Hodl, S.

Honigsmann, H.

Maier, H.

Salmhofer, W.

Soyer, H. P.

University of Queensland eSpace

Double-blind, Placebo-controlled, Randomized, Right­ left Study
Comparing Calcipotriol Monotherapy with a Combined Treatment
of Calcipotriol and Diucortolone Valerate in Chronic Plaque
Psoriasis
W. SALMHOFER1, H. MAIER2, H. P. SOYER1, H. HOÈ NIGSMANN2 and S. HOÈ DL1
1
Department of Dermatology, University of Graz, Graz and
2
Division of Special and Environmental Dermatology, University of Vienna Medical
School, Vienna, Austria
A double-blind, randomized clinical study was conducted to
compare the ef® cacy and tolerability of twice-daily topical
calcipotriol treatment with a combination treatment of
calcipotriol once a day in the morning and di¯ ucortolone
valerate in the evening. Sixty-three patients with a clinical
diagnosis of chronic plaque psoriasis and comparable psoriatic
lesions on both sides of the body were included. After a wash-
out phase of 1 week, psoriatic lesions were treated for 4 weeks
with calcipotriol ointment twice daily on one side of the body
and a combination of calcipotriol and di¯ ucortolone valerate
ointment on the other side. The treatment period was followed
by a period of 4 weeks without any treatment. The psoriasis
area and severity index (PASI) was used to compare the 2
groups. Furthermore, the overall therapeutic results were
assessed independently by the investigators and by the patients.
Both treatment regimens showed a signi® cant, nearly identical,
reduction in PASI. The mean PASI for calcipotriol alone was
5.7 at baseline, 1.9 after 4 weeks of treatment and 3.8 at the end
of the follow-up period. For combination therapy, these values
were 5.7, 1.8 and 3.8, respectively. There was a statistically
signi® cant advantage in favor of combined calcipotriol and
di¯ ucortolone valerate treatment at weeks 1 and 2 (p50.05);
however, at the end of the treatment phase the difference
between the 2 therapies was not signi® cant. Subjective
evaluation of ef® cacy by both the investigators and the patients
revealed no difference between the 2 treatments. The frequency
of side effects (e.g. irritation) was low in both groups. In
conclusion, both therapies were effective for the treatment of
chronic plaque-type psoriatic lesions. The combination of
calcipotriol and a topical steroid appeared to produce a more
rapid clinical response and was shown to be as effective as
calcipotriol therapy alone. Key words: psoriasis; calcipotriol;
di¯ ucortolone valerate..
Acta Derm Venereol 2000; Suppl 211: 5± 8.
Wolfgang Salmhofer, MD, Department of Dermatology,
University of Graz, Auenbruggerplatz 8, AT-8036, Graz,
Austria.
E-mail: wolfgang.salmhofer@kfunigraz.ac.at
INTRODUCTION
The vitamin D3 analog calcipotriol is well established as an
effective ® rst-line therapy in chronic plaque psoriasis. Although
highly effective, vitamin D3 analogs can cause problems,
including persistent erythema at the site of the former psoriatic
plaques, irritation and, rarely, allergic contact dermatitis of
lesional or perilesional skin. In recent years, different treatment
regimens have been devised to optimize therapy and minimize
associated adverse events. Studies have compared calcipotriol
monotherapywith a variety of other topical anti-psoriaticdrugs,
as well as with different combination therapies (1 ± 7). Calcipo-
triol and corticosteroidsconstituteone such combinationtherapy
that has been investigated. This combination was chosen as
steroids represent an effective alternative treatment for psoriasis
and are also a ® rst-line therapy for treatment of contact
dermatitis, which can be a problem associated with calcipotriol
therapy.
The aim of our study was to investigate whether the
combination of calcipotriol and the topical steroid di¯ ucor-
tolone valerate is as effective as calcipotriol monotherapy, and
to ascertain whether the addition of a corticosteroid reduced
the incidence/severity of residual erythema and the incidence
of contact dermatitis that can be associated with calcipotriol
