of hospital records, autopsy reports and other documents when requested and applicable.

If an investigator was in doubt whether to regard an adverse event as serious or not, the

event was serious until the opposite had been established .

The Independent Ethics Committee(s) and National Health Authorities were to be notified on such an event In writing according to local law.

All serious adverse event descriptions were also recorded on the adverse event page of the

CRF book in addition to being reported on the Serious Adverse Event (SAE) Form - CUNICAL TRIAL.

For ali serious adverse events (including those ongoing at the time the subject completed the trial), the investigator should follow-up for final outcome and all queries have been resolved.

Details of follow-up should be given (e.g., discontinuation of investigational t reatment, if specific treatment was required, if hospitalisation was required etc.).

11.7.6 LABORATORY EXAMINATIONS

11.7.6.1 Central Analysis

N/A

11.7.6.2 Local Analysis

A urine pregnancy test was performed at the investigative centre in the screening period (before first product application) in female patients of child bearing potential. The test kits (Clear Blue®) were provided by-


11.7.7

11.8

11.8.1

11.8.2

11.9

11.9.1

11.9.2

CHANGES TO PLANNED STUDY PROCEDURES

No change in the conduct of the study was instituted without written approval from -

and LEO Pharma. If both parties agreed on the change, an amendment to the protocol was written and, depending on the consequence of the change, sent to the CCPRB for approval or for information only.

EFFICACY EVALUATION

PRIMARY RESPONSE CRITERION

N/A

SECONDARY RESPONSE CRITERIA

N/A

SAFETY EVALUAnON

EVALUATION OF PHOTOSENSITIVITY

Response criteria were:

1} occurrence of photosensitive reactions 72 hours after Irradiation In the challenge phase

2) Global Clinical Score assessments during the challenge phase

3) grading of erythema during induction and challenge phase

4) occurrence of other reactions during induction and challenge phase

EVALUATION OF (SERIOUS) ADVERSE EVENTS

Adverse events were categorised according to lowest level terms and System Organ Class

(primary and secondary classifications) using the Medical Dictionary for Regulatory Activities (MedORA), version 5.1, before the treatment code was broken.

The number of subjects experiencing each type of adverse event (according to the level of

the system) during the treatment period was tabulated.

The causal relationship of events to t rial medication and the intensity of adverse drug reactions were presented. The same adverse event (i.e., with the same preferred term) recorded by a subject on different occasions counted as one event for that subject. There might, therefore, have been several recordings of causal relationship and intensity for an event. In such cases, causal relationship was taken from the last report of the event (since

that is when the investigator was in possession of most information and so best able to judge causal relationship) and intensity was taken as the maximal severity recorded. If the same adverse event was recorded more than once for a particular subject, the 'most related' relationship was tabulated.

of86 3 June 2003 MCB 0204FR

11.9.3

11.10

11.11

EVALUAnON OF LABORATORY DATA

N/A

QUAUTY AsSURANCE/ AUDIT

LEO has implemented a system of quality assurance, including all the elements described In this report. Within this system company Standard Operating Procedures (SOPs) are implemented to ensure that clinical studies are conducted in compliance with regulatory requirements and Good Clinical Practice. Quality control is applied to each stage of data

handling to ensure that data are accurate, reliable and processed correctly.

Investigational sites, facilities, laboratories and all data (including sources) and

documentation were available for GCP audit by LEO or Inspection by competent authorities.

DATA HANDUNG

LEO, as Sponsor of this study, is responsible to the Authorities for assuring the proper conduct of the t rial with regard to protocol adherence and validity of the data recorded on

the Case Report Forms. Monitors were assigned to serve as the principal link between (sub)investigators and LEO and advise the Investigator in the collection and maintenance of

complete, legible, well organised, and easily retrievable data for the trial. In addition, they were to explain Investigators any aspect of the (conduct of the) trial, including interpretation

of the protocol, and purpose of collection the specified data and reporting responsibilities.

Data recorded on the CRFs was to be entered into the LEO data base as soon as possible after receipt and verification of the data by LEO had taken place.

The computerisation of the data in the CRFs was to be done by means of two data entries,

which were validated to ensure identical data entry files prior to the statistical analysis.

Data processed are handled in accordance with the EU Data Protection Directive (95/46/EC).

11.12 STAnSnCAL ANALYSIS

11.12.1 PLANNED ANALYSIS

Details of the statistical analysis planned at the start of the study are given in Section 10.8 of the Study Protocol (Appendix I). A review of the proposed analysis was made and analysis sets derived before the treatment code was broken. Details are given in the Statistical

Analysis Plan (Appendix III). A summary of the Statistical Analysis Plan is provided below.

Trial Analysis Sets

The analysis sets were determined based on the criteria in the LEO GCP I-SOP, Statistical Analysis Plan.

There were no events during the study that gave rise to exclusion of subjects from any of the analysis sets; the baseline, the Intention-To-Treat, the safety, or the per protocol analysis sets. It follows that all randomlsed subjects were defined to comprise an Intention-To-Treat analysis sets.


The decisions regarding inciusion/exclusion of subjects from the trial analysis sets were documented before the treatment code was broken.

Baseline Characteristics

Baseline characteristics were tabulated for all randomised subjects. Tables were given for

age, sex, ethnic origin, weight, height, skin type according to the Fitzpatrick Scale, physical examination, vital signs, and irradiations for MED determinations.

Continuous data were summarised using the mean, standard deviation, minimum, and maximum, while discrete data were summarised using the number and percentage of

subjects in each category.

No significance tests on baseline data were carried out.

Analysis of Safety

Occurrence of photosensitive reactions at 72 hours following radiation on the first day In the

challenge phase was tabulated by treatment site.

The Global Clinical Score, grading scale of erythema, skin reactions, and other reactions were tabulated by visit and treatment site, as well as irradiated/non-irradiated side if applicable.

General Principles

Missing values due to premature withdrawals from the study were not dealt with by end of

treatment analyses. Tabulation of results were done for each separate visit, i.e., based on

the available data.

All the analyses specified in the protocol were reviewed in relation to the blinded data actually obtained and the Statistical Analysis Plan was finalised before breaking the

randomisation code.

11.12.2 CHANGES IN THE CONDUCT OF THE STUDY OR PlANNED ANALYSES

None.

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MCB 0204 FR 3 June 2003

12 STUDY PERIOD

For individual data on subjects, see Appendix IX, Usting 1.

