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CLINICAL STUDY REPORT
CALCIPOTRIOL/BETAMETHASONE DIPROPIONATE ONCE DAILY IN PSORIASIS
VULGARIS
A phase III study comparing a new ointment containing calcipotriol 50J1g/g plus betamethasone (as dipropionate) 0.5 mg/g with calcipotriol 50J1g/g in new ointment vehicle, betamethasone (as
dipropionate) 0.5 mg/g in new ointment vehicle and the new ointment vehicle, all used once daily, in psoriasis vulgaris
An International, Mult icentre, Prospective, Randomised, Double-blind, 4 Arm, Parallel Group, Four Week
Study
The clinical study rep crt has be en re da cte d using the following principles: Wllere nece ssazy, information is anonymise d to protect the priv acy of study subjects and named persons a s.so cia ted "'ith the trial as well as to retain commercial confidential information. Summary data are included but data on individual study subj: e cts, including data listings, areremov e d. This rna y re suit in page numbers not being consecutively numbered. Ac: c:e ss to anonymised data on indiv;dualstudy subject rna y be obtained up on approval of a research proposal by the Patient and Scientific Review Board. Appendices to the clinical study report are omitted. Further details and principles for anonymisation is a v a.ila ble in the document LEO PH.ARJ\1A PRING IPLES FOR A.NONYMISATION OF CLINICAL TRIALDATA
MCB 0003 INT
Leo Pharmaceutical Products
Dermatological Medical Department
Final
sth October 2001
MCB 0003 INT 8th October 2001 Page 1 of 148
1 CLINICAL STUDY REPORT APPROVAL
Leo Pnarmacculical P rodLCIS Medical Oei>arlment
GC P I-SOP 02
CLINICAL STUDY REPORT APPROVAL FORM Sr uov COOE: REPORT TtTLE: REPORT 0ATE (00/MM/Yv) :
MCB 0003 1NT Calcipotriollbetamethasone dipropionate once daily in psoriasis 8Hl October 2001 vulqaris
By signing below 1 confirm that I have read tile Ctinic.al Study Report and confirm that to the best of my knowledge it accurately describes the conduct and results olllle study.
APPROVAL BY INTERNATIONAL CO-ORDINATING INVESTIGATOR
Or PRINTED NAME
oaoe _,L..'~*-1 -'-:'.l,_f _._o.,r_ - DO
APPROVAL BY DERMATOLOGICAL MEDICAL DEPARTMENT, LEO DENMARK
Dr PRIN TED NAME
APPROVAL BY-BIOMETRIC ~ENT in UK
M r PRINTED NAME
APPROVAL BY LEO DENMARK
Or PaiNTED NAME
Oislributi.Qt'l: Original .. Trial Master File Copy . . S ttdy R ep0n
Version. 0 1105101
Date /SI // 1 0/ 00
Date _1-;:~:
Page 2 of 148 8th October 2001 MCB 0003 INT
MCB 0003 INT 8th October 2001 Page 3 of 148
2 REPORT STATEMENTS
2.2 COMPLIANCE WITH GOOD CLINICAL PRACTICE
This Clinical Study Report is designed to comply with the standards issued by the
International Conference on Harmonisation (ICH) (E3 Structure and Contents of Clinical
Study Report; E6 Good Clinical Practice; and E9 Statistical Principles for Clinical Trials).
Page 4 of 148 8th October 2001 MCB 0003 INT
MCB 0003 INT 8th October 2001 Page 5 of 148
3 STUDY AUTHENTICATION
Leo Pnarmaoeutical P roducts Medical Department
AUTHENTICATION FORM
GCP ~SOPD2
Sruov Cooe: REPORT TITLE! REPORT DATE (DDIIIM/VV):
MCB 00031NT Calcipotriolmetamethasone dlpropionate once daily In psoriasis 08/10/0t vuloarls
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 subsequent amendments, and respecting national rules/regulations.
The study was performed in accordance with the approved Study Protocol and with Leo Pharmaceutical Product Standard Operating Procedures for GCP. The report provides a true and accurate record of the resuns obtained.
