CLINICAL STUDY REPORT

Transcription

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CLINICAL STUDY REPORT
COMPARATIVE EFFECTS OF CALCIPOTAIOL (50 MCG/G)(DOVONEX®
OINTMENT) AND 5% COAL TAR/2% ALLANTOIN/0.5% HYDROCORTISONE
CREAM (ALPHOSYC81 HC CREAM) iN THE TREATMENT OF PSORIASIS
VULGARIS
A multicenter. randomised. open, parallel group comparison
VOLUME I
The clinical :;tudy report has. be en redacted us.ing the following principles.: Where necess.ary, information i:; anonymise d to
protect the privacy of study subject;. and named persons associated -.vith the trial a s well as to retain commerc:ia1 confidential
information.
Summary data are included but data on individual study subjects, including data listings, are remov ed. 1bis may result in
pagenumbersnot being consecutiv ely numbered.
Access to anonymise d data on individualstudy s.ubj ect may be obtained upon approval o fa research proposal by the·Patient
and S.cientifie Re-view Board.
Appendices to the clinical stu dy report are omitted.
Further details and principles for an onymisation is av ailable in the document LEO PH.ARMA PRINCIPLES FOR
ANONYMISATION OF CLINICAL TRIAL DATA
STUDY CA 9101 UK/GP 92
Medical Department
leo laboratories limited
longwick Road
Princes Risborough
Bucks
HP27 9RR
UNITED K1NGDOM
•,;
.
....
00147192
1 December 1993
Page 2
Study CA 9101 UKIGP92
Page 3
ABSTRACT
Objectives: To compare the antipsoriatic efficacy, tolerability and acceptability
of Oovone~ Ointment and Alphosyle HC Cream in patients with plaque psoriasis
affecting at least 100 cm 2 of the trunk and/or limbs.
Methods: The study was a multicenter, primary care, randomised, open, parallel
group comparison. General Practice patients of either sex, aged ~16 years, with a
clinical diagnosis of plaque psoriasis on the trunk and/or limbs of at least 100 cm 2
were included after giving signed informed consent. Eligible patients applied either
Dovone~ Ointment (50 meg/g) or Alphosyr HC Cream (5% coal tar, 2% allantoin,
0.5% hydrocortisone), twice daily for up to 8 weeks. The following assessments of
efficacy were made after 4 and 8 weeks; Investigators assessment of overall
response to treatment,redness, thickness, scaling, overall severity of psoriasis and
area of skin affected; patients assessment of severity, itchiness and skin
flakiness/scaliness, overall efficacy and acceptability of treatment and adverse events.
Results: Investigators assessment showed Dovonex® Ointment to be significantly
more effective than Alphosyl® HC Cream in respect of the primary efficacy criterion,as
shown below.
' Investigators also ·found Dovonex® Ointment significantly more effective. than
Alphosyf!> HC Cream in the reduction in the total sign score (p:::0.002}, and in
reducing scaliness (p<0.0001) and thickness (p=0.001 ). The proportion of patients at
end of treatment with <1 00 cm 2 of affected skin was significantly greater in the
· Devone~ Ointment group ·(p<0.05). Patients found. Dovonex® Ointment to be
significantly more effective than Alphosyfl HC Cream in overall efficacy (p<0.02), and
in reducing flakiness/scaliness of skin (p=0.001 ).
.
Adverse events, which were predominantly mild or moderate and .application related,
were recorded in 15 (23.1%). patients given Dovonex0 Ointment and in 10 {17.2%)
patients given Alphosyr HC cream. Adverse events contributed ·to treatment
withdrawal in 1 (1.5%) patient given Dovone~ Ointment and in 3 (5.2%} patients given
Alphosyj® HC Cream.
Conclusion: Dovone~ Ointment is .significantly more effective than Alphosyr HC
Cream in the ·t.reatment of General Practice patients with plaque. psoriasis,with 8imilar
tolerabil~. Acceptability of Dovone~ Ointment tends to be better · than that of
Alphosyr HC Cream.
Page 4
Study CA 91 01 UK/GP92
CliNICAL STUDY REPORT APPROVAL
This Clinical Study Report has been approved by:
rtment
Leo Laboratories Limited
Longwick Road
Princes Risborough
HP27 9RR
Bucks
UNITED KINGDOM
Tel:
Fax:
Signature
B Sc
Clinical Biometrics
oratories Limited
Longwick Road
Princes Risborough
HP27 9RR
Bucks
UNITED KINGDOM·
Tel:
Fax:
Signature
Date
.~~ J
t 2./
~3
-
NGDOM
Tel:
Signature
Date
' 0 - t2 -
,3
Study CA 9101 UK/GP92
Page 5
REPORT AUTHORS
ent
Longwick Road
Princes Risborough
Bucks
HP27 9AA
UNITED KINGDOM
Tel:
Signature
Page 6
tABLE OF CONTENTS
Page
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
CLINICAL STUDY REPORT APPROVAL . . . . . . . . . . . . . . . . . . . . . . . . 4
REPORT AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
TABLE OF CONTENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
INVESTIGATORS AND CENTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
COMPANY PERSONNEL.. . . ....... .. .. . . . ........... .. .. .. 12
1
INTRODUCTION AND RATIONALE . .... . ..... . ..... . ..... . ... 14
2
OBJECTIVES OF THE STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3
DESIGN OF STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4
CRITERIA FOR SELECTION OF STUDY PATIENTS ..... .. . . ..... 23
4.1
4.2
INCLUSION CRITERIA .. .... .. . ... ... . ... ... . ·. . . . . . . . . . . . . 23
EXCLUSION CRITERIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5
CRITERIA FOR EARLY WITHDRAWAL FROM THE STUDY ....... .. 24
6
TREATMENT ASSIGNMENT METHOD .. . .. .. . . .. . .... .. .. .... 24
7
BREAKING OF THE TREATMENT CODE . . . . . . . . . . . . . . . . . . . . . . 24
8
STUDY MEDICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
9
CONCOMITANT THERAPY . ... . ............ . ... . ...... ... .. 26
10
STUDY PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
10. 1 MEDICAL HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
10.2 CLINICAL ASSESSMENT . . .......... . . . ... . ..... . ..... . ... 27
10.3 RECORDING OF ADVERSE EVENTS . . . . . . . . . . . . . . . . . . . . . . . . . 29
Page 7
TABLE OF CONTENTS- confd
Page
11
CRITERIA FOR EFFECTIVENESS AND SAFETY . . . . . . . . . . . . . . . . . 29
12
COMPLIANCE WITH ETHICAL RESPONSIBILITIES . . . . . . . . . . . . . . . 30
13
RESULTS . .. .. . ........ . .. . . . .. . . ... . . .. .. .. ... ... . .... 31
13.1 STUDY PERIOD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13.2 STUDY POPULATION . . . . . . . . . . . . . . . . . . . . . . . . . . .
13.3 BASELINE COMPARISON OF TREATMENT GROUPS ...
13.4 DURATION OF RANDOMISED TREATMENT ........ .. .
13.5 EFFECT OF STUDY DRUGS ON PSORIASIS . . . . . . . . . .
13.6 CONCOMITANT DRUG TREATMENT .... . .... . ......
13.7· SAFETY OF STUDY DRUGS . . . . . . . . . . . . . . . . . . . . . .
.........
.. . . .. . . .
. ..... ...
. .. .. .. ..
.. . .. . . ..
. .. . ... . .
.........
31
31
35
39
40
65
65
14
COMPLIANCE WITH GOOD CLINICAL PRACTICE . . . . . . . . . . . . . . . 70
15
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
16
CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4
17
REFERENCES ... . .. .. ........· . . . . . . . . . . . . . . . . . . . . . . . . . . 75
APPENDIX 1:
APPENDIX Ill:
APPENDIX IV:
APPENDIX II:
Statistical Report
Study Protocol
Case Record Form
Individual Subject Data are contained in Volume 2
Page 8
INVESTIGATORS AND STUDY CENTERS
LRCP MRCS MB BS MRCGP DRCOG
Page 9
Page 10
BSc MB ChB DRCOG MRCGP
MB ChB BSc MRCGP DRCOG
Study CA 91 01 UK/GP92
MB ChB BSc DRCOG
Page 11
Page 12
COMPANY PERSONNEL
STUDY MONITORING AND DATA VALIDATION
Principal Clinical Project Co-ordinator
Longwick Road
Princes Risborough
Bucks
HP27 9RR
Trial Monitors
STATISTICAL ANAL VSIS
B Sc (Pharm) M R Pharm S
linical Biometrics
oratories Limited
Longwick Road
Princes Risborough
Bucks
HP27 9RA
Longwick Road
Princes Risborough
Bucks HP27 9RR .