monotherapy.
MATERIAL AND METHODS
Study design
The investigation was a double-blind, placebo-controlled, rando-
mized, right ± left study, conducted in two Departments of Dermatol-
ogy (Graz and Vienna). Calcipotriol monotherapy with 0.005%
calcipotriol ointment (Psorcutan1-Salbe; Schering Wien GmbH)
twice daily was compared with a combination therapy of 0.005%
calcipotriol ointment in the morning and 0.1% di¯ ucortolone valerate
ointment (Nerisona1-Fettsalbe; Schering Wien GmbH) in the
evening. The study was carried out according to good clinical
practice guidelines.
Patients
Patients of both genders were eligible for the study if they satis® ed the
following inclusion criteria: age419 years; chronic plaque psoriasis
with an unchanged clinical appearance for 2 weeks; and compar-
able, symmetrical psoriatic lesions on both sides of the body.
Patients with exanthematic, erythrodermatic or pustular types of
psoriasis were excluded, as were patients with an affected area of
430% of the total body surface. Further exclusion criteria were:
systemic drug therapy with vitamin D, calcium or drugs known to
have an in¯ uence on the course of psoriasis (e.g. lithium, b-blockers,
corticosteroids); pregnancy or lactation; hepatitis B, HIV and other
infectious diseases (herpes, tuberculosis, syphilis); other concurrent
dermatoses; and hypercalcemia, severe hepatic or renal diseases.
Treatment schedule
After a wash-out phase of 1 week without any topical therapy,
treatment was started with calcipotriol twice daily on one half of the
Acta Derm Venereol 2000; Suppl 211: 5± 8
Acta Derm Venereol Suppl 211# 2000 Taylor & Francis. ISSN 0365-8341
body and a combination therapy of calcipotriol in the morning and
di¯ ucortolone valerate in the evening on the other half. Four weeks of
treatment were followed by a further 4-week follow-up period.
Clinical assessment
Patients were examined 1 week prior to the start of treatment, at
baseline, and after 1, 2 and 4 weeks of treatment. They were then re-
examined at weeks 6 and 8 during the 4-week, treatment-free, follow-
up period. Thus, in total, the patients were examined on 9 separate
occasions. The severity of psoriasis was evaluated by a single
investigator at each center (W. S. in Graz, H. M. in Vienna), using the
psoriasis area and severity index (PASI). Furthermore, at each visit,
treatment response was assessed independently by the investigators
and by the patients, starting 1 week after the beginning of treatment.
The response was rated separately for both sides of the body and
scored in one of 7 categories (complete healing, marked improvement,
slight improvement, no improvement, slight deterioration, marked
deterioration, extreme deterioration) with respect to change since the
last clinical evaluation. Additionally, at the end of the follow-up
period, patients were asked for a global assessment of their condition,
rating the overall therapeutic ef® cacy of each treatment as good,
satisfactory or bad.
Laboratory parameters, including complete blood count, bilirubin,
alanine aminotransferase, aspartate aminotransferase, alkaline phos-
phatase, creatinine, phosphate, calcium, albumin and total protein,
were measured before enrollment in the study and at the end of the
follow-up period. All adverse advents, both objective and subjective,
were recorded at each visit.
Statistics
The strategy for statistical analysis was based on the intention-to-treat
principle. All data underwent a descriptive statistical analysis. The
primary endpoint (PASI) was analyzed using a 2-period analysis-of-
variance model, according to Pocock (8).
All the given type I error probabilities are 2-sided and refer to the
individual test. The 2-sided 5% level was de® ned for statistical
signi® cance of the primary endpoint. The statistical software
employed was a proprietary development written in IBM APL2 for
PCs. This software has been tested according to the guidelines of the
European Organization for Quality (9).
RESULTS