12.1 STUDY DATES

The first subject was enrolled

The first subject was randomised

The last subject was enrolled

The last subject was randomised

Last subject completed treatment

Last subject follow-up visit was on

19 August 2002

02 September 2002

02 September 2002

02 September 2002

11 October 2002

11 October 2002

Thus, the study had a duration of approximately 8 weeks.

For individual data on visit dates, see Appendix IX, Listing 2.

12.2 UNBUNDING OF THE STUDY

Page 57of86

The database was locked on 17 December 2002 following validation of the blinded data.

The randomisation schedule was released from the R&D, QA Department on 18 December

2002.

of 86 3 June 2003 MCB 0204 FR


13

13.1

13.1.1

13.1.2

STUDY POPULATION

PATIENT DISPOSITION

Thirty-two (32) subjects were enrolled in this study, all of which were randomised.

For individual data on randomisation and treatment allocation, see Appendix IX, Listing 3.

WITHDRAWAL PRIOR TO RANDOMISAnON

None of the enrolled subjects were withdrawn from the study prior to randomisation.

WITHDRAWAL POST RANDOMISAnON

The reasons for leaving/withdrawal from the study other than simply attending the final visit are shown in Table 1. Only one reason for leaving the study was to be given on the End of

the Study Form. In all, 30 subjects (93.8%) attended the scheduled end of treatment visit (visit 18}.

Table 1: Reasons for leaving/withdrawal from study as recorded on the End of the Study Form (m analysis set)

Reaaon for withdrawal All randomised subj ects <n•32 )

Number of subj ect s •

Adverse events 2 6. 3 Subject • s personal request 0 0 Protocol violation 0 0 t.ost t o follow-up 0 0 Sponsor termiMted study 0 0 Others 0 0

Total number of reasons for withdrawal 2

Subj ect compl eted the study 30 93.8

One subject (CRF . left the study due to a sore throat, and another subject (CRF • left the study due to colitis.

For individual data on reasons for leaving/withdrawal from study, see Appendix IX, Listing 4.

Figure 1 shows the disposition of study subjects during the study.


13.2

Flvure 1: Disposition of study subjects and reason for leaving/withdrawal from study

Enrolled at visit 1 (Oiy ·I• to Ooy O)

INDUCTION PHASE:

Randomlsed at visit 2 (Oiy I • Wool< I)

Attending visit 3 (DIY 2- WOtk I)

Attending visit 4 (Oiy 4 • Woek I )

Attending visi t 5 (Day 5 - week 1)

Attending visit 6 (Day I - WHk 2)

Attending visit 7 (Oiy 2 • WHk 2)

Attending visit 8 ( Oiy 4 - WOtk 2)

Attending visit 9 (Oiy 5 • Wllk 2)

Attending visit 10 (Oiy I - WHit 3)

Attending visit 11 (Oiy 2 - Weelc 3)

Attendlng visit 12 (Day 4 - Wool< 3)

Attending visit 13 (Oiy s - w- 3)

CHALLENGI! PHASE:

Attending visit 14 (Ooy 1 - week 6)

Attending visit 15 (Ooy 2 - WHk 6)

Attending visit 16 (Day 3 - Wook 6)

Attending visit 17 (Ooy • - w- 6)

Attending visit 18 (Dey 5 - Weelc 6)

Number of subjects

PROTOCOL DEVIATIONS

During the induction period, the assessment of erythema and other reactions after patch

removal was forgotten for one subject (CRF Ill at week 3, Day 2. This was not considered to

have any consequence for the study results.


14

14.1

14.1.1

14.1.2

14.1.3

14.2

14.2.1

EFFICACY EVALUATION

DATA SETS ANALYSED

INTENnON TO TREAT ANALYSIS SET

No events during the study gave rise to exclusion of any subjects from any of the analysis sets; the baseline, the Intention-To-Treat (ITI), the safety, or the per protocol analysis set. Throughout the report, all subjects are defined to belong to the ITI analysis set, comprising 32 subjects.

SAFETY ANALYSIS SET

N/A

PER-PROTOCOL ANALYSIS SET

N/A

DEMOGRAPHIC AND OTHER BASEUNE CHARACTERISTICS

The baseline characteristics of the 32 randomised subjects recorded at visit 1 are presented in this section.

DEMOGRAPHICS

Distributions of age, sex, weight, height, and skin type are shown in Table 2 - Table 6, respectively.

Table 2: Baseline characteristics: Aoe of subiects rrrr analysis set)

Age (years ) All randomised subjects (n•32 )

Me-an 38 .o SD l3 .l Minimum 19 Maximum 61 Number 32

Table 3: Baseline characteristics: Sex of subjects (ITT analysis set)

Sex Al l randomised subjects

Male Female Total

(n•32)

Number of subjects

1

25 32

21.9 18 .l

100 . 0

of86 3 June 2003 MCB 0204 FR

14.2.2

Table 4: Baseline characteristics: Weight of subjects (!IT analysis set)

Weight (kg ) All randomised subjects (n•32 )

Mean 64.6 so 12 . 2 Minimum 51 Maximum 95 Numbe r 32

Table 5: Baseline characteristics: Height of subj_ects (!IT analysis set)

Height (cml All ranc:lomised subjects (n•32)

Mean 166 . S SO S .l Minimum 153 Maximum 185 NUmber 32

Table 6: Baseline characteristics: Skin tvoe of subJects (liT analysis set)

Skin type (Fitzpatrick Scale)

II I I I IV Total

Al l randomised subjects ( n •32)

Number of patients

27 l

32

12 .s 84 . 4

3.1 100 .0

Individual subject demographic data are presented in Appendix IX, Ustlng 5.

PHYSICAL EXAMINAnON AND VITAL SIGNS

The distributions of the results of the various body systems of the physical examination are shown in Table 7. The vital signs are shown in Table 8 and Table 9.


Table 7: Baseline characteristics: Physical examination of subjects (ITT analysis set)

Body system

Eyes, ears , nose, throat Not done Total

Neck (:including thyroid) Normal Total

Lungs Normal Abnormal Total

Abdomen Normal Total

Nervous system Not done Total

Heart , vessels Normal Total

Lymph nodes Normal Total

Muacles, bone, joint& Not done Total

Sl<.in Normal 'Total

Genitalia Not done Tota l

All randomised subjects (n•32 )

Number of subjects

32 lOO .o 32 lOO . O

32 10 0 .0 32 100 . 0

31 96 . 9 1 3.1

32 100.0

32 100 .o 32 100.0

32 100.0 32 100 .0

32 100.0 32 lOO . 0

32 100.0 32 100.0

32 100 . 0 32 100.0

32 100. 0 32 100 .0

32 100 . 0 32 100.0

Table 8: Baseline characteristics: Blood pressure of subjects (ITT analysis set )

Blood pressure (mmHg)

Systolic Mean SD Minimum. Maximum Number

Diastolic Mean so Mini mum Maximum Number

All randomiaed subjects (n•32)

109.' 11.?