Study CA 91 01 UKIGP92
SECRETARIAL RJNCTIONS AND DATA COMPUTERISATION
-BSc(Hons)
Clinical Biometrics
Medical Department
Longwick Road
Princes Risborough
Bucks
HP27 9RR
Page 13
Page 14
1
INTRODUCTION AND RATIONALE
1.1
PSORIASIS
Psoriasis is one of the most common chronic skin diseases, with a prevalence
generally estimated at between 1.4 and 2.9% 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. Dermal blood vessels are dilated and there is infiltration of the
skin with immunologically active cells (3,4). The pathogenesis is not yet well
understood, and controversy still exists as to whether the primary abnormality
resides in the epidermal keratinocytes, dermal fibroblasts, cells of the immune
system, blood vessels, or a combination of these (3,4).
Psoriasis can be treated either by topical or by systemic methods.
The
commonly used topical treatments are corticosteroids, tar, dithranol, ultra-violet
light (UVA) and grenz rays. Systemic treatments are generally reserved for
severe disease as they are all associated with significant toxicity. The most
commonly used are psoralen combined with UVA (PUVA) methotrexate,
etretinate (vitamin A), hydroxyurea, and cyclosporin A (5,6).
1.2
PSORIASIS AND VITAMIN D ANALOGUES
A number of studies have suggested that calcitriol (1,25 dihydroxyvitamin 0 3)
and various vitamin 0 3 analogues may offer a new.therapeutic approach in the
treatment of psoriasis.
Receptors for calcitriol (the biologically active form of vitamin 0 3) have been
demonstrated in skin cells (5,6) and calcitriol has been shown to inhibit cell
proliferation (7,8) and induce terminal differentiation in cultured human
keratinocytes (6,7,9). An immunomodulating role for calcitriol and other vitamin
0 3 analogues has recently been suggested (10, 11), as calcitriol exerts an
inhibiting effect on the T lymphocyte proliferative response to interleukin I (12).-
Page 15
Data from various clinical studies using calcitriol and closely related analogues
is accumulating, but with the exception of calcipotriol the currently available
clinical documentation is based upon studies which include small or modest
numbers of patients and some of the trials are open and/or uncontrolled.
However, their results may be summarised as follows:
1.
Calcitriol and alfacalcidol (1a OH-03 ) given by the oral route may
improve the clinical condition in patients with psoriasis. However, it can
take several weeks or months for this effect to become apparent and the
dose of vitamin 0 used is limited by an increase in blood and urinary
calcium {6,13, 14,16,21 ).
2.
Preliminary work suggests.that topical 1,24 dihydroxyvitamin 0 3 may be
effective and safe in a concentration of 2 J.Lg/g in petrolatum for the
treatment of psoriasis but·further studies are needed (15,17,18).
3.
Tapically applied calcitriol has been reported to be effective for the
treatment of psoriasis vulgaris (6,21 ,22). Other studies, however, failed
·to demonstrate an antipsoriatic effect of topically applied calcitriol
(19,20). Its therapeutic effect depends on the formulation used, the
strength of the formulation (ie. 11g 1,25(0H):PJg) and on whether or not
occlusion is used. The risk of development of hypercalcaemia primarily
relates to the amount of calcitriol applied on the skin, ie. on the strength
of the formulation and on the amount of ointment or cream used. For
an adequate antipsoriatic effect to be obtained with calcitriol. the
strength of the topical preparation needs to be in the order 3 - 15 119/g
(22,23).
As a consequence, research has been directed to developing new vitamin. 0
analogues that possess a more favourable therapeutic profile than calcitriol.
Page 16
1.3
CALCIPOTRIOL
1.3.1 Pharmacology
Calcipotriol is a new vitamin D analogue synthesized at the research
laboratories of Leo Pharmaceutical Products.
Pre-clinical studies have demonstrated calcipotriol to have a high binding affinity
to the cellular receptor for calcitriol (1 ,25 dihydroxyvitamin 0 3), the biologically
active form of vitamin 0 3 (24) and calcipotriol has been shown to be both a
potent regulator of cell differentiation and an inhibitor of cell proliferation in
human keratinocytes (24,25). Its systemic effect on calcium metabolism in rats
is 100 to 200 times less than that of calcitriol (24).
1.3.2 Completed clinical studies in psoriasis
Clinical studies of calcipotriol started in 1987.
Initial work showed that
calcipotriol cream containing 33 J.lg/g and 100 J.Lg/g applied twice daily for 6
weeks was statistically significantly better than placebo in terms of reducing
redness, thickness and scaling in patients with psoriasis vulgaris (26). There
were no adverse events reported and laboratory analyses showed no significant
changes. It was especially noteworthy that no change in serum ionised oalcium
was found. In another dose-ranging study in psoriasis, calcipotriol ointment 50
J.lg/Q was found to be slightly but statistically significantly superior to 25 J.LQ/g
and equally effective as the ointment containing 100 119/g after 8 weeks
. treatment {27). consequently, calcipotriol ointment 50 119/g was selected for
further study in a large scale clinical trial programme in patients with psoriasis
vulgaris.
A range of studies in this programme have been completed so far. A modified
PASI (Psoriasis Area and Severity Index) (28) was the primary method of
assessment of antipsoriatic efficacy. Each study commenced with a 2 week
wash-ouVqualification phase when· the patients used only emollient. on their
psoriasis.
Page 17
In a prospective randomised, double-blind, right/left comparison of calcipotriol
ointment 50 Jlg/g and placebo ointment (vehicle alone) applied twice daily, the
reduction of PASI with calcipotriol was significantly greater than that for placebo
at 2 and 4 weeks of treatment (29). Sixty-six patients were treated. In 46
patients (75.4% of the patients available for assessment after 4 weeks
treatment), both the investigator and the patient considered that the response
of the side of the body treated with calcipotriol for 4 weeks was better than that
on the side treated with placebo. In these cases all of the body was then
treated with calcipotriol ointment for another 4 weeks. A further improvement
was recorded on the side previously treated with calcipotriol and a significant
improvement was seen on the side previously treated with placebo.
Calcipotriol ointment 50 Jlg/g was also compared with betamethasone ointment
0.1% (as 17-valerate) in two prospective randomised, double-blind studies, one
parallel group and one right/left comparison.
In the parallel group study 409 patients with psoriasis were randomised . to
receive either calcipotriol 50 Jlg/g or betamethasone 0.1% treatment applied
twice daily for 6 weeks (30). There was a statistically significant fall in PASI in
both groups after 2,4 and 6 weeks of double-blind treatment. The greatest rate
of improvement was observed during the first 2 weeks of treatment. Further
improvement occurred in the subsequent 4 weeks especially in the scores for
redness and infiltration. In the patients' overafl assessment of response to
treatment, 61.2% of patients on calcipotriol ointment and 50.5% of patients on
betamethasone recorded a "marked improvementa or ·cleared". This study
showed that calcipotriol was as effective as (PASI) or superior to (patients'
overall assessment) betamethasone ointment.
In the righVIeft comparison, 345 patients were randomised and treated in
double-blind fashion for 6 weeks with calcipotriol 50 J.Lg/g twice daily on one
side of the body and betamethasone 0.1% twice daily on the other side (31).
Again there was a statistically significant fall in PASI for both treatments after
Page 18
Study CA 9101 UK!GP92
2,4 and 6 weeks treatment. However, the reduction in PASI with calcipotriol
ointment was statistically significantly greater than that for betamethasone at
all visits. There was also a highly statistically significant difference in favour of
calcipotriol ointment recorded in both the patients' and investigators' overall
assessment of response to treatment at 2,4 and 6 weeks. When asked to state
a preference, 31.9% of investigators and 29.2% of patients thought the
response with calcipotriol was better than with betamethasone at end of doubleblind treatment. Only 13.2% of both the investigators and the patients thought
the response was better with betamethasone.
Both the parallel group and the righVIeft calcipotrioVbetamethasone comparative
trials were followed by optional follow-up phases.
In both studies it was concluded that a repeat course of treatment with
calcipotriol ointment
SO~glg
applied twice daily for up to 12 weeks in patients
who had experienced a flare-up/relapse following an earlier satisfactory .
response to 6 weeks treatment with calcipotriol is safe, well tolerated and
effective.