Sixty-three patients (34 men, 29 women; mean age 47+15.4
years; range 19 ± 83 years) were included in the trial. The
mean duration of psoriasis was 141+124 months. Of these
patients, 4 had never previously received any treatment; the
majority, however, had previously used corticosteroids as
monotherapy or in combination with tar preparations or
dithranol. A further 26 patients had also received treatment
with phototherapy (UVB, PUVA), some in combination with
systemic drug therapy (retinoids, methotrexate). Overall, the
median duration of previous treatment regimens was 7
months.
A total of 58 of the 63 patients completed the study.
Compliance was excellent (490%), and the course of
treatment was never interrupted for 45 days. One patient
had to be withdrawn during the treatment phase due to
lesional and perilesional contact dermatitis of the lower
extremities. A further 4 patients were withdrawn due to
concomitant diseases (arthralgia, erysipelas, climacteric symp-
toms and dyshidrotic eczematous dermatitis).
Ef® cacy
Baseline PASI values were similar for both sides of the body.
Treatment with both calcipotriol alone and with the combina-
tion of calcipotriol and di¯ ucortolone valerate resulted in a
rapid and marked reduction of the PASI during the treatment
phase of the study, the greatest improvement being observed
during the ® rst 2 weeks (Table I; Fig. 1). A statistically
signi® cant bene® t of combination treatment over calcipotriol
monotherapy (p50.05) was observed after 1 (PASI 3.3 vs. 3.0)
and 2 weeks of treatment (PASI 2.4 vs. 2.1). However, at the end
of the treatment phase after 4 weeks of treatment and during the
follow-up period no signi® cant difference between the 2
treatment groups was detected.
Analysis of the PASI data for individual criteria (psoriatic
area, erythema, in® ltration, scaling) revealed a slight bene® t
for combination therapy in terms of reduction of scaling
during the treatment period. However, this bene® t did not
achieve statistical signi® cance.
Table I. Effect of calcipotriol monotherapy and calcipotriol and di¯ ucortolone valerate combination therapy on PASI. Mean
values with SDs in parentheses
Therapy
Week
± 1 0 1 2 4 6 8
Treatment phase Follow-up
Calcipotriol (am); calcipotriol (pm) 5.5 (2.7) 5.7 (2.9) 3.3 (2.1) 2.4 (1.6) 1.9 (1.4) 3.5 (2.4) 3.8 (2.4)
Calcipotriol (am); di¯ ucortolone valerate (pm) 5.5 (2.6) 5.7 (2.9) 3.0 (1.8) 2.1 (1.3) 1.8 (1.2) 3.5 (2.2) 3.8 (2.3)
P Ns ns 0.039 0.0077 ns ns ns
Fig. 1. Mean PASI before (-1) and during treatment (weeks 0 ± 4)
and in the follow-up period (weeks 4 ± 8). Statistically signi® cant
differences between treatments: *p50.05, **p50.01.
6 W. Salmhofer et al.
Acta Derm Venereol Suppl 211
Complete healing of psoriatic plaques occurred in 4 patients,
but not all individual lesions responded to the same extent.
Tolerance
Both treatment regimens were generally well tolerated. Slight-
to-moderate itching and burning at lesional sites was observed
with both treatments, occurring in 6 patients associated with
calcipotriol monotherapy and 8 patients associated with
combination therapy. There were no statistically signi® cant
differences between the 2 treatments; however, these side
effects tended to be milder and to occur later with combination
therapy than with calcipotriol monotherapy. One patient
receiving calcipotriol monotherapy developed severe contact
dermatitis and had to be withdrawn from the study. No
contact dermatitis occurred in response to combination
therapy. Laboratory parameters showed no severe abnorm-
alities in any of the patients in the study.
Subjective evaluation of ef® cacy
Subjective assessments by investigators and patients made
during therapy, as well as global assessment by the patients at
the end of the study, revealed no difference between the 2
treatments.
DISCUSSION
Several well-designed studies have shown that calcipotriol is
an effective treatment for mild-to-moderate chronic plaque
psoriasis (1, 2), but an insuf® cient response to therapy can be
expected in 5 ± 20% of patients. In addition, although
