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SYNOPSIS

Name or Sp!)nsor/Manufacturer: Location of study report In-Regulatory (For National Authon ty Use only)

LEO Pharma A/S Dossier for authorities .. Name of Investigational Product/ Finished 'Product, If available:

Volume:

Dqvobet®, Daivobet®

Name of A<ztlve Substance: Page:

C~lclpotrio l . + betamethasone dipropionate

Title or study/Protocol Code Number: . -· :

Rep.eated coUts~s of calcipotrlol/betamethason-e dip~opionate in psoriasis vulgaris /MCB

01Q2' I~T (

Intem.ational Co-ordinating Investigator:

Professor-

Centre details:

There were a total of 67 centres, 5 in Belgium, 7 in Canada, 2 in Denmark, 4 in Finland/

13 in France, 3 in Germany, 3 in Ireland, 4 in Norway, 3 in Spain, 4 in Sweden_and 19

in the United Kingdom

Publication references:

Not applicable

Study period 'details: Phase of development:

23-Aug-2002 to 20-Apr-2004; total duration of 20 Phase IH

months

Objectives:

To determine t_he safety and efficacy of the following In the treatment of patients with

psoriasis vulgaris: 52 weeks of combination (calcipotriol + betamethasone dipropion-

ate) treatment; 52 weeks of alternating 4 week periods of combination/calcipotriol treatment; 4 weeks of combination treatment followed by 48 weeks of calcipotriol

treatment.

Study methodology :

An international, multicentre, prospective, randomised, double-blind, 3 arm, parallel --

group, 52 week safety study. Patient with psoriasis vulgaris were randomised in a

1:1 :1 ratio to one of the three treatment groups described above. Every 4 weeks

invest igators assessed adverse events and the global disease severity on a 6 category

scale (disease absent to very severe}, and patients assessed study treatment as either

sat isfactory or not satisfactory. Adrenal fu nction testing was performed at week 0, 4,

12, and end of stu_dy in patients at~K centres.

Number of patients ~nro!led :

636 enrolled, 634 randomised: 212 to the combination group, 213 to the combina-

~ L E 0

MCB 0102 INT 24-Aug-2004 --------------~~-----------------

Name of Sponsor/M~nufacturer : .

LE9 Pharma NS · · L.ocatlon of stud.Y report In Regulatory (For National Authority Use only) Dossier for authorities

Name of.Investigational Product/ Finished Product; If av,allable: ·

oovobet~, Dai.vobet®

Name of Actiye Substance:

Calcipotriol + betamethasone <;Jipropiorate

Volume:

Page:

tion/calcipotriol (4/4 alt.) group and 209 to the combination/calcipotriol (4/48) group.

All randomised patients were included in .the. iTT analysis set, 626 patients were ·

included in the safety analysis set.: 207 .in the co111bination group, 213 in the combina­

tion/calcip~triol · (4/4 alt.) group and 206 in the combination/calcipotriol.(4/ 48)group.

Diagnosis and malri criteria ·for patient selection:

Patients 2::. 18 years of age with . a diagnosis of p soriasis vulgaris of the b'ody of at least

moderate se\'ferity anq amenable to topical treatment were selected. Patients with any·

of t he following were e~cluded: more than 30% of body surface. area affected;

erythrodermic, exfoliative or pustular psoriasis; concurrent use of anti-psoriatic t reat­

ments (systemic, topical or UV); disorders of calcium metabolism; other skin cond itions

present on psoriatic areas of the body.

Investigational product, dose; method of administration, lot . numbers:

Combination (caldpotriol SO!ig/g + betamethasone dipfopionate O.Smg/g) ointment· . . . .

applied once daily as required. See 'Object ives' sectiori for the treatment group

reg imens. Lot numbers:

Reference product, dose, method of administration, lot numbers:

Calcipotriol SO~ig/g ointment applied once daily as required. See 'Objectives' sect ion for

the t reatment group. regimens. Lot numbers:

Duration of treatment:

52 weeks Criterla .for evaluation

Efficacy: The investigators' global assessment of disease severity (with disease absent,

very mild or mild being considered as 'satisfactory') and the patients' global assessment

of study treatment (secondary response criteria).