Calcipotriol ointment (50 p.g/g) applied twice daily without occlusion has been
compared to self-treatment with short-contact dithranol therapy in a multicentre, randomised, open, parallel group study performed in the United
Kingdom, Canada and Ireland (34). Dithranol cream was used at the highest
strength tolerated: up to 2%. Two well matched groups, each comprising 239
out-patients with mild to moderate psoriasis vulgaris completed up to 8 weeks
of treatment with either calcipotriol or dithranol. The mean PASI fell by 58% in
the calcipotriol group and by 42% in the dithranol group. Investigators and
patients assessed calcipotriol as significantly more effective than. dithranol and
patients
also assessed calcipotriol as significantly more · acceptable.
Significantly more side effects were seen on dithranol than on calcipotriol.
Approximately 300 patients have been recruited to an open-label nor:tcomparative 12-month extension of this study, which is currently under analysis.
Page 19
In all the studies calcipotriol was well tolerated, adverse events being mainly
application related lesional/perilesional irritation which both tended to be mild
and to subside despite further treatment.
(Irritation was also reported for
betamethasone, for placebo treatment and for dithranol cream). Laboratory
parameters showed no evidence of haemopoietic abnormality or adverse effect
on hepatic or renal function. Mean serum calcium did not change.
Excess use of calcipotriol ointment has been associated with hypercalcaemia
in a number of cases. In one case (30) a patient was reported to have used
400g calcipotriol ointment over 10 days and in another case (32) a patient with
exfoliative psoriasis was treated with 200g ointment over a week. Both patients
had a temporary elevation of serum calcium wh ich returned to normal after
discontinuing calcipotriol treatment.
The safety of treatment with cafcipotriol ointment in terms of its effect on
systemic calcium metabolism and on biochemical indices of bone turn-over was
investigated in a randomised, double-blind, placebo-controlled, parallel group
study of 34 patients with mild to moderate psoriasis vulgaris (37). The patients
applied calcipotriol ointment (50 Jlg/9) or placebo ointment twice daily (without
occlusion) for 3 weeks. The mean amount of calcipotriol ointment used over
the 3-week period was 40.3 g per week (range 8.2 -?95.4). Serum values of
ionized calcium, parathyroid hormone, 1.25(0H)20 3, calcitonin, alkaline
phosphatase (bone specific isoenzyme), osteocalcin and 24-hour urinary
excretion of calcium were not affected by treatment of calcipotriol ointment.
In a small open, non-comparative trial, 15 patients who had completed the
above ointment dose-ranging study (27) were treated for an average of 31
weeks (range
15 ~ 41 weeks) with calcipotriol ointment {50 J.Lg/g) up to 100
g per week (33). At the end of treatment 80% of the patients had achieved at
least "moderate improvementa of their psoriasis .
Mild and transient
lesionaVperilesional skin irritation was seen in 3 patients. Skin biopsies showed
no evidence of skin atrophy having developed during long-term treatment with
Page 20
calcipotriol ointment.
Open, long-term multicentre studies involving
161 out-patients(35) with
psoriasis vulgaris,and 203 psoriatic patients in General Practice(36) and who
were treated continuously or intermittently over a one year period with
calcipotriol ointment
50~g/g,have
shown that twice daily application of
calcipotriol ointment which was not allowed to exceed 1OOg per week was both
safe and efficacious.
Some research has already been performed on combining calcipotriol with other
antipsoriatic treatments. A small pilot study in 20 patients investigating the
effect of combining calcipotriol therapy and UVB therapy has previously been
reported (38). No significant benefit was demonstrated by the addition of UVB.
The combined therapy was well tolerated. A larger randomised, open, right/left
comparative study of calcipotriol ointment combined with UVB treatment has
recently been completed. One hundred and one patients received calcipotriol
:t UVB therapy on one side of the body and calcipotriol ointment alone on the
opposite side of the body for a period of up to 8 weeks. Combined treatment
was found to be significantly more effective than calcipotriol alone.
The
combined therapy was well tolerated (MC390 Study Report paper in
preparation).
A study to assess the value of combining PUVA therapy with calcipotriol
ointment has recently been completed in France. This was a double-blind,
parallel group study of 12 weeks duration in 107 patients. Patients applied
calcipotriol (50J.Lg/g) or placebo ointment for 2 weeks and then started PUVA
therapy for up to 10 weeks while continuing the ointment treatment. The study
demonstrated that combined treatment with calcipotriol ointment and PUVA is
highly effective and is safe and well tolerated for the treatment of extensive
plaque psoriasis. Pre-treatment with- and subsequent addition of - calcipotriol
ointment to PUVA did not significantly reduce the cumu lative dose of UVA
Page 21
irradiation given to the subset of patients who achieved the target treatment
response (>90% reduction of PASI). However, when all patients analysed were
considered calcipotriol significantly reduced the total dose of UV A needed to
clear the patients' psoriasis (MC590 Study Report; paper in preparation).
In a randomised, multi-centre, double-blind, placebo controlled, parallel group
study the possible beneficial effect of adding catcipotriol to cyctosporin A has
been investigated in 69 patients with severe psoriasis. The patients were
treated for up to 6 weeks with cyctosporin A capsules at a dose of 2mglkg/day
combined with either calcipotriol ointment (50!-!g/g) or placebo ointment applied
twice daily without occlusion.
A statistically significant difference in the
frequency of complete clearing or >90% reduction in PASJ was seen between
the two groups: 53% in the catcipotriol group versus 13% in the placebo group.
Also, in the reduction in PASt from baseline to end of treatment, a statistically
significant difference was observed: 85% reduction in the calcipotriof group and
50% in the placebo group.
Combined treatment, with catcipotriol and
cyclosporin A was well tolerated (Study Report and paper in preparation).
The safety and efficacy of treating children with calcipotriol ointment for up to
8 weeks is currently being addressed in an open, non-comparative study of
approximately 70 children. The study has recently been completed and the
results are currently being analysed. Furthermore, a randomised, double-blind,
vehicle controlled, parallel group study to include 70- 80 children is currently
running.
Efficacy and tolerability to treatment of psoriasis of the scalp with calcipotriot
lotion (50J.lg/mt) applied twice daily for ·4 weeks was compared to those of a
placebo lotion in two double-blind studies, which included approximately 100
· patients each. (MC490 and MC1190 Study Reports; paper in preparation).
The calcipotriol lotion was also compared to a lotion of betamethasone 17valerate in a double-blind study which included 475 patients (MC290 Study
Report). In these studies catcipotriol lotion was found to be effective for the
Page 22
treatment of scalp psoriasis but less effective and less well tolerated than
betamethasone scalp application. Large scale trials investigating the use of gel
and
1.4
a cream formulation
for treating scalp psoriasis are currently in progress.
ALPHOSVLe HC CREAM
Alphosyr' HC Cream is a topical presentation of 5% coal tar/2% affantoin/0.5%
hydrocortisone which has been shown to be effective clinically in patients with
psoriasis vulgaris (38,39).
1.5
PRESENT STUDY: RATIONALE
Both Dovonex® Ointment and Alphosy~ HC Cream are used as first line topical
therapies for patients with psoriasis vulgaris.
However, there are no data
comparing their efficacy, tolerability and acceptability. This study, therefore,
was conducted to determine the relative merits of Dovonex® Ointment and
Alphosyfb HC Cream in treating psoriatic patients.
Page 23
The following description up to and including Section 13, COMPLIANCE WITH
ETHICAL RESPONSIBILITIES, represents a synopsis of the protocol. The protocol
itself is presented in Appendix Ill.
2
OBJECTIVES OF THE STUDY
To compare the clinical effect of Dovone~ Ointment with that of
Alphosy~ HC Cream in patients with chronic plaque psoriasis.
To compare the tolerability of Dovonex® Ointment with that of Alphosyl®
HC Cream in the above group of patients.
3
DESIGN OF STUDY
A multicentre, prospective, randomised, open parallel group com parison.
4
CRITERIA FOR SELECTION OF STUDY PATIENTS
4.1
INCLUSION CRITERIA
4.1.1
Clinical diagnosis of plaque psoriasis on the trunk and/or limbs of at
least 100 cm2 •
4.1.2
General practice patients
4.1.3
Aged
4.1.4
Either sex
4.1.5
Woman of child-bearing potential using adequate method(s) of
~
16 years
contraception.
4.1.6
Written informed consent given.