generally well tolerated, calcipotriol monotherapy can cause
local irritation, as well as burning and itching sensations and,
rarely, allergic contact dermatitis. In recent years, several
clinical trials have been conducted to optimize the ef® cacy of
calcipotriol by using combination therapy. These therapeutic
regimens have included the combination of calcipotriol with
PUVA (10), UVB (11 ± 14), cyclosporin (15, 16) and acitretin
(17). Furthermore, several trials have compared the ef® cacy of
calcipotriol alone and topical preparations such as dithranol
(2) and corticosteroids in monotherapy (1), as well as in
combination with calcipotriol (3 ± 7). It can be seen from the
results of these studies that calcipotriol can be combined
effectively with practically every other systemic or topical
psoriatic therapy.
Calcipotriol and corticosteroids are both known to be
effective in the treatment of psoriatic lesions. A bene® cial
effect of the combination therapy of calcipotriol with
di¯ ucortolone valerate might therefore be expected due to
the binding of calcipotriol and corticosteroids at different
cellular receptors. As they show a different mode of action,
combination therapy could result in an additive or synergistic
effect on psoriatic plaques. Furthermore, side effects such as
irritation due to calcipotriol or atrophy of the skin due to
corticosteroids could probably be minimized by a combina-
tion therapy which results in lower total doses of both
components.
In the right ± left comparative study reported here it has
been shown that a combination treatment of calcipotriol with
di¯ ucortolone valerate is at least as effective as calcipotriol
monotherapy. The results suggest a more rapid response at
the beginning of treatment with the combination therapy, a
signi® cantly greater reduction in the PASI values being
observed at weeks 1 and 2. At the end of the 4-week treatment
period, however, no difference in response to therapy could be
demonstrated. Detailed analysis of the PASI values revealed
no signi® cant differences with respect to changes in erythema,
in® ltration or area of psoriatic lesions, but a slight bene® t was
observed in favor of combination treatment in terms of
reduction of scaling, mainly in the ® rst 2 weeks of treatment.
This effect did not, however, reach statistical signi® cance,
probably due to the relatively small number of patients in the
study which did not allow accurate detection of small
differences. Complete healing of psoriatic plaques was
achieved in only 4 patients; however, this was not an
unexpected outcome due to the relatively short duration of
the treatment phase of the study.
Both treatments were well tolerated, with only mild side
effects such as itching and burning. There was no signi® cant
difference in the frequency of side effects between the 2
treatments. Only 1 severe local adverse event was seen, a
case of contact dermatitis occurring in response to
calcipotriol monotherapy and leading to the withdrawal of
the patient from therapy. In response to combination
treatment, no irritation or contact dermatitis was noted,
presumably as a consequence of the lower total dose of
calcipotriol and the suppressive effect of di¯ ucortolone
valerate.
Based on the results of our study it can be concluded that
the combination of calcipotriol and di¯ ucortolone valerate to
treat chronic plaque psoriasis is at least as effective as
calcipotriol monotherapy and may offer some clinical
advantages. The response rate with combined calcipotriol
and di¯ ucortolone valerate may be more rapid than that with
calcipotriol alone and side effects such as itching and burning
may be less intense with combination therapy. These ® ndings
are in agreement with expectation from a theoretical
perspective, but require con® rmation in a larger, longer-
term study.
Acknowledgement
This study was kindly supported by a research grant from Schering
Wien GmbH. The statistical analyses were performed by Dipl. Ing.
Kurt Neumann and his team in Vienna.