Authorised by: PCPC
Dale D'S 1 I ~ 1 O/ PRINTED NAME 00 ...... vv
Distribution: Original ~ Tria Master File Copy -+ Sl>Jdy Report
Vetsion: 0 1/05101
Page 6 of 148 8th October 2001 MCB 0003 INT
MCB 0003 INT 8th October 2001 Page 7 of 148
4 SYNOPSIS
Name of Sponsor/Manufacturer:
LEO PHARMACEUTICAL PRODUCTS
Location of study report in RegulatoryDossier
Name of Finished Product, if available:
DAIVOBET /DOVOBET
Volume:
Name of Active Substance:
Calcipotriol & betamethasonedipropionate
Page:
T tle of Study:
Calcipotriol/betamethasone dipropionate once daily in psoriasis vulgaris (MCB 0003 INT)
Internat onal Co-ordinating Investigator:
Dr
Centre Details (number, countries):
A total of 106 centres enrolled patients; nine centres in Belgium, 15 in Canada, 22 in France, 10 in Germany, four inIreland, six in Spain, five in Sweden and 35 in the Un ted Kingdom
Publ cat on References (intended references):
Study period details (start, end):
The first patient entered the study on 1st February 2001 and the last patient vis t was on 19th June 2001, giving astudy durat on of 20 weeks.
Major Objectives:
To compare the clinical efficacy of calcipotr ol plus betamethasone dipropionate combinat on ointment with calcipotriolin new ointment, w th betamethasone dipropionate in new ointment and w th new ointment veh cle, all used oncedaily, in patients with psoriasis vulgaris after up to four weeks treatment.
Study Methodology (trial rat onale and design, response variables):
Tw ce daily use of the combinat on ointment has been demonstrated to be an effective treatment for psoriasisvulgaris. Recent data has shown that once daily use has similarly good efficacy. The purpose of this study was toconfirm the high efficacy of once daily use of the combination treatment.
This was an internat onal, mult centre, prospective, randomised, double blind, 4 arm, parallel group, four week study.Patients were randomised to receive treatment with either calcipotriol plus betamethasone dipropionate combinationointment, or calcipotriol ointment, or betamethasone dipropionate ointment or ointment veh cle, in a 3:3:3:1 ratiorespectively.
Patients were assessed on inclusion and after 1, 2 and 4 weeks. Assessments performed were the Psoriasis Area andSever ty Index (PASI, wh ch is calculated from the assessments of redness, thickness, scaliness and extent), theinvestigators global assessment of disease severity on a 6-point scale (disease absent, very mild, mild, moderate,severe, or very severe) and the patients global assessment of treatment response compared to baseline on a 6-pointscale (worse, unchanged, slight improvement, moderate improvement, marked improvement, cleared).
At every vis t after visit 1, adverse events reported by the patient or observed by the investigator were recorded.
Number of Patients enrolled (according to treatment groups):
1605 patients were enrolled, and 1603 of these were randomised, 490 to combinat on, 480 to calcipotr ol, 476 tobetamethasone dipropionate and 157 to vehicle. All randomised patients were included in the intention-to-treatanalysis set on wh ch all efficacy analyses were performed. 1589 of the randomised patients were included in thesafety analysis set, 486 in the combination group, 475 in the calcipotriol group, 474 in the betamethasonedipropionate group, and 154 in the vehicle group.
Diagnosis and Main Cr teria for inclusion:
The main inclusion cr teria were:
Page 8 of 148 8th October 2001 MCB 0003 INT
Name of Sponsor/Manufacturer:
LEO PHARMACEUTICAL PRODUCTS
Locat on of study report in RegulatoryDossier
Name of Finished Product, if available:
DAIVOBET /DOVOBET
Volume:
Name of Active Substance:
Calcipotriol & betamethasonediprop onate
Page:
A clinical diagnosis of psoriasis vulgaris affecting at least 10% of arms, and/or 10% of trunk, and/or 10% of legs.
An investigators global assessment of at least mild disease sever ty.
Aged 18 years or above.
Signed informed consent provided before enrolment.
The main exclusion criteria were:
A current diagnosis of unstable forms of psoriasis in the area to be treated.
Other inflammatory skin diseases that may confound the evaluation of the psoriasis.
Systemic antipsoriatic treatment or PUVA therapy within the 4 week per od prior to or during the study.
UVB therapy w thin the 2 week period prior to or during the study.
Topical antipsoriat c treatment of psoriasis of trunk or limbs during the study.
Initiat on of or changes to non antipsoriat c concom tant medication that could affect psoriasis during the study.
An abnormality in calcium homeostasis associated with hypercalcaemia.
Concomitant treatment of scalp or facial psoriasis with retinoids, calcipotr ol, tacalc tol, or WHO group IV topicalcort costeroids.
Concomitant treatment of facial psoriasis with WHO group III top cal corticostero ds.
Treatment of lesions with study med cation where top cal corticostero d is not ind cated.
Females who are pregnant or breast feeding.