4.2
EXCLUSION CRITERIA
4.2.1
Acute guttate or pustular psoriasis
4.2.2
· Patients taking ~ 400 iu vitamin D daily or any prescribed calcium
supplements daily.
4.2.3
Treatment with any other medication (topical or systemic) that would
Page 24
affect the course of the disease during the study period . eg:
corticosteroids.
4.2.4
Known hypersensitivity to the active or inactive components of
Dovonex® Ointment or Alphosy~ H Cream.
4.2.5
Pregnancy or breast feeding.
4.2.6
Considered unable to comply with the study protocol (ie psychotics,
alcoholics, drug abusers etc)
5
CRITERIA FOR EARLY WITHDRAWAL FROM THE STUDY
5.1
Patient's voluntary withdrawal.
5.2
Medical deterioration.
5.3
Any unacceptable adverse events.
5.4
Exclusion criteria emerging during the study.
5.5
Non-compliance or default
6
TREATMENT ASSIGNMENT METHOD
At visit 1, qualifying patients were randomly assigned treatment with
either Dovone~ Ointment or Alphosyl® HC Cream. Randomisation was
according to a computer generated, random numbers table in balanced
blocks of 4.
Each block of treatments contained 2 treatments with
Dovone~ Ointment and 2 treatments with Alphosyl® HC Cream.
7
BREAKING OF THE TREATMENT CODE
This was an open study, treatment allocation was known to each
investigator.
8
Page 25
STUDY MEDICATION
Dovone~ Ointment (calcipotriol 50 meg/g)
Batch no:
BN 8 16A
Expiry date: 15/06/93
Manufactured and certified by Leo Pharmaceutical Products, Ballerup,
Denmark
Alphosyl~ HC Cream (5% coal tar/2% allantoin/0.5% hydrocortisone)
Batch no:
011156
Expiry date: 12/92
Manufactured by Stafford-Miller Ltd.• Broadwater Road, Welwyn Garden
City, Hereford and purchased from a pharmaceutical wholesaler in the
United Kingdom.
8.1
STORAGE OF STUDY MEDICATION
Study medication was stored at room temperature, for dispensing by the
investigator.
8.2
ADMINISTRATION OF STUDY MEDICATION
Dovone~ Ointment was applied to the lesions twice daily.
Alphosyl~ HC Cream was massaged well into the affected areas twice
daily.
8.3
DURATION OF THERAPY
The duration of open, randomised treatment was 8 weeks.
8.4
DRUG ACCOUNTABILTV
Supplies of study medication were delivered to each study center by
hand. An inventory was kept of all supplies issued to and returned by
patients. At the end of the study, all unused and returned supplies were
collected by Leo personnel.
Page 26
9
CONCOMITANT THERAPY
Concomitant medication for conditions other than psoriasis could be
contined throughout the study, without change in dosage if possible.
Usage of concurrent medication was to be recorded. Treatment with
lithium or corticosteroids was not allowed during the study period.
No other active treatment for psoriasis was permitted.
Emollients not containing any active ingredients were permitted.
10
STUDY PROCEDURES
Visit
1
2
3
weeks
0
4
8
Date of visit
X
X
X
Patient to sign a Consent Form
X
Patient's Initials
X
X
X
Inclusion/Exclusion Checklist
X
History of Psoriasis
X
Recent Treatment for Psoriasis
X
Concurrent Medication
X
X
X
Clinical Assessment
X
X
X
X
X
Record Adverse Events
Dispense Treatment
Collect used/unused treatment
X
X
X
X
Page 27
10.1
MEDICAL HISTORY (visit 1)
At visit 1, (baseline) all details pertinent to the protocol's inclusion and
exclusion criteria were checked. Demographic data, history of psoriasis
and previous treatment for psoriasis were recorded.
10.2
CLINICAL ASSESSMENT
10.2.1
Investigator assessments
The investigator made the following assessments.
10.2.1.1
Severity of psoriasis
At each visit, the presence and severity of the following signs of
psoriasis (redness, thickness and scaliness) were assessed and graded
according to the following scale:
Absent
Mild
Moderate
Severe
To aid in this assessment, investigators were provid~d with photographs
illustrating "mild•, "moderate" and •severe" psoriasis.
10.2.1 .2
Area of psoriasis
At each visit, the total area of affected skin was estimated and
recorded.
To aid in this assessment. investigators were provided with a series of
area scales {300, 200, 150, 100, 75,
so, 10 an~ 1 cm2 )
Page 28
10.2.1.3
Study CA 91 01 UKJGP92
Overall severity of psoriasis
At each visit, the investigator assessed the overall severity of psoriasis
and recorded it as
Absent
Mild
Moderate
Severe
10.2.2
Patient Assessments
The patient made the following assessments
At baseline (visit 1) the patient recorded on a 100 mm visual analogue
scale their response to the following statement.
i)
Effect on life style
I lind my psoriasis
causes total interterence
with my life
My psoriasis
does not
interfere with
my life
At each visit, the patients recorded on a 100 mm visual analogue scale
their response to the following statements.
i}
Severity of psoriasis
My psoriasis is as
bad as I can Imagine
ii)
My skin is
completely clear
Flakiness/scaliness
My skin Is
flaking very
badly
My skin is not
flaking/scaling
at all
Page 29
At visits 2 and 3, the patient recorded on a 100 mm visual analogue scale their
response to the following statements.
i)
ii}
The treatment has
has been
superbly effective
The treatment is
The tffi<ltment Is
completely
acceptable to use daily,
If necessary
totally unacceptable
to use dally, if necessary
iii)
10.3
The treatment
not worked at all
My treated skin
is extremely
itchy
l can feel
no itchiness
RECORDING OF ADVERSE EVENTS (aU on-treatment visits)
The investigator asked the patient a non-leading question such as:
"Since I last saw you, has the treatment upset you in any way or have
you noticed any uncharacteristic skin changes on the scalp?" If so, the
11
nature, date of onset. duration, severity ("mild", "moderate or "severe")
and causal relationship to trial medication ("unlikelt, "possible" or
"probableu) were recorded.
The investigator also observed the patient for any uncharacteristic skin
changes which were recorded.
Any serious and unexpected adverse events were to be reported to the
company immediately {ie within 24 hours).
11
CRITERIA FOR EFFECTIVENESS AND SAFETY
The two treatment groups were compared in ·respect of the following
11.1
PRIMARY RESPONSE CRITERION
The investigators overall assessment of the clinical response at the end
of treatment (last on-treatment visit attended).
Page 30
11.2
OTHER RESPONSE CRITERIA
11.2.1
The investigators overall assessment of the clinical response at visits 2
and 3.
11.2.2
Change from baseline (visit 1) to subsequent visits in the severity of
redness, thickness, scaliness and overall severity of the psoriatic lesions.
11.2.3
Change from baseline (visit 1) to subsequent visits in the total area of
affected skin.
11.2.4
The patients assessment of the efficacy and acceptability of treatment.
12
COMPLIANCE WITH ETHICAL RESPONSIBILITIES
12.1
The study was conducted to conform with the Declaration of Helsinki II
as adopted by the 18th World Medical Assembly, 1964, and revised by
the 29th World Medical Assembly, Tokyo 1975, Venice, 1983, and Hong
Kong, 1989.
12.2
The patient only participated after giving signed consent having received
verbal and written information about the study.
The information
emphasized that participation in the study was voluntary and that the
patient could withdraw from the study at any time and for any reason.
12.3
The clinical trial was approved by local Health Authorities and Ethics
Committees.
12.4
Patients were covered by the product liability insurance of Leo
Pharmaceutical Products.
Page 31
13
RESULTS: RANDOMISED, COMPARATIVE TREATMENT
13.1
STUDY PERIOD
13.1.1
Commencement of study
The first patient was randomised on 17 January, 1992.
13.1.2
Completion of study
The last patient was randomised on 10 November, 1992, and the last
patient completed the trial on 7 January 1993.
13.1.3
Duration of study
The comparative treatment phase of the study was completed over a
period of 51 weeks.
For individual data on the dates patients attended each of the visits see
Appendix II, Table II. 1
13.2
STUDY POPULATION
13.2.1
Disposition of study subjects
13.2.1.1
Recruitment of patients
Patients were recruited for the present study by 25 investigators.
A total of 133 patients were randomised at visit 1. 69 patients were
assigned to treatment with Oovonex® Ointment and 64 patients were
assigned to treatment with AlphosyfB' HC Cream.