88 132

32

69 .s 7. 7

56 84 32


14.2.3

Table 9: Baseline characteristics: Heart rate of subjects (m analysis set)

Hear~ ra~e (bpm)

Mean so Minimum Maximum Number

All rall4omised subjects (n•32 )

77.6 9.8

56 100

32

For individual data on the physical examination, see Appendix IX, Listing 6.

For individual data on vital signs, see Appendix IX, Listing 5.

IRRADIAnONS FOR MED DETERMINAnON

The distribution of the intensity of irradiations and doses for MED determination are shown in

Table 10 and Table 11, respectively.

Table 10: Baseline characteristics: Intensity of irradiations for MED determination of subjects rm analysis set)

Hole Intensi~y (MED/min)

Hole 1 Mean SD M.init'I'I'Um Maximum Number

Hol e 2 Mean SD Minimum Maximum Number

Hole l Mean so Minimum Maximum Number

Hole 4 Mean so Minimum Maximum Number

Bole 5 Mean so Minimum Maximum Number

Hole 6 Mean so Mi nimum Maximum Number

All randomised subjects (n• 32)

1. 76 0.05 1. 68 1. 83

32

1. 77 o. os 1 .67 1. 83

32

l. 78 0 .OS 1.69 1.85

32

1. 73 0 . 04 1 -64 1.80

32

1.87 0.04 1. 79 1. 95

32

1.90 0.06 1-80 1. 99

32


14.2.4

Table 11: Baseline characteristics: Doses of Irradiations forMED determination of subjects (liT analysis set)

Hole Dose (MED/min x sec)

Hole 1 Mean SD Mi nimum Maximum Numboer

Hole 2 Mean SD Minimum Maximum Number

Rol e 3 Mean SD Minimum Maximum Number


Hole 5 Mean SD Minimum Maximum Number


All randomiaed subj ll!!!cts (n•3 2 )

85.0 7 .6

70.0 100. 0

32

106.3 9.5

87.5 125.0

32

132 .8 11 .9

109 . 4 156.3

32

1 66 .0 14 . 9

136.7 195 .3

32

207.5 18 . 6

170 . 9 244 . 1

32

259.4 23.3

213.6 305 .2

32

For individual data on irradiations forMED determination, see Appendix IX, Listing 7.

CONCOMITANT DIAGNOSES

Of the 32 randomised subjects, 14 subj ects (43.8%) had one or more diagnoses not requiring treatment recorded at visit 1. The distribution of the diagnoses (MedORA, version

5. 1) is shown by preferred term in Table 12.


14.2.5

14.3

14.3.1

Table 12: Baseline characteristics: Concomitant diagnoses not recorded In conjunction with concomitant medication of subjects by preferred term I ) (17T analysis set)

Preterred term All randomised subj ects (n•32)

Number of Number of diagnose& subjects 2)

Arthralgia 1 1 Herpes simplex 7 7 Hiat.ua hernia 1 1 Hyperc:ho l e s terolaemia 1 1 Migraine NOS 2 2 Orthostatic hypotension 3 3 Rhinitis a llerg ic NOS 2 2 Seborrhoeic dermatit i s 1 1 Sinusitis chronic NOS 1 1 Spondylol isthesis acquired 1 1 Venous insufficiency 3 3

Total number ot diagnoses 2)

Total number of subjec ts (\} 14 (43 . 8)

1} Classification according to MedDRA (Medical Dict ionary for Regulatory P.ctivitiea) version S.l . 2 } A single subject coul d appear in more than one category.

For individual data on concomitant diagnoses, see Appendix IX, Listing 9.

VARIABIUTY AMONG STUDY CENTRES WITH RESPECT TO BASEUNE PATIENT

CHARACTERISTICS

N/A

TREATMENT

USE OF AND COMPLIANCE WITH PRESCRIBED TRIAL MEDICATION/INVESTIGATIONAL

PRODUCT

The patches were checked at 7 visits to see if they were in place. The compliance Is shown in

Table 13.

·- -··------

MCB 0204 FR 3 June 2003

14.4

14.4 .1

14.4.2

14.4.3

Table 13: Compliance: Are the patches in place? (liT analysis set)

Visit Patches in p l ace

Vis i t 3 Yes Total numbe r of subjects with cornplia.nce data

Visit. s Yes Tota l. nu.mber of subjects with compliance data

Visit 7 Yes Total n\U'I'ber ot sUbj ects with compliance data

Visit ~ Yes Total nu1!'J>er o! subj ects with compliance data

Vi sit 11 Yes Total nUll'.ber of subjects with compliance data

Visit ll Yes Total number of subj ects with compliance data

Visit 1 5 Yes Total nu1!'J>er of s ubj ecu with compliance data

All randomisecl subjects (n• 32)

Number of subjects

32 100.0

32 100.0

32 100. 0

32 100 .o

32 100 .o

32 lOO.O

)2 l OO.O

)2 100.0

30 100 .0

30 100 . 0

30 100.0

30 100.0

30 l OO .O

30 100.0

No subjects had their patches taken off during the study period.

For individual data on compliance, see Appendix IX, Listing 8.

EFFICACY RESULTS

PRIMARY RESPONSE CRITERION

N/A

SECONDARY RESPONSE CRITERIA

N/A

STATISTICAL/ ANALYTICAL IssUES

For planned analyses, see Section 11.12.1. No further issues apply.

Page 67 of86

of86 3 June 2003 MCB 0204 FR

14.4.4 CoNCOMITANT TREATMENT

At visit 1, the use of concomitant t reatment was recorded. These medications were coded according to the WHO Anatomical Therapeutic Chemical (ATC) Classification (version 2002 1. quarter).

The number of subjects receiving concomitant treatment at baseline (visit 1) Is presented in Table 14 by ATC Classification.

Table 14: Baseline characteristics: Concomitant treatment by ATC Classification for which the subJects started before the study (ITT analysis set)

ATC Classiticat i on Al l ranclomised aubject.s (n• 32J

Number of N\lml>er o f drugs subje-cts 1

•

Alimenu.ry tract and metaboliom 3 3 Cardiovascular system 3 3 Geni to urinary system and s ex hormon~s 17 16 Nervoua system 4 4 Various 1 1

Total number of drugs 28 Total numl>er of subj ects m 19 (59.4 )

1) A singl e subject coul d appear in more than one category.