REFERENCES
1. Kragballe K, Gjertsen BT, de Hoop D, Karlsmark T, van de
Kerkhof PCM, LarkoÈ O, et al. Double-blind, right/left compar-
ison of calcipotriol and betamethasone valerate in treatment of
psoriasis vulgaris. Lancet 1991; 337: 193 ± 196.
2. Berth-Jones J, Chu AC, Dodd WAH, Ganpule M, Grif® ths
WAD, Haydey RP, et al. A multicentre, parallel-group compar-
ison of calcipotriol ointment and short-contact dithranol therapy
in chronic plaque psoriasis. Br J Dermatol 1992; 127: 266 ± 271.
3. Lebwohl M. Topical application of calcipotriene and corticoster-
oids: combination regimens. J Am Acad Dermatol 1997; 37:
S55 ± 58.
4. Austad J, Bjerke JR, Gjertsen BT, Helland S, Livden JK, Morken
T, et al. Clobetasol propionate followed by calcipotriol is superior
to calcipotriol alone in topical treatment of psoriasis. J Eur Acad
Dermatol Venereol 1998; 11: 19 ± 24.
5. Ruzicka T, Lorenz B. Comparison of calcipotriol monotherapy
Calcipotriol in chronic plaque psoriasis 7
Acta Derm Venereol Suppl 211
and a combination of calcipotriol and betamethasone valerate
after 2 weeks’ treatment with calcipotriol in the topical therapy of
psoriasis vulgaris: a multicentre, double-blind, randomized study.
Br J Dermatol 1998; 138: 254 ± 258.
6. Kragballe K, Barnes L, Hamber KJ, Hutchinson P, Murphy F,
Mù ller S, et al. Calcipotriol cream with or without concurrent
topical corticosteroid in psoriasis: tolerability and ef® cacy. Br
J Dermatol 1998; 139: 649 ± 654.
7. Sander P, StuÈ cker M, Hermes N, Hoffman K, Altmeyer P.
Mometason und Calcipotriol optimieren den therapeutischen
Initialeffekt von Dithranol auf die chronisch stationaÈ re Psoriasis.
Hautarzt 1998; 49: 291 ± 294.
8. Pocock SJ. Clinical trials: A practical approach. Chichester: John
Wiley & Sons, 1983: 112 ± 119.
9. European Organization for Quality. Principles of computer use in
a regulated pharmaceutical industry. Berne: European Organiza-
tion for Quality, 1989.
10. Speight EL, Farr PM. Calcipotriol improves the response of
psoriasis to PUVA. Br J Dermatol 1994; 130: 79 ± 82.
11. Kokelj F, Lavaroni G, Guadagnini A. UVB versus UVB plus
calcipotriol (MC 903) therapy for psoriasis vulgaris. Acta Derm
Venereol 1995; 75: 386 ± 387.
12. Kerscher M, Plewig G, Lehmann P. Kombinationstherapie der
Psoriasis vulgaris mit einem Schmalspektrum UV-B-Strahler
(Philips TL 01, 311 nm) und Calcipotriol. Akt Dermatol 1993;
19: 151 ± 154.
13. Bourke JF, Iqbal SJ, Hutchinson PE. The effects of UVB plus
calcipotriol on systemic calcium homeostasis in patients with
chronic plaque psoriasis. Clin Exp Dermatol 1997; 22: 259 ± 261.
14. Koo J. Calcipotriol/calcipotriene (Dovonex/Daivonex) in combi-
nation with phototherapy: a review. J Am Acad Dermatol 1997;
37: S59 ± 61.
15. Kokelj F, Tosello P, Plozzer C. Calcipotriol improves the ef® cacy
of cyclosporine in the treatment of psoriasis vulgaris. J Eur Acad
Dermatol Venereol 1998; 10: 143 ± 146.
16. Grossmann RM, Thivolet J, Claudy A, Souteyrand P, Guihou JJ,
Thomas P, et al. A novel therapeutic approach to psoriasis with
combination calcipotriol ointment and very low-dose cyclospor-
ine: Results of a multicenter placebo-controlled study. J Am Acad
Dermatol 1994; 31: 68 ± 74.
17. van de Kerkhof PC, Cambazard F, Hutchinson PE, Haneke E,
Wong E, Souteyrand P, et al. The effect of addition of
calcipotriol ointment (50 micrograms/g) to acitretin therapy in
psoriasis. Br J Dermatol 1998; 138: 84 ± 89.
8 W. Salmhofer et al.
Acta Derm Venereol Suppl 211


Double-blind, placebo-controlled, randomized, right-left study comparing calcipotriol monotherapy with a combined treatment of calcipotriol and diflucortolone valerate in chronic plaque psoriasis

http://espace.library.uq.edu.au/view/UQ:301440/UQ301440_OA.pdf

Double-blind, placebo-controlled, randomized, right-left study comparing calcipotriol monotherapy with a combined treatment of calcipotriol and diflucortolone valerate in chronic plaque psoriasis

Abstract

Similar works

Full text

Available Versions

University of Queensland eSpace