13.2.1.2
Withdrawal of patients from comparative treatment
A total of 27 (20.3%) out of 133 patients randomised in the study were
withdrawn from comparative treatment.
Page 32
The reasons for withdrawal from the study are given in Table 1.
The most frequent reason for withdrawal was default. A total of 20
patients, 10 assigned Dovonex®Ointment and 10 assigned Alphosyl®HC
Cream defaulted.
13.2.2
Protocol violators
The protocol listed a number of inclusion and exclusion criteria (see
Section 4) with which the patients had to comply to be eligible for
randomisation.
A distinction has been made between major and minor protocol eligibility
criteria. This distinction was made prospectively and is apparent from
the study protocol.
13.2.2.1
Major protocol inclusion/exclusion criteria
The major protocol inclusion criterion was a diagnosis of psoriasis
vulgaris affecting at least 100 cm2 of skin.
Study CA 9101 UKJGP92
13.2.2. 2
Page 33
Minor protocol inclusion/exclusion criteria
Protocol inclusion/exclusion criteria other than the major protocol
inclusion crite rion .
13.2.2.3
Patients violating the protocol's major inclusion/exclusion criterion
One patient given Alphosy~ HC Cream violated the major protocol
inclusion criteria (Table 2)
Table 2
Reasons for exclusion from efficacy analyses
This patient was included in the "intention to treat" analysis (Section
13. 5.1 ), but was excluded from the patient population included in the
efficacy analyses (Section 13.5.2)
13.2.2.4
Patients violating the protocol's minor eligibility criteria
There were no patients who violated the protocol's minor. eligibility
criteria.
Page 34
13.2.3
Number of patients considered and analysed for safety and efficacy
of study medications
13.2.3.1
Safety
The protocol required that all patients who were randomised in the study
be accounted for in respect of the safety (ie adverse events) of the study
medications. However, 10 patients failed to attend any follow up visit
and were not analysable as they did not contribute any data.
Therefore safety assessment was based upon 123 patients, 65 in the
Dovonex0 Ointment group and 58 patients in the Alphosyl~ HC
Cream group.
13.2.3.2
Efficacy
Intention to treat analysis
All 133 randomised patients were included in an intention to treat
analysis in respect of the primary efficacy criterion (Section 13.5.1)
Efficacy analyses
As stated in the above Section 13.2.2.3, one patient who was given
Alphosyl® HC Cream had less than 100cm 2 of psoriasis and was
excluded from the efficacy analysis.
The remaining 132 patients, 69 patients in the Dovonex® Ointment
group and 63 patients in Alphosyl® HC Cream group were included
in the analyses of efficacy in respect of all response criteria. (Section
13.5.2).
However, 10 patients, 4 patients in the Dovonel19 Ointment group and
6 patients in the Alphosyl119 HC Cream group failed to attend for any
follow up visit and hence provided no efficacy data.
Page 35
13.3
BASELINE COMPARABILITY OF TREATMENT GROUPS
13.3.1
Baseline comparability of the two treatment groups for all
randomised patients.
The two treatment groups were well matched at baseline with respect to
baseline recordings, see Sections 13.3.1.1 , 13.3.1.2 and 13.3.1.3.
13.3.1.1
Sex distribution and age
The two treatment groups were well matched at baseline with respect to
sex distribution and age (Table 3)
Page 36
Table 3
Baseline comparison of patient characteristics:
Randomised patients - Demography and severity of psoriasis
For data in individual patients, see Appendix If, Table II, 2
13.3.1.2
History of psoriasis
The medical history recorded at visit 1 revealed no important differences
between the groups in respect of:
a)
Duration of psoriasis {Table 3)
b)
Previous psoriasis treatment (Table 4)
Table 4
Page 37
Randomised patients - Previous psoriasis treatment
For data in individual patients see Appendix II, Table 11.3.
13.3.1 .3
Concomitant drug treatment
There were no significant differences between the two treatment groups
with regard to concomitant non-psoriatic drug treatment taken at visit 1.·
The concomitant treatment classified according to the ATC system
(WHO Anatomical Therapeutic Chemical Classification Index 1991) is
given for the two treatment groups in Table 5.
Page 38
Table 5
Randomised patients - Concomitant drug treatment
For data in individual patients, see Appendix II, Tables 11.4 and 1/.5
13.3.1.4
Extent and severity of psoriasis
The two treatment groups were also well matched at baseline in respect
of the extent and severity of psoriasis (Table 3)
13.3.2
Baseline comparability of treatment groups In respect of patients
included In the efficacy analyses.
The patients included in the efficacy analyses in the two treatment
groups were well matched at baseline in respect of numbers, age, sex
distribution, duration of psoriasis and severity of psoriasis (Table 6).
Table 6
Baseline comparison of treatment groups:
Patients Included in efficacy analysis
Page 39
Page 40
13.4
DURATION OF RANDOMISED, COMPARATIVE, TREATMENT
The mean duration of treatment in all randomised patients (patients who
completed the entire comparative treatment period and patients who
were withdrawn) was 8.0 weeks for Dovone~ Ointment and 7.9 weeks
for Alphosyl® HC Cream.
The mean duration of treatment among patients who completed the
entire comparative treatment phase was 8.6 weeks for Dovone~
Ointment and 8.9 weeks for AlphosyfD HC Cream.
For data in individual patients, see Appendix II, Table /1.6
13.5
EFFECT OF STUDY DRUGS ON PSORIASIS
Efficacy data in 3 patients at visit 3 were omitted from the analysis
because the visit assessment was made more than 14 days after the
patient stopped usjng the study medication.
NOT£:
All safety data (ie adverse events), irrespective of the time
post-randomisaUon they were recorded, have been
included in the presentation of adverse events.
13.5.1
Clinical effect of study drugs on psoriasis in all randomised
patients - intention to treat analysis.
The primary criterion for efficacy was the proportion of patients
whose psoriasis was 'cleared' or 'markedly improved' at the end of
treatment.
The clinical effect of the study drugs in respect of the primary efficacy
criterion is shown in Table 7.
Table 7
Page 41
Intention to treat analysis: Primary efficacy criterion
Dovonex® Ointment was significantly more effective than Alphosyl® HC
Cream. The 24.1% difference in response between the two treatments
had 95% confidence intervals (Dovonex®- Alphosyl~ of 7.0
13.5.2
-7
41.2.
Clinical effect of study drugs on psoriasis in patients included in
the efficacy analyses.
13.5 .2.1
Primary efficacy criterion
The primary efficacy criterion for was the proportion of patients
whose psoriasis was 'cleared' or 'markedly improved' at the end of
treatment.
The clinical effect of the study drugs in respect of the primary efficacy
criterion is shown in Table 8.
Page 42
Table 8
Patients included in efficacy analysis:
Primary efficacy criterion
Oovonel~ Ointment was significantly more effective than Alphosyl® HC
Cream (P=0.015). The 23.2% difference in response between the two
treatments had 95% confidence intervals (Oovonex® - Alphosyl®) of 6.1
~
40.3.
13.5.2.2
Page 43
Investigators assessment of Overall Clinical Response
The overall clinical response at visits 2 and 3 and at the end of
treatment (last on-treatment visit) is shown in Table 9 and Figure 1.
Table 9
Overall Clinical Response
Page 44
FIGURE 1
Overan clinicaJ response
Th ere was no significant difference between the two treatments in
respect of the distribution of the overall clinical response.
For data in individual patients see Appendix II, Table II. 7
The overall clinical response in patients who received 8
Page 45
±1
weeks
treatment is shown in Table 10.
Table 10
Patients included in efficacy analysis: Overall clinical response in
patients who received 8±1 weeks treatment
There was no significant difference between the two treatments in
respect of the overall clinical response in patients treated for 8 ± 1
weeks.
Page 46
13.5.2.3
Investigators assessment of Overall Severity of Psoriasis
The overall severity of psoriasis at visits 2 and 3 and at the end of
treatment (last on-treatment visit} is shown in Table 11.
Table 11
Overall severity of psoriasis
Page 47
The changes in overall severity from baseline to subsequent visits is
shown in Table 12.
Table 12
Change in overall severity from baseline to subsequent visits.
The reduction in overall severity was significantly greater in the
Dovonex® Ointment group at visits 2 and 3 and at the end of treatment
(p ranging from 0.016
~
0.005}.