A total of 19 subj ects (59.4%) received concomitant treatment at baseline, the majority

belonging to the group of the genito urinary system and sex hormones.

For individual data on concomitant treatment at baseline, see Appendix IX, Listing 10.

Concomitant t reatment for which the subjects started during the study is shown in Table 15.

Table 15: Concomitant treatment by ATC Classification for which the subjects started during the study (ITT anajysis setl

ATC Cl euitieation All randomised subject• (n • 32 )

Number of Number of drugs subj ects 1

•

Alimentary tract and metabolism ' 4 Nervous system 12 9 Respiratory system 2 1

Total nurr.ber of drugs 1 8 Total number ot subjects (\) 1 0 (31. 3)

1} A single subject could appear in more than one category.

For individual data on concomitant treatment, see Appendix IX, Usting 10.


15 SAFETY EVALUATION

15.1

15.1.1

15.1.2

The statistical analysis was performed in accordance with the protocol.

EVALUATION OF PHOTOSENSinVITY

PHOTOSENSITIVE REACTIONS

The occurrence of photosensitive reactions at 72 hours following radiation on the first day in the challenge phase was tabulated by treatment site. Table 16 shows the distribution of the assessments.

Table 16: Occurrence of photosensitive reactions by treatment site 72 hours following radiation on the first day In the challenge phase (In" analysis set)

Occurrence of photosensitive reactions

Ne-gative Equivocal Positive Total

Oaivobet• (n·32)

Number of subjects

30 1 00 .o 0 0 0 0

30 100.0

D&ivobet• vehic l e Control (n•3 2l (n• 32 )

Number of Number of subj ects s ubjects

30 100 .0 30 100.0 0 0 0 0 0 0 0 0

30 100. 0 30 100.0

Two subjects (CRF - left the study before the assessments of the photosensitive reactions took place.

All test sites were assessed as negative. Thus, there were no differences between treated

sites and control sites.

For individual data on photosensitive assessments, see Appendix IX, Usting 11.

GLOBAL CUNICAL SCORE DURING THE CHALLENGE PHASE

The Global Clinical Score assessments are tabulated by treatment site and irradiated/nonirradiated side during the challenge phase, see Table 17.

of86 3 June 2003 MCB 0204 FR

15.1.3

Table 17: Global Clinical Score by treatment site and irradiated/non-Irradiated side during the challenge phase (I7T analysis set)

Visit !Challenge phu e) Daivobet"' Daivobet"' vehicle Control Global (n•3 2) !n•32) (n•32) Clinical Score Irra - Non-irra- I rra - Non-irra- trra- Non-irra-

diated diated diated diated diated dia ted side side side aide aide side

MSbj • Number of subj ects ISbj ' ISbj ISbj ' #Sbj #Sbj t ISbj

Day 2 - Week 6 Nomal skin aspect 29 96.7 29 96.7 30 100 .0 30 100 .0 28 93 . 3 28 93.3 Equivocal reaction l l.3 l 3. 3 0 0 0 2 6. 7 2 6.7 Total 30 100.0 30 100 .0 30 100.0 30 100 . 0 30 100 . 0 30 100 .0

Day 3 - Week 6 Normal skin aspect 11 36.7 13 43.3 23 76.7 28 93.3 24 80 .o 27 90.0 Equivocal reaction 19 6l. 3 16 53.3 23.3 2 6. 7 6 20 . 0 3 10.0 ND• 0 0 1 3. 3 0 0 0 0 0 0 0 Total 30 100 .0 30 100.0 30 100.0 30 100.0 30 100.0 30 100.0

Day 4 - Week 6 Normal skin aepec:t 28 93.3 28 93.3 30 100 .o 30 100.0 30 100.0 30 100.0 Equivocal reaction 2 6. 7 2 6. 7 0 0 0 0 0 0 0 0 Total 30 100.0 30 100.0 30 100.0 30 100.0 30 100.0 30 100 .0

Day 5 - Week 6 Nomal skin aspe ct 30 100.0 30 100.0 30 100.0 30 100. 0 30 100. 0 30 100 . 0 Total 30 100.0 30 100.0 30 100.0 30 100 .o 30 100.0 30 100.0

*NO: not done.

Table 17 indicates that, during the challenge period only normal skin aspect or equivocal

reactions were observed after irradiation. On Day 2, just after patches removal, almost all the test sites had normal skin aspect. On Day 3, twenty-four 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 and control sites. This phenomenon was no longer visible on Day 4 and all irradiated and non-irradiated sites had

normal skin aspect on Day 5, whatever the treatment.

For individual data on Global Clinical Scores, see Appendix IX, Listing 12.

GRADING SCALE OF ERYTHEMA DURING THE CHALLENGE PHASE

The grading scale of erythema was reported at the same visits as with the Global Clinical

Scores. The distributions of the assessments at the visits during the challenge phase are

shown in Table 18.

MCB 0204 FR 3 June2003 Page 71 of86

15.1.4

Table 18: 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) scale of

<n•32) (n•32)

erythema lrra- Non·irra- Irra - Non- irra .. Irra- Non- i rra-diated diated diated diated diatad diated side side side side side side

#Sbj • NUmber of subjects tSbj ' fiSbj IISbj \ #Sbj Ubj ' ISbj

Day 2 - Week 6 No reaction 27 90.0 27 90.0 27 90.0 27 90.0 25 83.3 25 83.3 Doubtful erythema 3 10.0 3 10 . 0 3 10. 0 3 10.0 5 16.7 5 16 . 7 Tota l 30 100 .o 30 100 .0 30 100 . 0 30 100 . 0 30 100.0 30 100 . 0

Day 3 • Week 6 No reaction 4 13 .3 13 4 3 . 3 12 40 .0 28 93.3 ll 36 .7 27 90.0 Doubtful erythema 17 56.7 10 33 . 3 18 60 .o 6. 7 19 63 .3 3 10.0 Mild erythema 9 30.0 7 23.3 0 0 0 0 0 0 0 0 Total 30 100.0 30 100.0 30 100.0 30 100.0 30 100.0 30 100 .0

Day 4 - Week 6 No react i on 16 53.3 26 86.7 27 90 .0 29 96 . 7 24 80 .o 29 96.7 Doubtfu l erythoma 13 43 . 3 3 10.0 3 10.0 3.3 6 20.0 1 3. 3 Mild erythema 1 3.3 1 3. 3 0 0 0 0 0 0 0 0 Total 30 100.0 30 100.0 30 100.0 30 100 . 0 30 100.0 30 100.0