Current participation in another clin cal trial.
Investigational Product (name, dose [amount and frequency], dosage form, route of administration, batch numbers):
Ointment containing calcipotr ol 50g/g plus betamethasone dipropionate 0.5mg/g was applied topically once daily topsoriasis of the trunk and/or limbs. Batch number used : 00 361 83 01.
Treatment Duration (washout, treatment, follow-up):
Four weeks.
Reference Therapy:
There were three reference therapies:
Calcipotriol 50g/g in the same ointment base as the combination product. Batch number used: 00 372 8201.
Betamethasone dipropionate 0.5mg/g in the same ointment base as the combination product. Batch numberused: 00 372 81 01
The ointment vehicle of the combination product. Batch number used: 00 351 83 01.
All medicat ons were applied top cally once daily to psoriasis of the trunk and/or limbs.
The three controls were chosen following the CPMP gu deline on Fixed Combination Med cinal Products.
Cr teria for evaluation
Eff cacy :
Patients who were classified as having absence of disease or very mild disease by the investigators global assessmentof disease severity were considered to have controlled disease.
Patients who were classified as having marked improvement or clearance by the patients global assessment oftreatment response were considered to be a treatment success.
There were two primary measures of efficacy: the mean percentage change in PASI from baseline to endof treatment and the proportion of patients having controlled disease at the end of treatment.
MCB 0003 INT 8th October 2001 Page 9 of 148
Name of Sponsor/Manufacturer:
LEO PHARMACEUTICAL PRODUCTS
Location of study report in RegulatoryDossier
Name of Finished Product, if available:
DAIVOBET /DOVOBET
Volume:
Name of Active Substance:
Calcipotriol & betamethasonedipropionate
Page:
There were two secondary measures of eff cacy: the proport on of patients having treatment success at the end oftreatment and the mean percentage change in PASI after one weeks treatment (to measure speed of response).
Safety:
Adverse events were assessed by the investigator for relat onship to study med cation and, if they occurred on theskin, whether they were lesional/periles onal or not. Events were classified using MedDRA version 3.3.
Statistical Methodology (as in protocol, or, especially, if different than originally presented in protocol):
The percentage change in PASI from baseline to end of treatment was compared between the treatment groups usinganalysis of variance including centre and treatment in the model as design variables. The difference between thecombinat on group and the other three groups, its 95% confidence interval and a P-value were calculated from theanalysis of variance. The percentage change in PASI from baseline to week 1 of treatment was analysed in the sameway.
The proport on of patients w th controlled disease at the end of treatment was compared between the treatmentgroups using logist c regression including centre in the model as a design variable. The odds of controlled disease forcombinat on treatment relative to each of the other treatments, ts 95% confidence interval and a P-value werecalculated. The proport on of patients w th treatment success at the end of treatment was analysed in the same way.
The percentage of patients experiencing adverse events and the percentage of patients experiencinglesional/periles onal adverse reactions was compared between treatments by chi-square tests. The differencebetween treatments was estimated by the odds rat o with 95% confidence limits.
Patient Summary (patient dispos t on, demographics and baseline characteristics):
111 (6.9%) patients w thdrew during the study, 20 (4.1%) in the combinat on group, 40 (8.3%) in the calcipotriolgroup, 26 (5.5%) in the betamethasone group and 25 (15.9%) in the vehicle group.
The treatment groups were well balanced at baseline for age, sex, ethnic origin, PASI, investigators globalassessment of disease sever ty and duration of psoriasis (Table S1)
Table S1: Demographics and baseline characteristics of randomised patients_________________________________________________________________________ Combinat on Calcipotriol Betamethasone Vehicle
(n=490) (n=480) (n=476) (n=157)_________________________________________________________________________
Mean age (years) 47.6 48.9 48.2 49.8Males (%) 62.9 59.0 61.1 56.1Caucasians (%) 96.5 96.0 97.7 97.5Mean PASI 9.9 10.4 9.8 9.5Patients with moderatedisease severity (%) 63.5 62.5 62.4 63.1Mean duration ofpsoriasis (years) 18.3 20.3 19.4 18.3_________________________________________________________________________
Efficacy Results (for primary and secondary endpoints, with tables):
PASI (change from baseline to end of treatment)The mean percentage change in PASI from baseline to end of treatment was -71.3 in the combination group, -46.1 inthe calcipotriol group, -57.2 in the betamethasone group and -22.7 in the veh cle group (Table S2). The differences inthese changes between the combinat on group and each of the other three groups were all statist cally significant (P