For data in individual patients see Appendix II Table 11.8
Page 48
13.5.2.4
Investigators assessment of Overall Severity of Signs of Psoriasis
The overall severity of signs of psoriasis at baseline (visit 1) and at visits
2 and 3 and at the end of treatment (last on-treatment visit) is shown in
Table 13 and in Figure 2.
Table 13
Total sign score
FIGURE 2
Total sign score
Page 49
Page 50
The change in the total sign score from baseline (visit 1) to subsequent
visits is shown in Table 14.
Table 14
Change in total sign score
The reduction in total sign score was significantly greater in the
Dovonel81 Ointment group at visits 2 and 3 and at the end of treatment
(p ranging from 0.01
--7
0.001 ).
13.5.2.5
i)
Page 51
Severity of individual signs of psoriasis
Redness
The severity of redness at baseline (visit 1) and at visits 2 and 3 and at
the end of treatment (last on-treatment visit) is shown in Table 15.
Table 15
Severity of redness at respective control visits
The change in redness from baseline (visit 1) to subsequent visits is shown in
Table 16.
Page 52
Study CA 9101 U KJG P92
Table 16
Patients included in efficacy analysis: Change in redness from
baseline to subsequent visits
Both treatments significantly reduced redness at visits 2 and 3 and at
the end of treatment. There was no significant difference between the
two treatments in the reduction of redness.
For data in individual patients see Appendix II, Table f/.9.
ii)
Page 53
Scaliness
The severity of scaliness at visits 2 and 3 and at the end of treatment
(last on-treatment visit) is shown in Table 17.
Table 17
Severity of scaliness at respective control visits
Page 54
The change in scaliness from base line to subsequent visits is shown in
Table 18
Table 18
Change in scaliness from baseline to subsequent visits
..
~
' ·'
..
. ·
. ·,,
..
~
·. ~
.I ••: ·
.;:.;
Both treatme nts significantly reduced scaliness at visits 2 and 3 and at
t he end of treatment.
The reduction in scaliness was significantly
greater in the Oovonex® Ointment group (p always <0.005).
For data in individual patients, see Appendix II, Table II 10.
iii)
Page 55
Thickness
The severity of thickness at visits 2 and 3 and at the end of treatment
(last on-treatment visit) is shown in Table 19.
Table 19
Severity of thickness at respective control visits
...
~··
DOVONEX
'
.:.:::,· .
.....
... ~··.··
'· .:::·
~;~t~::'
: ... ,.
..~ ·
: ::;:v
·..:
'
., '
.};#
.A'<f._-:.
.
~<= ·~
·'·\' .
.....
:·.
2 0·-
38 ' ·~
:-.~;.;:·.
'
• -?.-<·'·'"1-· ·t ... H~~,.f:~g~,.
:?-
..-..:·~•··
5 /;.,
· •>'<,•
<'
~
. ·:·.:
: ~ .::;:.~}::
. :~~::;~=< ·.
"' '····
...· : <
:.·
2 ~;y; .
33~(:
7 ,'
1:
4 .' ~
·.•.·
....
. ..,:
.
.·~,.
.
,.
·:·:::.;:·:·
Page 56
The change in thickness from baseline to subsequent visits is shown in
Table 20.
Table 20
Changes in thickness from baseline to subsequent visits
·o
.5
. .· :28
.: 2 3
1
o. .·ooo(
·.
6
..
Both treatments significantly reduced thickness at visits 2 and 3 and at
the end of treatment. The reduction was significantly greater in the
Dovonel~ Ointment group (p ranging from 0.006 --) <0.0001 ).
For data in individual patients,
see Appendix II, II 11
13.5 .2.6
Page 57
Investigators assessment of Area of Psoriasis
The total area of psoriasis at visits 2 and 3 and at the end of treatment
(last on-treatment visit) is shown in Table 21 .
Table 21
Area of psoriasis (cm2 )
The number of patients with less than 100 cm2 of psoriasis at b~seline
and at the end of treatment (last on-treatment visit) is shown in Table
22.
Page 58
Table 22
Number of patients with less than 100 cm 2 of psoriasis
·.:~:::~r,;~~~i2~\7.t{;;.~:~..
. :..-.)·:::- ··::;;·:; .
There were significantly fewer patients in the Dovonel!) Ointment group
with <1 00 cm2 of psoriasis at the end of treatment (p<0.05).
For data in individual patients, see Appendix II, Table II. 12
13.5.2.7
Patients assessment of affect of psoriasis on their lifestyle.
Patients assessment of the affect of psoriasis on their lifestyle (as
recorded on a 1OOmm analogue scale} at baseline is shown in Table 23.
Table 23
Patients assessment of affect of psoriasis on lifestyle11
For data in individual patients see Appendix II, Table fl. 13
13.5.2.8
Page 59
Patients assessment of severity of psoriasis
Patients assessment of the severity of psoriasis (as recorded on a 100
mm analogue scale) at baseline and at respective control visits is shown
in Table 24.
Table 24
Patients assessment of severity of psoriasis1 )
Page 60
The change in the patients assessment of the severity of psoriasis (as
recorded on a 100 mm analogue scale) from baseline to subsequent
visits is shown in Table 25.
Table 25
Patients included inefficacy analysis:
Changes in patient assessment of severity of psoriasis
Both treatments significantly reduced the patients assessment of severity
of psoriasis at visits 2 and 3 and at the end of treatment. The difference
between the two treatment groups was not significant (p=O.OB in favou r
of Dovonel~' Ointment at end of treatment).
For data in individual patients, see Appendix II, Table 11.14
13.5.2.9
Page 61
Patients assessment of flakiness/scaliness of skin.
Patients assessment of flakiness/scaliness of skin (as recorded on a 100
mm analogue scale} at baseline and at respective control visits is shown
in Table 26.
Table 26
Patients assessment of flakiness/scaliness1,
Page 62
The change in patients assessment of flakiness/scaliness (as recorded
on a 100 mm analogue scale) from baseline to subsequent visits is
shown in Table 27.
Table 27
Change in patients assessment of flakiness/scaliness of skin
Both treatments significantly reduced the patients assessment of severity
of skin flakiness/ scaliness at visits 2 and 3 and at the end of treatment.
The reduction was significantly greater in the Dovonex(19 Ointment group.
(p=0.001 ).
For data in individual patients, see Appendix II, Table II 15
13.5.2.1 0
Page 63
Patients assessment of the efficacy of treatment
Patients assessment of the efficacy of treatment (as recorded on a 100
mm analogue scale) at respective control visits is shown in Table 28.
Table 28
Patients assessment of treatment efficacy<1>
........
:..·
:·· :.~t·.~·.
··:.> ·
.... :..:
~
··:(::::~ .
.: ··:;:~-..
·~r:.,
Patients assessed the efficacy of Dovonex(il! Ointment to be significantly
better than that of Alphosyl® H Cream (p ranging from <0.05 ~ <0.02).
For data in individual patients, see Appendix II Table II 16
Page 64
13.5.2.11
Patients assessment of treatment acceptability
Patients assessment of the acceptability of treatment (as recorded on a
100 mm analogue scale) at respective control visits is shown in Table
29.
Table 29
Patients assessment of treatment acceptability<1l
Patients tended to assess the acceptability of treatment with Dovonex(~
Ointment as better than that of Alphosyl'~ HC Cream, but the difference
was not significant (p<O.OB at end of treatment).
For data in individual patients, see Appendix II, Table II. 17
13.5.2.12
Page 65
Patients assessment of itching
Patients assessment of itching (as recorded on a 100 mm analogue
scale} at respective control visits is shown in Table 30.
Table 30
Patients assessment of itching<l)
~·:.72
5 -·'· 100
39
. . ·;;.
·~{::: ··
'
.
.'.'.:,•.~~.;;··.·.:.·...
~
For data in individual patients, see Appendix II· Table II 18
13.6
CONCOMITANT DRUG TREATMENT
Use of concomitant medication at study entry is accounted for in Table
5.
Change in use of concomitant medication during comparative treatment
is accounted for in individual patients in Appendix II , Table II
13.7
SAFETY OF STUDY DRUGS
13.7.1
Adverse events recorded
Methodology: Adverse events were elicited at each post-randomisation
visit by the investigator asking the patient a general, non-leading
question such as: "Since I last saw you, has the treatment upset you in
Page 66
any way or have you noticed any uncharacteristic skin changes?"
If the patient's answer to the open question was "NO", no further
questions were asked.
Further, the investigator observed the patient for adverse effects on the
skin.
For each adverse event, the following related details were recorded in
the Case Record Form.