Day 5 - Week 6 No reaction 27 90.0 29 96.7 30 100 .o 29 96.7 30 100. 0 30 100. 0 Doubtful erythema 3 10.0 1 3. 3 0 0 1 3 . 3 0 0 0 0 Total 30 100.0 30 100 . 0 30 100.0 30 100 . 0 30 100.0 30 100.0

During the challenge period, the grading of erythema was no reaction, doubtful erythema and mild erythema. On Day 2, just after patches removal, almost all the test sites had no

reaction or doubtful erythema. On Day 3, twenty-four hours after Irradiation, a higher number of doubtful erythema and mild erythema reactions were observed on both Irradiated and non Irradiated Daivobet/ Dovobet sites compared to vehicle of Daivobet/ Dovobet and control corresponding sites. This difference could be due to the irritating character of

Daivobet/ Dovobet when placed under occlusion. This phenomenon was no longer visible on Day 5 and almost all irradiated sites and non-irradiated sites had no reaction and only

four of the Daivobet/ Dovobet treated sites had doubtful erythema.

For individual data on the grading scale of erythema, see Appendix IX, Listing 13.

ERYTHEMA AND OTHER REACTIONS DURING INDUCTION PHASE

During the induction phase, assessments of erythema and other reactions were made at the treatment sites. Erythema was graded and occurrence of other reactions was recorded, and the distribution of these assessments is shown in Table 19 and Table 20, respectively.

of86 3 June 2003 MCB 0204 FR

Table 19: Assessments of skin reactions: Erythema by treatment site during the induction phase (ITT analysis set)

Visit (Induction phasf!} Oa ivobet• Daivobet* vehicle Control Erythema score (n•32 ) (n• 32) (n•32 )

Nu~er of NU~er of NU~er ot subjects s ubj ects subjects

Day 2 • Week 1 No reac tion 30 93.8 28 87.5 24 75 .o Doubtfu l erythema 6. 3 4 12. 5 8 25 . 0 Total 32 100.0 32 100.0 32 100 . 0

Day 4 · week 1 Mild erythema 13 40 .6 13 40 . 6 13 40.6 Moderate erythema 19 59.4 19 59.4 19 59.4 Total 32 100 . 0 32 100.0 32 100.0

Day s - week 1 Doubtful erythema 1 3.1 3 .l l 3 . 1 Mild erythema 20 62.5 19 59.4 20 62.5 Moderat e erythema ll 34 . 4 12 37. s 1l 34.4 Total 32 100.0 32 100 . o 32 100.0

Day 1 • week 2 Doubtful erythema 19 59. 4 18 56.3 19 59.4 Mild erythema 13 40.6 14 43.8 13 40.6 'Iotal 32 100.0 32 100 .o 32 100.0

Day 2 - Week 2 No reaction 2 6.3 4 12. 5 5 15.6 Doubtful erythema 29 90.6 26 81.3 26 81 . 3 Mild erythema 1 3 .l 2 6.3 1 3 .1 Total 32 100.0 32 100.0 32 100.0

Day 4 • week 2 Doubtful erythema 13 40.6 15 4 6.9 15 4 6.9 Mild erythema 19 59.4 17 53.1 17 53.1 Tocal 32 100.0 32 100.0 32 100.0

Day 5 • week 2 Doubtful erythema 25 78 .l 27 84.4 26 81.3 Mild erythema 7 21.9 5 15 . 6 6 18 .8 Total 32 100 .o 32 100.0 32 100.0

Day 1 • wuk 3 No reaction 21.9 9 28.1 7 21.9 Doubtful erythema 24 75.0 22 68 . 8 23 71.9 Mild erythema 1 3.1 l 3.1 2 6. 3 Total 32 100.0 32 100.0 32 100 .0

Day 2 • week 3 No reaction 10 33.3 30.0 20.0 Doubtful erythema 19 63.3 20 66.7 23 76.7 Not done • 1 3. 3 1 3.3 l 3.3 Total 30 100.0 30 100 .0 30 100.0

Day 4 week 3 No reaction 3 10.0 3 10 . 0 3 10.0 Doubtful e rythema 26 86 . 7 26 86.7 26 86 . 7 Mild erythema 1 3.3 l 3.3 l 3 .3 Tota l 30 100.0 30 100.0 30 100.0

Day 5 • Week 3 No reaction 10 33.3 l3 43 . 3 12 40.0 Doubtful erythema 19 63.3 16 53 .3 1 7 56 . 7 Mi l d erythema 3 . ) l 3.3 1 3 . 3 Total 30 100 . 0 30 100.0 30 100.0

* Not done : missed assessment for one subject.

Table 19 indicates that the erythema observed during the induction period on the different tested sites was similar, whatever the t reatment.


Table 20: Assessments of skin reactions: Other reactions by treatment site during the induction phase (liT analysis set)

Visit (Incll.lction phase) Da i vobett!l Daivobet• vehicle Control Other reactions (n•32) (n•32) (n • 32)

Nu-mber of Number of NUmber of subj ects subjects t subjects

Day 2 - week 1 Absence of reaction4 32 100 . 0 32 100 . 0 32 100.0 Total 32 100 . o 32 100 .o 32 100 . 0

Day • - Week 1 Absence of reaction~ 22 68.8 22 68 .8 22 68.8 UV pigmentation 10 31.3 10 31 . 3 10 31.3 Total 32 100 .0 32 100.0 32 100 .o

Day 5 - Week 1 Absence of reaction., 12 37. 5 12 37 .s 12 37.5 uv pigmentation 20 62 . s 20 62.5 20 62 .s Total 32 100.0 32 100.0 32 100.0

Day 1 - Week 2 UV pigmentation 32 100.0 32 100 .0 32 100.0 Total 32 100 . 0 32 100 .o 32 100.0

Day 2 - Week 2 W pigmentation 32 100 .o 32 100.0 32 100.0 Total 32 100.0 32 100 .0 32 100 .o

Day • - Week 2 W pigmentation 29 90.6 28 87.5 28 87 .5 w pigmentation • peeling 3 9. 4 4 12.5 4 12 . s Total 32 100 .o 32 100. 0 32 100.0

Day 5 - week 2 uv pigmentation 30 93.8 30 93.8 29 90.6 W pigmentation + peeling 2 6. 3 2 6 . 3 3 9 . 4 Total 32 100 .0 32 100 . 0 32 100 .o

Day 1 - week 3 W pigmentation 30 93.8 30 93.8 32 100.0 UV pigmentation + peeling 2 6. 3 2 6. 3 0 0 Total 32 100.0 32 100.0 32 100.0

Day 2 - week 3 ND• 1 3. 3 1 3 . 3 1 3 . 3 tJV pigmentat ion 28 93.3 29 96.7 29 96 . 7 1JV pigmentation + peeling 1 3. 3 0 0 0 0 Total 30 100.0 30 100.0 30 100 .o

Day 4 - Week 3 tN pigmentation 29 96.7 29 96.7 29 96 . 7 UV pigmentation • peeling 1 3 . 3 1 3. 3 1 3.3 Total 30 100 .o 30 100 .o 30 100 .0

Day 5 - week 3 W pi gment ation 30 100.0 30 100 . 0 30 100 .o Total 30 100 .o 30 100.0 30 100.0

Absence of reaction: normal skin aspect.

