MCO 9701 NL Study 27 February 1998 Page 7of84

2 SYNOPSIS

Study code:

MC09701 NL.

Title:

Calcipotriol Ointment and Cream and the Minimal Erythema Dose.

Subtitle:

Effect of Calcipotriol Ointment 50 ~g/ g and Calcipotrio1 Cream 50 J.tg/ g on the

Minimal Erythema Dose in Healthy Volunteers.

Study objective:

To determine the optimal time of application of calcipotriol ointment and cream

when combined with UVB-therapy.

Study design:

This was a single-centre, single-blind, within-subject controlled, randomised,

prospective study divided into 2 phases. Phase l, the qualification phase, lasted

up to 14 days and Phase II, the MED test phase, lasted 3 days.

Sample size;

A total of 20 subjects were to be included in the study for each formulation.

Eligibility criteria:

Included were healthy subjects with Skin Types II to III, of either sex, aged ~18

years. Females of child-bearing potential had to use an adequate method of

contraception and to have a negative pregnancy test at inclusion.

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Excluded were subjects with uneven pigmentation of the back or the buttocks,

thought to interfere with the results of the study, who had been sunbathing or

used artificial sun 6 weeks prior to study entry, who used any concurrent

medication other than oral contraception or who were hypersensitive to any of

the excipients of calcipotriol ointment or cream. Women who were pregnant,

wishing to become pregnant during the study or were breast-feeding were also

excluded. Finally, subjects who were known or suspected of not being able to

comply with a study protocol, who were concurrently participating in any

other trial, who had been treated with an investigational drug within 3 months

prior to Visit 1 or who had previously been randomised in this study were

excluded. All subjects gave their signed informed consent before being enrolled

into the study.

Investigational productsjUVB:

Calcipotriol ointment 50 ~g/ g and calcipotriol cream 50 ~g/ g were used in the

study. Calcipotriol ointment or cream (approximately 7mg/cm2) was applied to

areas of the back the evening before, in the morning of, 2 hours before,

immediately before and immediately after the MED test. One area acted as

control with no application at all. UVB from a TL20W /12 lamp (Philips) was

used for MED testing and the following doses were used: 20, 25, 32, 40, 50 and

64 mJ/cm2.

Primary response criterion:

The Minimal Erythema Dose for each application time.

Assessments:

All assessments of response and safety took place at Visit 4. The erythemal

reaction was determined for each test site, using a scale from 0 to 4. For each

application time the Minimal Erythema Dose was determined as the lowest UV

dose resulting in a erythemal reaction of at least 2 (a uniform redness with

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MCO 9701 NL Study 27 February 1998 Page9 of84

sharp borders). Also, the skin reflectance of every site was measured. Adverse

events were similarly recorded at Visit 4.

The study procedures are summarised in the schedule below:

Phase I Phase II

Qualification MED test

Visits 1 2 3 4

Days -14-1 1 2 3

Subjects history ...

Pregnancy test 1) .. Randomisation ...

Application of investigational * ... product

MEDtest ...

Clinical assessment:

Erythemal reaction ...

* MEDreading ... Skin reflectance measurement

Clinical photo .. Recording of adverse events ..

n In female of child-~aring potential.

Efficacy results:

The first subject was enrolled in the study on 10 July 1997 and the last subject

completed the study on 5 September 1997, thus the study was conducted over a

period of 57 days.

Forty subjects were emolled in the study. One subject was lost to follow-up

prior to randomisation and one subject was lost to follow up following the first

application at visit 2. Thus the safety population consisted of 38 subjects. One

subject had the wrong treatment applied to some of the area and was excluded

from the Intention-to-Treat population which consisted of 37 subjects. The Per

Protocol population was identical to the Intention-to-Treat population.

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The primary efficacy criterion was the Minimal Erythema Dose (MED) for each

application time. The distribution of the MED for the different application times

and the analysis of the distribution of the MED for the different application

times are shown for calcipotriol ointment and calcipotriol cream, respectively in

the four tables below.

Minimal En; them a Dose for calcipotriol ointment by application time (efficaet; lation)

Application Appl i cation Application Application Appl icat ion No the ev .. ning in th" 2 hours i!Miediacely ilMlediately

application before UV morning before !N before UV after UV In 191 In 19) (n 1 9 ) (n c 191 (n 19) (n 19)

Number of Number of ~Wilber of Null'.ber o f Number of Number of su.bjects su.bjects sllbje::ts su.bjeets subj ects subject s

20 mJ/cm' 5 6 4 s 1 4 25 mJ/cm' 6 2 5 3 () 6 32 rr.J/cm' 4 6 5 4 0 4 40 rr.J/cm1 2 ) 3 3 0 s 50 mJ/cm' 1 2 0 0 64 rr.J/cm' 1 0 0 0 >64 mJ/cm' 0 0 0 2 19 0

Analysis of the Minimal Erythema Dose for calcipotriol ointment b1J application time (efficacv population)

Median o f ME:O

Compar i son" lo'ith:

No applicaeion

Application the evening before

Application in ehe morning

Applicat ion 2 hours before

Applicat i on immediately before

Applicat.ion immediately a f ter

Jlpplication No the evening

application before UV (n 19) (n a 19)