1)
The adverse event in the investigator's own terminology.
2)
The investigator's opinion on the severity_of the adverse event,
classified as "mild", "moderate" or "severe"·:·
3)
Whether the investigator considered the relationship of the
adverse event to the study drug to be "unlikely", "possible" or
"probable".
In the analysis and presentation of adverse events, the following
approach was used:
1)
Adverse events as described by investigators were categorised
according to an arbitrary system by the Principle Project Coordinator before the treatment identities were revealed (Leo
code). If a particular adverse event category appeared more than
once for a particular patient, the category was counted as one
event.
Adverse event descriptions were also categorised according to
the WHO System Organ Classification.
The labels used to categorise all Adverse Events are shown in Appendix II tables.
Page 67
For individual adverse event data, using the investigator's terminology and Leo
code, see Appendix II Tables II. 19, 11.20. For individual adverse event data using
SOC code see Appendix 11, Table 11.21.
13.7.1.1
Adverse events presented by WHO System Organ Class
The analysis of adverse events grouped according to the WHO System Organ
Class is presented in Table 31.
Table 31
Adverse events reported/observed after randomisation by System Organ
Class
·~ ·.:,·~·:·~~·l~:i~L;
:
•,
. :. ·~:.;~{().~
For data in individual patients, see Appendix II, Tables II. 19 and 11.20.
Page 68
13.7.1 2
Adverse events presented by investigator's term/Leo category
Table 32 presents the adverse events that were reported during the
tri al.
Table 32
Adverse
events
reported/observed
after
randomisation
by
investigator's term/Leo category
. "..
1
1
'W::V$%~ft:Ji~l?f: \.~~1~1~L 1€r~~>~~~~~~~~g ~:;;
•
·-.<::
.
·.·.·. · ·.·.· ·.·.·.·.· ·: .· .· ........ ..
-· ~·~:·~ ·; :;;·~:- ~-( ·~· ·~·
.
..-:
::·:·· •
• "
• , • •·••• ••'t'·.•·:: · :.· • • .· :,:·.···· .
•
ov
,•
;·~:~.: ~:·'\·;.
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~-
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·· .:· · ·.
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·,~--;<;.: ,{;,,~
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~-=~·
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.:.; ,:_.:_:·.·~.:.~ :.\' .~:,/.~.: . .
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.·..
·.·..
::;.,~~~:~;_ :~>-1~:~:~~~~~t·/:~~:~~~;;;::~:~ _:;~;:i;..:::::··!·: ~ ·:·.::·:<.<
7
~
.;
. '·· ·.....:,~·. :;.•' ' -~
.·.· ,..;-.;· ;. ·~:
--~~ .£· ~/~ ·:::::1
. .. .· . ::::· ..~ ~.:;
.·.:r
-~:.:( :·.~:_,:~·:_:~;_;._·.;_:_~-~, ..'
.:~
.·~ .:. :,: ...:.~::
fi:;"~1ffj~~J&j~!~:,; J; ; iJ+*j~J;:,;J,"'i"'.(~!;. ~;. t:,; ~. ;~ 1,; i:~;:,;:7.;l~_ ~:'j:o.~:J. ;.;J,J."!,:.i;;. ,.;l-jJ"'i"'."~'·":':"!':-,"t:',~:;.:~-;:.:~;i~J:1.(-i~.i;).:~;:.~.;_;.l:!i;:l,;t.!,.-li:~-:i;;:i~:i~S~i·~: ,:;."'---.: :-. , .:·;ll
...
...: x:.: ·· .
.....
"'•.:
. ...:...
••.,.:.,..
\
''"·.
·. .·· .. ..··
The severity of the adverse events and relationship to treatment was
assessed as follows.
Overall, the severity of adverse events in the Oovonexcf9 Ointment group
was 11 (47.8%) "mild", 10 (43.5%) "moderate" and 2 (8.7%) "severe".
In the Alphosy~ HC Cream group there we re 5 (41.7%) "mild", 6 (50.0%)
"moderate" and 1 (8.3%) "severe" adverse event.
Page 69
In the Dovonelill Ointment group, the relationship to treatment was
assessed as "unlikely" in 10 (43.5%), "possible" in 7 (30.4%) and
"probable" in 6 (26.1 %).
In the Alphosylrfll HC Cream group, the
relationship to treatment was assessed as "unlikely" in 4 (33.3%),
"possible" in 3 (25.0%) and "probable" in 5 {41.7%).
For data in individual patients, see Appendix II, Tables 11.21 and 11.22.
13.7.1.3
Adverse events causing/contributing to withdrawal of treatment are
shown in Table 33.
Table 33
Adverse events causing/contributing to withdrawal from study
medication
For data in individual patients, see Appendix II, Table 11.24
Page 70
14
COMPLIANCE WITH GOOD CLINICAL PRACTICE
This study complied with the general principles of Good Clinical Practice, as
drawn up in the European Community Commission Guideline 3/3976/88 (as of
July, 1991).
15
Page 71
DISCUSSION
This study has shown that 8 weeks treatment with Oovonel
11
Ointment is
significantly more effective than 8 weeks treatment with Alphosyl<io HC Cream
in the treatment of General Practice patients with plaque psoriasis. According
to the primary criterion of efficacy, the proportions of patients treated
successfully were 72.3% for Dovonexr!!l Ointment and 49.1 % for Alphosyl® HC
Cream (p<0.01 ).
The study was conducted in General Practice.
The protocol required 120
patients to be recruited. This requirement was achieved with 25 investigators
recruiting a total of 133 patients. The patients recruited complied well with the
protocol's inclusion and exclusion criteria. Only one patient was excluded from
the efficacy population due to having less than the specified area of affected
skin. Patients complied well with the trial procedures and only 10 patients, 4
given Dovonex® Ointment and 6 given AlphosylrB! HC Cream failed to attend for
follow-up.
The study design was an open, parallel group comparison. This may have
allowe.d some investigator bias in the assessment of response. However, a
true double-blind design for topical therapies which differ in appearance is
impossible in General Practice. Furthermore, inclusion of patients' assessment
of the respon se to treatment improved the study design and helped to minimise
the effect of investigator bias on the overall conclusions of the study.
The two treatment groups were well matched at baseline in respect of numbers,
age and sex distribution, history of psoriasis, previous antipsoriatic therapy and
extent and severity of psoriasis.
Both treatments reduced the severity and extent of psoriasis. According to the
investigators assessment of treatment efficacy, Dovone/l! Ointment was
Study CA 9101 UK./GP92
Page 72
superior to Alphosylr!D HC Cream in respect of the numbers of patients 'cleared'
or 'markedly improved' at the end of treatment (p<0.01 ), in the reduction in
overall severity at the end of treatment (p<0.02), reduction in the area of
affected skin at the end of treatment (p<O.OS) and in reducing the total sign
score at the end of treatment {p=0.002) and in reducing thickness (p=0.001)
and scaliness (p<0.0001} at the end of treatment.
Patients considered
Dovonel~ Ointment superior in respect of overall efficacy at the end of
treatment (p<0.02) and reduction in skin flakiness/scaliness at the end of
treatment (p=0.001 ).Although
significa~t
differences were not found in respect
of some other efficacy assessments,the results always favoured Dovonex@
Ointment.
Patients also considered Dovonel gl Ointment to be more acceptable than
Alphosyj® HC Cream, but not significantly so (p=0.08). The similarity of the
assessment of efficacy by both patients and investigators is reassuring in
respect of the study conclusions. It also indicates that there was no significant
bias by investigators in assessing the relative efficacy of the two topical
treatments.
Adverse events were recorded in 15 (23.1 %) out of the 65 Dovonex®Ointment
treated patients assessed. Adverse events were recorded in 10 (17.2%) out
of the 58 Alphosylr[9 HC Cream patients assessed.
statistically significant.
The difference is not
The majority of adverse events seen with both
treatments were mild or moderate and were application related. Few patients
given Dovonel
61
Ointment or Alphosylr~P HC Cream withdrew from the study
wholly or in part due to adverse events.
The efficacy and tolerability of the two topical treatments seen in this study are
comparable with those reported from other studies. In this study 72.3% of
patients given Dovonex® Ointment were 'cleared' or 'markedly improved'. In
previous studies the proportion of patients 'cleared' or 'markedly improved'
ranged from 61% (30) to 78% (34). 49.1% of Alphosyr~ HC Cream treated
Page 73
patients in this study were 'cleared' or 'markedly improved'. The design of
previous studies employing Alphosyl® HC Cream (and Alphosyr!il without
hydrocortisone) is not compatible with this study(39,40).Therefore it is not
possible to compare previous results with the results obtained in this study.