* NO: not done (missed assessment for one subject)

Other local reactions observed during the induction period were mainly UV pigmentation,

which was observed in all subjects on all irradiated sites starting from week 2.

UV pigmentation with peeling was also observed in some subjects.

For individual data on the erythema scores and other skin reactions during the Induction phase, see Appendix IX, Listing 14.

of86 3 June 2003 MCB 0204 FR

15.1.5

15.2

OTHER REAcnONS DURING THE CHAUENGE PHASE

During the challenge phase, the occurrence of other reactions was recorded and the assessments were tabulated by treatment and by irradiated/non-Irradiated side, see Table 21.

Table 21: Assessments of skin reactions: Other reactions by treatment site and irradiated/non-irradiated side during the challenge f)hase (ITT analysis set)

Vis it (Challenge phase) Other react ions

Daivobete (n•32)

Ir:ra - Non- i rra-

Da ivobat«> vehicle Centro~

(n•32) (n· 32 l

I rra- Non- irra - Irra- Non- irra-diat&d <Ha ted diated diated diated diated

ISb j • ~umber of subjects

Day 3 - Week 6 W pigmentation Tot a~

Day 4 - Week 6 UV pigmentation Total

Day s - Week 6 Absence ot reaction• l1V pigmentation Total

side

I Sbj

26 100.0 26 100 . 0

22 100.0 22 100 . 0

s.o 19 95.0 20 100.0

side

t •sbj

0 0 0 0

0 0 0 0

1 100.0 0 0 1 100.0

*Absence of reaction: normal skin aspect.

side side aicle side

ISbj \ Ubj •sbj t ISbj

26 100.0 0 0 26 100.0 26 100.0 0 0 26 100 .o 0

22 100 .0 0 0 22 100 .o 0 22 100.0 0 0 22 100 .o 0

s .o 1 100.0 5 .o 1 100 .0 19 95.0 0 0 19 95 .o 0 0 20 100 .0 1 100 .o 20 100 .0 1 100.0

The only other local reaction observed during the challenge period was UV pigmentation, which was observed on the irradiated sites in most of the subjects.

For individual data on other reactions during the challenge phase, see Appendix IX, Usting 15.

DURA nON AND EXTENT OF EXPOSURE TO TRIAL MEDICATION

Thirty subjects completed the planned treatment period. Fifty IJI of each formulation was

applied twice weekly for 3 weeks in the induction phase and 2 times 50 IJi once in the challenge phase. Fifty (50) IJI of Dalvobet/ Dovobet ointment contains 2.3 IJg calcipotriol and 23 IJg betamethasone and each subject received eight applications. Thus, a total amount

of 18.4 IJg calcipotriol (8 x 2.3 IJg) and 0.184 mg betamethasone (8 x 23 IJg) was given to each subject over the whole study period. The corresponding amount of Daivobet/Dovobet ointment (with the concentration of 50 IJg calcipotriol and 0.5 mg betamethasone per gram)

can be calculated as follows:

SO IJg calcipotriol/1g ointment = 18.4 IJg calcipotriol/x

or

0 .5 mg betamethasone/1 g ointment= 0.184 mg/x

where

x = total amount given

x = 18.4/50 g = 0.184/0.5 g = 0.368 g ointment


15.3

15.3.1

15.3.2

Thus, a total amount of 368 mg of Dalvobet/ Dovobet ointment (and the same amount of the Dalvobet/ Dovobet ointment vehicle) was given per subject during the whole study period.

For individual data on duration of exposure to trial medication, see Appendix IX, Listing 4.

ADVERSE EVENTS REPORTED

Adverse events, as described by investigators, were categorised according to the MedORA (Medical Dictionary for Regulatory Activities) System Organ Class (SOC) coding system. All coding was done prior to unblinding of the study.

NUMBER OF SUBJECTS WITH ADVERSE EVENTS

The number of subj ects with adverse events within each MedORA preferred term is given in Table 22.

Table 22: Adverse events listed by preferred term 1 {ITT ana~is seu_

Pre ferred t erm All randomised subjects (n•32 )

Back pai n 1 Colitis NOS l Oys-menorrho~a l Gastritis NOS l Headache 4 Nas o pha ryngitis 3 osteoarthri t is NOS l Pharyng i t is 1

Total nun'l;)er of adve r s e e ve n t s 1 ) 13 Tota l number o f subjects (\) 10 (31. 3)

l ) Cl assificat ion accordi ng to MedDRA (Medi cal Dictionary for Regulatory Ac tivities) version 5 .1. 2) Di f ferent adve rs e events wi th the same pre ferred t e rm and involving the same subject have been

c ounted as one . A single subj ect could appear in multiple preferred terms.

Ten of the 32 randomised subjects (31.3%) reported 13 adverse events. The most commonly reported adverse events were headache and nasopharyngitis, reported by 4 and 3 subjects, respectively.

For individual data on the presence/absence of adverse events and on the preferred terms assigned to adverse events, see Appendix IX, Listing 16.

RELATIONSHIP OF ADVERSE EVENTS TO TRIAL MEDICA nON

The relationship of adverse events to trial medication is presented in Table 23 by preferred term.

of86 3 June 2003 MCB 0204 FR

15.3.3

Table 23: Relationship of adverse events to trial medication listed by preferred term tJ (ITT analysis set)

Pref erred term All randomi s ed subjec t s (n• 32)

Not rel ated Possib l e

Back pain 0 1 Colitis NOS 1 0 Dysmenorrhoea 1 0 Gas trit is NOS 0 1 Headache 2 2 Nasopha ryngitis 2 1 Osteoar thri t is NOS 1 0 Pharyngitis 1 0

Tot a l numbe r o f adverae event a ' ' 8 5

ll Classifica t i on according to MedORA (r'.edieal Dictionary for Regulat o r y Activit i es) version 5 . 1 . 2) Different a dverse events wi"h " he same preferred term and i nvolving "he same allbj ect have been

counted aa one. A single s ubj ect coul d appe ar in multiple pr• ferred t erms.