Safety: Adverse drug reactions of any type and adverse events of concern associated with long term topical corticosteroid use where relationship to study medication was at

least a reasonable possibility as identified by an independent Adjudication Panel

(primary response criteria) and adverse events of any type, weight of stt:Jdy medication

used, reasons for withd rawal and results of adrena l function tests (secor:~dary response

criteria).

Statistical methodology: . .

Safety data were_presented fo~ the safety analysis set, efficacy da~a wer-e presented for the intention-to-treat analysis set.

~ L E 0

MCB 0102 INT

Name of Sponsor/Manufacturer:

LEO Pharm'a A/S

Name of'lnvestigational Product/ Finished Product,' It available:

Dovobet®, Daivobet®

Narrre of Activ'~. Substance:

ca.lcip_otriol + betamethasone dipropionate

24-Aug-2004

Location of study repoi't in Regulatory (For National Authority Use only) Dossier for authorities

Volume:

The !)roportion of patients _who experienced adverse drug reactions of any type during

the studY w~s cor:npared for all three pairWise t reatme.nt group comRarisons using the

cbi-square test.

The.proporti_9n of ·patre'nts with advetse events of concern· associated with long term

topical C:orti·c~s~roid use where relationship to study medication was at least a reason­abre possibilit/w.as compared 'for al'l three.-pairwise treatm·ent group comparis~ns using

The percentage bf ass~ssments across visits defined as 'satisfactory' by the investiga­

tor~· 'gl~bal assessment of disease severity and by the patients' global assessment of

study t reatment were compared across· treatment groups using the Kruskaii -Wallis test

for t he overall treatment effect and the Wilcq)<an rank-sum test for each pairwise

t reatment group comparison. This was a change f rom the protocol-specified analysis

(analysis of va riance) because the data were skewed and was addressed in the. stat isti­

cal analysis plan prior to unblinding. Summary - Condusions

The mean age of randomised patients was 48.8 years, 61.0% were male, 97.3% were

caucasian and 69.1% had psoriasis of a moderate severity at visit 1.

Efficacy results:

The overa ll test of treatment effect for the percentage of satisfactory assessm ents

across visits for the investigators' global assessment of disease severity showed a t rend

towards a difference between treatments (P=0.071L which appeared to be due to the comparison of the combination and combination/calcipotriol (4/48) groups (P=0 .025) .

The median percentage was 84.0 in the combination group, 75.0 in the combina­

tion/ca lcipotriol (4/4 alt.) group, and 70.0 in the combinationjcalcipot riol {4/ 48) group.

The number of patients with 100% sat isfactory assessments during the study were 76 (35.8%) in the combination group, 59. (27.?%) in the combinationjcalcipotriol (4/4 alt.)

group, and 51 (24.4%) in the combination/caleipotriol {4/48) group. It is concluded

that t here is a trend in favour of_ the combination group compared to the combina­

.tion/calcipot rio l (4/48) group. The overall test of treatment effect for the percentage of satisfactory assessments

across visits for the patients' global assessment of study treatment showed a trend

towards a difference between t reatments (P:=0.071), whic~ appeared to be due to the

comparison of the combination and combin~tion/calcipotriol (4/48) groups (P=0.036)

! and the combinat ion and combination/calcipotriol (4/4 alt.) groups (P= 0.061). The

. MCB 0102 INT .

Name of Sponsor/Manufacturer:

LEO Pharma A/S

Name of lnvestlgatlonal Product/ Finished Product, If available:

Dovobet®, Daivobet®

Name of Active Substance:

Calcipotriol + betamethasone dipropionate · · ·

. 24-Aug-2004

Locat ion of study report in Regulatory (For National Authority Use only) Dossier for authorities

Volume:

Page:

median percentage was 87.3 in the combination group, 76.9 in the combina­

tion/calcipotriol (4/4 alt.) group, and 83.3 in the combination/calcipcitriol (4/48) group.

The n\Jm~er of patients with 1q0% satisfactory assessments during the study were ·80

(37.7%) in the combinati6n ·group, 61 (28 .. 6%) in the combinationjcalcipotriol (4/4 alt.)

group, and 60 (28:7°iof.ln. the combination/calcipotrrol (4/48) group. It is concluded

that there is a t rend in favour of the combination group compared to the combina­

tion/calcipotrlol (4/48) group.