Treatment with Dovonex161 Ointment is known to be associated with,
predominantly mild and application site related, adverse events in 20-35% of
patients (30,34). In this study 23.1% of patients had adverse events, most of
which were application related.
Adverse events, primarily application site disorders, were reported in 17% of
patients given Alphosyl® H Cream. A similar pattern and incidence of adverse
events has been reported previously for Alphosyl([o (38)
1
Few patients (1 given Dovonex® Ointment and 3 given Alphosyl 6l HC Cream)
ceased treatment with either topical agent due to unacceptable adverse events.
Page 74
16
CONCLUSIONS
In an 8 week study of General Practice patients with > 100 cm 2 of plaqu e
psoriasis, treatment with Dovonel;y Ointment proved significantly more effective
than treatment with Alphosyf!P H Cream and tended to be more acceptable to
patients.Tolerance of both treatments was similar.
17
Page 75
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.
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3
Christophers E, Schubert C. Psoriasis. In: Thody AJ , Friedmann PS,
Eds:
Scientific basis of dermatology, a physiological approach. London:
Churchill Livingstone, 1986: 151-7 4.
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Bas JD. The pathomechanisms of psoriasis; the skin immune system
and cyclosporin. Br J Dermatol1 988; 118:1 41 -55.
5
Clemens Tl, Adams JS, Horiuchi N et al
Interaction of 1.25-dihydroxyvitamin 0 3 with keratinocytes and fibroblasts
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Smith El, Pincus SH, Donovan L, Holick MF.
A novel approach for the evaluation and treatment of psoriasis
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7
Smith EL, Walworth NC, Holick MF.
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biochemical differentiation of cultured human epidermal keratinocytes
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J Invest Dermatol 1986; 86:709-7 14
8
Kondo S, Satoh Y, Yamaguchi J.
The inhibitory effects of 1a., 25-dihydroxy-vitamin 0 3 on DNA synthesis
in cultural epidermal cells of patients with psoriasis vulgaris.
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9
Hosomi J, Hosoi J, Abe E. Suda T, Kuroki T.
Page 76
Regulation of terminal differentiation of culture mouse epidermal cells by
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Endocrinology 1983; 3: 1950-57.
10
Bhalla K, Amenta EP, Serog B, Glimcher MH.
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11
Rigby WFC, Stacy T, Fanger MW.
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J Clin lnvest1984; 74: 1451-55.
12
Muller K, Svenson M, Bendtzen K.
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potent inhibitors of human interleukin 1 in vitro.
Immunology Letters 1988; 17: 361-366.
13
Takamoto S, Onishi T, Morimoto Setal,
Effect of 1ex - Hydroxycholecalciferol on Psoriasis Vulgaris: A Pilot Study.
Calcif Tissue lnt 1986; 39: 360-364.
14
Morimoto S, Yoshikawa K, Kozuka T et al.
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Br J Dermatol 1986; 115: 421-29.
15
Kato T, Rokugo M, Terui T, Tagami H.
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Br J Oermatol 1986; 115: 431-33.
16
Yoshikawa K, Morimoto S, Kumahara Y.
Treatment of psoriasis with oral 1ex, 25-dihydroxy-vitamin 0 3 .
Skin Research HIFU 1988; 30: 566-69.
17
Tagami H, Kato T, Terui T , Tadaki T.
Successful treatment of psoriasis with topical application of the active·
vitamin 0 3 analog , 1cx 24-dihydroxycholecalciferol (TV-02). In: Vitamin
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Gruyter W & Co.,
1988: 958-67.
Page 77
18
Nishiyama S.
Efficacy and tolerability of 1,24 - (OHh 0 3 in psoriasis.
18th World Congress of Dermatology. New York, June 12-18, 1992.
19
Henderson CA, Papworth-Smith J, Cunliffe WJ, et al.
A double ~ blind, placebo-controlled trial of topical,
dihydroxychotecalciferol in psoriasis.
Br J Dermatol 1989; 121: 493-96.
1 ,25-
20
van de Kerkhof PCM, van Bokhoven M, Zultak M, et al.
A double-blind study of topical1a., 25-dihydroxy-vitamin 0 3 in psoriasis.
Br J Dermatol 1989; 120: 661-64.
21
Holick MF, Po chi P, Bhawan J.
Topically applied and orally administered 1,25-dihydroxy-vitamin 0 3 is a
novel safe and effective therapy for the treatment of psoriasis. A three
year experience with histologic analysis.
J Invest Dermatol 1989; 92: 446-
22
Langner A, Verjans H, Stapor V, Mol M.
1a~ 25-dihydroxy-vitamin 0 3 (-1-;25/QH/203)-ointments in-psoriasis.
Fifth International Psoriasis Symposium, San Francisco, 1991.
23
Sultak M.
Calcitriol cream in the treatment of psoriasis: Efficacy and safety
considerations.
24
Binderup L, Bramm E.
Effects of a novel vitamin D analogue MC 903 on cell proliferation and
differentiation in vitro and on calcium metabolism in vivo.
Biochem Pharmacal 1988, 37: 889-95.
25
Kragballe K.
MC903, a non-calciotropic vitamin 0 3 analogue stimulates differentiation
and inhibits proliferation of cultured human keratinocytes.
J Invest Dermatol 1988; 91: 383.
Page 78
26
Kragballe K, Beck HI, Sogaard H.
Improvement of psoriasis by a topical vitamin 0 3 analogue {MC 903) in
a double-blind study.
Br J Oermatol 1988; 119 : 223-30.
27
Kragbelle K.
Treatment of psoriasis by the topical application of th e novel vitamin 0 3
analogue MC 903.
Arch Dermatol 1989; 125: 1647-52.
28
Frederiksson T, Petterson U.
Severe psoriasis- oral therapy with a new retinoid.
Dermatologica 1978; 157: 238-44.
29
Oubertret L, Wallach D, Souteyrand P et al.
Efficacy and safety of calcipotriol (MC 903) ointment in psoriasis vulgaris.
J Am Acad Dermatol 1992; 27: 933-988.
30
Cunliffe WJ, Berth-Jones J, Claudy A et al.
Comparative study of calcipotriol (MC 903) ointment and betamethasone
1?-.v~le_rate C?!~!'!_lentJn patien_t~_ ~ith ps~rJasi.~ vul.~aris.
JAm Acad Oermatol 1992; 26: 736-43 .
31
Kragballe K et al.
Double-blind right/left comparison of calcipotriol and betamethasone
valerate in treatment of psoriasis vulgaris.
Lancet 1991; 337: 193-96.
32
Dwyer C, Chapman RS.
Calcipotriol and hypercalcaemia.
Lancet 1991 ; 338: 764-65.
33
Kragballe K, Fogh K, Sogaard H.
Long-term efficacy and tolerability of topical calcipotriol in psoriasis.
Acta Derm Venereal 1991 ; 71: 475-78.
34
Berth-Jones J, Chalmers RJG, Chu AC et al.
A multi-centre, parallel-group comparison of calcipotriol ointment and
short-contact dithranol therapy in chronic plaqu e pso ri asis.
Br J Dermatol 1992; 127 : 266-271.
Page 79
35
Ramsay CA and an International Study Group.
Risk/Benefit profile of calcipotriol (MC 903) in long term treatment of
psoriasis.
36
Poyner T,Hughes IW,Dass BK,Adnitt PI
Long-term treatment of chronic plaque psoriasis with calcipotriol.
J Dermatol Treat(1993} In press
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37
Mortensen LS, Kragballe K, Schifter S, Charles P.
A double-blind placebo controlled study on calcipotriol (MC 903) and CaMetabolism.
38
Kragballe K.
Combination of topical calcipotriol (MC 903) and UVB radiation for
psoriasis vulgaris.
Dermatologica 1990; 181: 211-214.
39
Harrington Cl
Low concentration dithranol and coal tar (Psorin) in psonas1s
comparison with alcoholic coal tar extract and allantoin (Aiphosyl)
Br J Clin Prac 1989; 43: 27-29
40
a
Almeyda J, Wood H
Treatment of psoriasis : a comparative study using allantoin coal tar
extract combined with hydrocortisone and betamethasone valerate
Br J Clin Prac 1979; 33:106-108

CLINICAL STUDY REPORT

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