Table 24 shows the adverse drug reactions listed by preferred term. An adverse drug

reaction is defined as an adverse event that the investigator considered to be either "not assessable", "possible" or "probable" In its relation to use of trial medication.

Five adverse events were classified possibly re lated to the study drug and thus classified as adverse drug reactions.

Table 24: Adverse drug reactions listed by preferred term z) (ITT ana/y_sis setl

Prefe rre d t e rm All randomiaed subjects (n•32 )

Back pai n 1 Gast r i t i s NOS l Headache 2 Nasophar yngi t i s 1

To t a l number o f adve rse drug reacc i ons n 5 Total number ot s ubj ects (\) 4 (12 .5)

1) Claooif i cat i o n acco rding to MedORA (Medi ca l Dic t i onary f o r Regulatory Ac t ivi ties) ve ra ion 5 .1. 2) Different adverse events with the s ame pre f e rred term and invo l ving the same subj ect have been

count ed as one . A s ingle subjec t. cou l d appear i n mul tipl e prefe r red t e rms.

These 5 adverse drug reactions were reported by 4 of the 32 randomised subjects (12.5%).

For individual data on the relationship of adverse events to trial medication, see Appendix IX, Listing 16.

INTENSITY OF ADVERSE DRUG REACTIONS

The intensity of adverse drug reactions is listed by preferred term in Table 25.


15.3 .4

15.4

15.4 .1

15.4.2

15.5

Table 25: Intensity of adverse drug reactions listed by preferred term JJ (m analysis set)

Preferred term .~<11 randomised subjects (n• 32)

Mild Moderate

Back pain 0 l Gastritis NOS l 0 Headache 2 0 Nasopharyngi tis 0 1

Total number o! adverse drug reactions H ) 2

l) Clasaification according to MedllRA (Medical Dict ionary !or Regulatory Act i v i ties) version s. l. 2) Different adverse events with the same preferred term anQ i nvolving the same subje~t have been

counted as one. A singl e subject cou ld appear in mul tiple preferred terms.

Two of the adverse drug reactions were of moderate intensity, and the other 3 were graded as mild.

For Individual data on the Intensity of adverse drug reactions, see Appendix IX, Listing 16.

LESIONAL/PERILESIONAL ADVERSE EVENTS REPORTED

None of the adverse events reported during the study were considered to be skin related,

i.e., lesional/peri lesional adverse events.

DEATHS, OTHER SERIOUS ADVERSE EVENTS AND O THER SIGNIFICANT ADVERSE

EVENTS

PREMATURE WITHDRAWAL DUE TO UNACCEPTABLE ADVERSE EVENTS

Two subjects were withdrawn from the study prematurely due to unacceptable adverse events. They left the study after visit 10 (Day 1, Week 3).

One subject (CRF . left the study due to a sore throat. The event was considered mild in

intensity and not related to trial medication.

The other subject (CRF • left the study due to colitis. The event was severe in intensity

and not related to trial medication.

DEATHS AND OTHER SERIOUS ADVERSE EVENTS

No deaths were reported during the study, and none of the adverse events were considered

to be serious.

lABORATORY DATA

N/A


15.6 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY

15.7

Vital signs and physical examinations were performed during the selection of the subjects before the start of the study according to the local regulation and the protocol. No final examination was planned or conducted. Medical histories and main previous therapies as well

as results of the screening medical examination were noted in the medical record of each subject.

SAFETY RESULTS

No systemic adverse drug reactions were expected to occur due to the low amount of investigational and reference products used (SO J,JI/application).

However, 5 of the systemic adverse events reported were rated by the investigator as

adverse drug reactions: back pain, gastritis, headache (2 reports) and nasopharyngitis.

The study did not show any unexpected significant safety issues arising during the study period.


16

16.1

16.2

DISCUSSION

SUMMARY OF RESULTS

The objective of this single-centre, randomised, Investigator-blinded, vehicle controlled phase I study with intra-individual comparison was to assess the photosensitisation potential of Daivobet/Dovobet ointment and Its ointment vehicle after repeated applications and Irradiations to the skin of 32 healthy subjects. A total of 32 subjects were enrolled and 30

subjects completed the study as planned. Two subjects discontinued the study due to adverse events considered as not related to study medication.

The test consisted of 3 phases, an induction phase, a rest phase and a challenge phase. During the induction phase, both investigational products were applied under occlusive

conditions on the back during 24 hours, twice weekly for 3 weeks. Twenty-four hours after each product application, irradiation was performed on test site after patch removal.

After 2 weeks without product application/irradiation (the rest phase), 2 sets of the 2 products were applied on new sites on the back, 24 hours under occlusive conditions. Two untreated but occluded sites would be used as well (challenge phase).

The photosensltisation reaction and erythema on the test sites were evaluated using a 5-point scale. All test sites were evaluated for photosensitisation reactions 24, 48 and 72 hours after irradiation.

No differences were seen between the treatments since all assessments of the 30 subjects' sites were regarded as negative with respect to the occurrence of any photosensitive reactions. Thus, no photosensitive reactions were observed with Daivobet/Dovobet ointment.

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 investigational products, and none of these events were related to the skin. No deaths were reported during the study, and none of the

adverse events were considered to be serious.

DESIGN AND CONDUCT OF THE STUDY

The sample size was based on FDA recommendations stating a requirement of 30 subjects for this type of study.

Thirty-two subjects were included and 30 subjects completed the study as planned. Thus,

the required number of subj ects was met and is sufficient for the evaluation of the study results.

The study was conducted by an investigator and two sublnvestigators at one single centre, which minimised the variabil ity in the assessments. The randomisation procedure was followed and the Investigator-blinded design was ensured by having a study assistant applying the test product.

The treatment code was not broken during the study. The study population comprised the intended healthy subjects as evidenced in the physical examination at screening where no abnormal find ings were found. The inclusion criteria were fu lly met, and no subjects were

included in v iolation of the exclusion criteria.

The study site with its staff was properly qualified and trained and had extensive previous

experience in conducting cl inical trials according to GCP.

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16.3

Thus, the study design was adequate, the study population representative and the study was adequately conducted, ensuring reliability and relevance of the study results.