Safety results:

There were 58.ADRs.in 45 {21.7%) patients in the c;:ombination group, 89. in 63 ·

(29.6%) patients In the combination/caldpotriol (4/4 alt.) group, and 111 in 78

{37·.9%) patients In t he combination/calcipotriol {4/48) group. The odds ratio for an

ADR in the combination gro'up relative to the combinationjcalcipotriol (4/48) g roup was

0.46 (95% CI 0. 30 to·0.70; P<0.001). I n addition to ·psoriasis, the most common ADRs

were those related to irritation of the skin (burning, pruritus, -erythema).

The Adj udication Panel identified AQ~ of conce~n associated with long term topical

corticosteroid use. There were 11 ~~~h ADRs i ~ lO (4.8%) patients in the combination

group, 7 in 6 (2.8%) patients in the combination/calcipotriol {4/4 alt.) group, and 6 in 6

(2. 9%) patients in the combination/calcipotriol ( 4/48) group. No statistically significant

differences were found between the treatment groups. Skin atrophy was identified in 4

(1.9%) patients in the combination group, 1 {0.5%) in the combin'ation/calcipotriol (4/4

alt.) group a·nd 2 (1.0%) in the combination/calcipotriol {4/48) group.

There were 379 adverse events in 137 {66.2%) patients in the co'mbination group, 439

in 146 {68.5%) patients in the combination/calcipotriol (4/4 alt.) group, and 444 in 1'51

(73.3%) patients in the combination/calcipotriol (4/48) group. The·most CQmmon events were nasopharyngitis, pru ritus and psoriasis.

There were no patient deaths during the study. Th irty-nine serious adverse events were reported for 29 patients in the study. All the events were considered unrelated ·to

study treatment , apart'from three events of psoriasis: one in a patient in the combina­

tion group, and one in each of two patients in the combination/calcipotriol (4/48) group. All these .three events resoi)Jed.

In the combinat ion group, 64 po.2%) randomi$ed patients w ithdrew from the study,'

compared to 56 (26.3%) in the combination/calcipotriol (4/ 4 alt.) group and 70

(33.5o/o) in the combination/calcipotrio1'(4/48)·.group. In terms of patients w ithdrawing

~ L 0: 0

./

MCB 0102 INT

Name of SponsortManufa~rer:

LEO Pharma A/S

Name· ~r-rnvestlgatlorial Product/ Finished Product, lr available:

Dovobet®, Daivobet®

Nil me or Active Substance:

Calci potr:iol + .betamethasone dipropionate

24-Aug-2004

Location ot study report in Regulatory (For National Authorit y Use only) Dossier for authorities

Volume:·.

Page:

due to adverse events, the figures were 14 (6.6%) patients in the combination group·,

11 (5.2%) in the ·combination/ca.lcipotriol (4/4 alt.) group and 16 (7._7%) in t he combi-

nation/calcipotriol (4/48) group.

During the whole $tudy, the mean weight of study medication used per patient was

898.8g in th~ .... ·c~mbinationgroup, 894.5~ in the combination/calci.potriol· ( 4/4 alt.)

gr6up, and 1044.09 in the conibir:'ation/calcipotriol ·( 4/48) group.

Nit:~ete~n patients underwent laborator-Y t_esting of adrenal function, 7 in the combina­

tion group, 6 in.t he combination/calcipotriol (4/4 alt.) group and 6 in the combina ­

tion/cal cipot riol (4/ 48) group. Only c;me patient had evidence of adrena_l suppression of

possible clinical significance post v isit i , and this patient was in the combina­

t ionjcalcipotr iol (4/48) group; this event appeared after 11 months of calcipotrio l

treatment.

Conclusion :

Combination t reatment for up to 52 weeks would appear to be safe ·and well tolerated

whether used on its own or alternating everv 4 weeks with ca lcipotriol treatment.

There'· is a trend towards the efficacy of com~i nation treatment used on its own for up to

5.2 weeks· bein9' better than that of 4 weeks combination treatment followed by 48

weeks of calcipotriol treatment~

Report date :

24-Aug-2004