2SmJ /cm' 32mJ/cm'

p . 0 .4 5

Applica t i on in the

morning In 191

l2rnJ/cm1

p : 0.52

p 1.00

Jlpplication 2 hours

before W (n 1 9)

J2mJ/cm'

p O.l3

p = 0.34

p 0 .22

Application imme:Hately before W

In = 19)

>64mJ/c m'

p < 0.001

p < 0.0()1

p < 0 . 001

p < O.OOl

Application i!Mied iately lifter W In z 19)

25mJ/cm'

p 0 .92

p o.so

p 0 .46

p 0.13

p < 0.001

1) Comparison by Wilcoxon S i gned Rank Test and a Bonferroni corrected significance level of 0 . 05115 0 .0033 .

MCO 9701 NL Study 27 February 1998 Page11 o/84

Minimal En;thema Dose for calcipotriol cream by applicntion time (efji_caetJ po]?_ulation)

Applicu i on Application Appl ication Appl ica tion Appl i ca t i on No the evening in the 2 hours immediately iiMiediately

64 mJ/cra' 0 0 0 0 13 0

Analysis of tile Minimal Enjtlzema Dose for calcipotriol cream by application time (efficaetJ J?SPulation)

Application Application Application Applicuion Application No ~he evening in the 2 hours i mmediacel y immediacely

a pplicat. i on before W morning before IN be!on w af t er W (n lB In 19) In 19) In 19) en 191 (n Ul

Median o! M0 28.SmJ/c:m' 25mJ/J/cm' 2SmJ/cm'

Comparison' with:

No ilpplica tion p 0.06 p . 0 . 34 p 0 .56 p < 0 .001 .. . 0 .27 Application the evening before - p 0 . 53 p 0 . 03 p < 0.001 p 1.00

Applicat ion in the morning p 0 .09 p < 0.001 p - 0 .73

Application 2 hours before p c 0 .001 p o.os

Applicat ion im~~~ediately

before p < 0.001

Application im.'!lediately atter

ll Comparison by Wilcoxon Signed Rank Teet and a Bonferron i correct.ed s i gni ficance level o f o. os/1 s- o. oon .

The results for the ointment and the cream are similar. The distribution of the

MED for the areas with application immediately before UVB was statistically

signifkantly different from the distribution in aJI other groups, including the

control (no application). There was no statistically significant difference

between the distribution of the MED in the control group and all other groups

and no statistically significant difference between all the other application

groups.

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A secondary efficacy criterion was the skin reflectance measurements expressed

as the Erythema Indext in the various groups. The skin reflectance for the

various groups for different doses of UVB is shown in the two figures below for

calcipotriol ointment and calcipotriol cream respectively.

Skin re eclance: Cnlci trio! ointment

Skin reflectance

20 30 40 50 Light dose (mJI cm2)

60 70

- No application

-- Application the evening before UVB

-Application in the morning

--Application 2 hours before UVB

--Application immediately before UVB

-Application immediately after UVB

1 The Erythema Index is calculated with the following equation: 100 [log (R660nnIGs?Onm)], where

~run = (red reflectance from skin) 1 (red reflectance from white normal) and Gs70 nm = (green reflectance from skin) I (green reflectance from white normal).

MCO 9701 NL Study 27 February 1998

Skin reflectance: Calcipotriol cream

Skin reflectance

10~------------------------------~

20 30 40 50 60 70 Light dose (mJ/ cm2)

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--No application

--Application the evening before UVB

--Application in the morning

-- Application 2 hours before UVB

-Application immediately before UVB

--Application immediately after UVB

Again the results for the ointment and the cream are similar. The graph for the

application immediately before UV irradiation is dearly different from all the

other graphs, showing that calcipotriol ointment and cream blocks transmission

of UVB when applied immediately before UVB irradiation. There is no

difference between the other application times, including the control.

Safety results:

There were 2 adverse events in 2 subjects, as listed in the table below.

Adl'erse el'ents listed b]L system -organ class1

System-organ class'

Skin and appendages diso~ders

Total nu=ber of adverse events

Total nucber o! subjects (tl

Calcipotriol ointment so "g/g (n 201

0

0

0 10.01

calcipOtriol ere~ 50 1'919 (n 181

2

2

2 111.11

11 classificat ion according to tne WHO Adverse Reaction Dictionary, 31. oececber 1992 .

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One subject had a sunburn of the treated skin of mifd severity. One subject

experienced painful skin at the treated areas of moderate severity. Both adverse

events were judged to be probably related to the study drug. There was no

indication as to whether the adverse events were limited to areas with a specific

application time. The adverse events were recorded at the last visit and follow-

up was considered unnecessary.

There were no serious adverse events or other significant adverse events

reported.

Conclusion:

This study showed that calcipotriol ointment as weiJ as the cream blocks UVB

transmission when applied immediately before UVB irradiation. There was no

statistically significant difference between the control (area with no application

of study drug) and the other application times, and no difference between the

other application times.

From an efficacy point of view calcipotriol ointment or cream may be applied at

any time up to 2 hours prior to UVB therapy.