INTERPRETATION OF STUDY RESULTS

The study results observed in this study indicated that no photosensitisation reaction was observed neither for Dalvobet/Dovobet nor its vehicle. The Increase in equivocal reactions and mild or doubtful erythema observed on both irradiated and non-irradiated

Daivobet/Dovobet treated sites compared with the vehicle treated or untreated sites may be explained by a slight irritative effect of Dalvobet/Dovobet ointment when applied under occlusion.

The occurrence of UV pigmentation and peeling are well-known reactions associated with UV

Irradiation in doses higher than 1 MED. Pigmentation is the normal result of UV induced melanogenesis (mainly due to UVB) combined with UVA-induced Immediate pigmentation

(Meirowsky phenomenon).

No systemic adverse drug reactions were expected to occur due to the low amount of Investigational and reference products used (50 IJI of each). However, 5 of the systemic adverse events reported were rated by the Investigator as adverse drug reactions: back pain, gastritis, headache (2) and nasopharyngitis. Given that all subjects received 122l.!l investigational products concomitantly, it may be questioned whether assessment of the causal relationship of a systemic adverse event to a specific or individual investigational

product is of relevance.

In addition, the amount of approximately 368 mg of each of the investigational products applied under occlusion during the study period is regarded to be so low that a systemic effect is very unlikely, considering that Daivobet/Dovobet ointment has been shown to be

safe in doses up to 100 g per week In the phase III clinical trials [18].

Furthermore, it should be noted that the reported adverse drug reactions have not previously been reported in clinical trials with Oaivobet/Dovobet ointment (>2,500 patients) and in

therapeutic use after it was marketed in 2001.

Overall, the study conclusions are considered to be valid.


17 CONCLUSIONS

The results observed in this study indicated that no photosensltisatlon reaction was 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.

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18 REFERENCES

1 U.S. National Health Survey 1971-74. Vital and Health Statistics. Series II No. 212.

2 Brandrup F, Green A. The prevalence of psoriasis in Denmark. Acta Derm Venereal 1981; 61 : 344-6.

3 Christophers E, Schubert C. Psoriasis. In: Thody AJ, Friedmann PS, eds: Scientific basis of dermatology, a physiological approach. London: Churchill Livingstone, 1986: 151-74.

4 Bos JD. The pathomechanisms of psoriasis; the skin immune system and cyclosporin. Br J Dermatol 1988; 118: 141-55.

5 Baker H. Psoriasis. In: Rook A, Wilkinson DS, Champion RH, Ebling FJG, Burton JL eds. Textbook of Dermatology. Oxford: Blackwell Scientific Publications, 1992: 1391-1457.

6 Powles AV, Baker BS, Valdimarsson H, Hulme B, Fry L. Four years of experience with

cyclosporin A for psoriasis. Br J Dermatol 1990; 122: Suppl 36, 13-19.

7 Berth-Jones J, Chalmers RJG, Chu ACetal. A multi-centre, parallel-group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br

J Dermatol 1992; 127: 266-271.

8 Tham SN, Urn KC and Cheong WK. A comparative study of calcipotriol ointment and tar

in chronic plaque psoriasis. Br J Dermatol 1994; 131: 673-677.

9 Cunliffe WJ, Berth-Jones J, Claudy A et ai. Comparative study of calcipotriol (MC 903)

ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992; 26: 736-43.

10 Kragballe Ketal. Double-blind right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337: 193-96.

11 Kragballe K, Fogh K, Soegaard H. Long-term efficacy and tolerability of topical

calcipotriol in psoriasis. Acta Derm Venereal 1991; 71: 475-78.

12 Ramsay CA, Berth-Jones J, Brundin G et al. Long-term use of topical calcipotriol in

chronic plaque psoriasis. Dermatology 1994; 189: 260-264.

13 Poyner T, Hughes JW, Dass BK et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. J Dermatol Treat 1993; 4 : 173-177.

14 Ellis J P, Griffiths W A D, Klaber MR. Long-term treatment of chronic plaque psoriasis with calcipotriol ointment in patients unresponsive to short contact dithranol. Eur J Clin

Res 1995; 7: 247-257.

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15 Roberts DT. Comparison of fluticasone propionate ointment, 0.005%, and betamethasone 17, 21-diproplonate ointment, 0.05%, in the treatment of psoriasis. Cutis 1996; 57:27-31.

16 Shupack JL, Jandreau L, Kenny C, Stiller MJ . Diplorasone diocetate ointment 0.05% versus betamethasone dlpropionate ointment 0.05% in moderate-severe plaque-type psoriasis. Dermatology 1993; 186:129-132.

17 Chuang 'TY, Samson CR. Clinical efficacy and safety of augmented betamethasone

dipropionate ointment and difloresone diacetate ointment for psoriasis, a multicentre, randomised, double-blind, study. J Derm Treat 1991; 2:63-66.

18 Investigator's Brochure. Daivobet ointment (calcipotriol/betamethasone combination product) in psoriasis. Edition no. 7. 16 January, 2003.

19 Photo-toxicity study. Assessment of the phototoxic potential of Daivobet/Dovobet 0.5 mg/g and calcipotriol 50 IJg/g).

France. LEO Study

Report dated 15 July 2002.

20 Kaldbey KH, Kligman AM. Identification of topical photosensitizing agents in humans. J

Inv Derm 1978; 70 (3): 149-151.

21 Kaidbey KH, Kligman AM. Photo maximisation test for identifying photoallergic contact

sensitizers. Contact Dermatitis 1980; 6: 161-169.

22 Pathak MA, Fitzpatrick TB, Grelter F, and Kraus EW. Preventive treatment of sun burn, dermatoheliosls, and skin cancer with sunprotective agents. In : Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg, Austen KF, eds. Dermatology in general medicine. New York:

McGraw-Hill Book Company 1987: 1507-1522.


19 LIST OF APPENDICES

APPENDIX I :

APPENDIX II:

APPENDIX III

APPENDIX IV:

APPENDIX V:

Study Protocol and Amendments

Case Report Form (print) (unique pages only) and other data collection

forms, e.g., Patient Diary Cards

Statistical Analysis Plan

Confirmation of Statistical Information Form

Representative Patient Information and Informed Consent (e.g., PCPC master version)

APPENDIX VI: List of IEC/IRBs consulted and name of IEC/JRBs chairperson

APPENDIX VII: List of Investigators and Summary CVs

APPENDIX VIII: List of Subinvestigators

APPENDIX IX : Individual Subject Data

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