Journal of the European Academy of Dermatology and Venereology

11 (1998) 19–24

Clobetasol propionate followed by calcipotriol is superior to

calcipotriol alone in topical treatment of psoriasis

Joar Austad a ,*, Jens R. Bjerke b, Bjørn T. Gjertsen c, Svein Helland d,

John K. Livden e, Tore Morken d, Nils-Jørgen Mørk a
a
Sandvika Bad, Kinoveien 4, 1300 Sandvika, Norway
b
Oslo Hudklinikk, Hegdehaugsveien 36B, 0352 Oslo, Norway
c
Hudpoliklinikken Sentralsykehuset i Sogn og Fjordane, avd. Florø, 6900 Floro, Norway
d
Hudavdelingen, Haukeland sykehus, 5021 Bergen, Norway
e
Hudpoliklinikken, Teatergt. 37, 5010 Bergen, Norway

Abstract

Background Although potent, topical corticosteroids offer effective and rapid healing of psoriatic lesions. Their long term
use is limited because of the risk of side effects. Calcipotriol is safe for long-term treatment, but its initial efficacy is lower
than with topical corticosteroids.
Objectives To investigate whether 2 weeks of treatment with clobetasol propionate 0.05% ointment bd followed by 4 weeks
of treatment with calcipotriol 50 mg/g bd would offer therapeutic advantages over 6 weeks of continuous treatment with
calcipotriol.
Methods Forty-nine patients with moderate to severe plaque psoriasis were recruited from five centres in Norway. In a
randomised, double-blind, right- versus left-side comparison, ointments were applied to two symmetrically-located areas.
Results Two weeks of treatment with clobetasol propionate produced a significantly greater decrease in total symptom score
(combined scores of erythema, induration and scaling) than calcipotriol treatment (P , 0.0001). This improvement on the
clobetasol propionate-treated side of the body was maintained throughout a subsequent 4-week treatment period when
calcipotriol was applied to both sides of the body (P , 0.0001). The superiority of the clobetasol propionate followed by
calcipotriol treatment was maintained during a 4-week, treatment-free, observation period. Treatments were well tolerated
with no rebound effect.
Conclusions Clobetasol propionate ointment bd for 2 weeks followed by treatment with calcipotriol ointment bd for 4
weeks was superior to calcipotriol ointment alone in the treatment of plaque psoriasis.  1998 Elsevier Science B.V. All
rights reserved

Keywords: Psoriasis; Clobetasol propionate; Calcipotriol

1. Introduction because corticosteroids act by suppressing symp-

World-wide, corticosteroids are the most common
first-line topical treatment for psoriasis [1], being safe
and effective under proper supervision. However,
* Corresponding author. Hudavdelingen, Rikshospitalet, N-0027
Oslo, Norway. Tel.: +47 22 868430; fax: +47 22 868433.
toms, producing improvement only when applied,
the potency and cumulative amount of the corticoster-
oid applied, together with the use of occlusion, may
cause side-effects in some patients with psoriasis [1].
In addition, tolerance and a fast relapse rate have been
associated with the use of corticosteroids in the treat-
ment of psoriasis [1].

0926-9959/98/$19.00  1998 Elsevier Science B.V. All rights reserved

PII S0926-9959 (98 )0 0008-7
20 J. Austad et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 19–24
Clobetasol propionate, thought to be the most
potent topical corticosteroid available, offers effective
and rapid healing of psoriatic lesions [2,3] To avoid
potential side effects, full-dose treatment does not
normally exceed a duration of 2 weeks. The remission
period may be extended by applying other non-ster-
oidal, psoriatic treatments such as calcipotriol, a vita-
min D3 analogue, which is comparable in effect with
moderately potent (Group III; British National For-
mulary) corticosteroids [4,5]. Calcipotriol has been
shown to be a safe and effective treatment for chronic
plaque psoriasis and is normally used continuously for
6–8 weeks or more as monotherapy [6].
The aim of this study was to investigate whether 2
weeks of initial therapy with clobetasol propionate to
induce rapid healing, followed by 4 weeks of treat-
ment with calcipotriol, offered therapeutic advantages
over 6 weeks of continuous treatment with calcipo-
triol alone.
2. Materials and methods
2.1. Subjects
This study involved 49 patients (age 18–68 years)
of both sexes with stable, moderate to severe plaque
psoriasis and a mean duration of psoriasis of 15.6
years (range 1–57 years). The lesions were symme-
trically distributed, including one or more anatomical
areas of the trunk, upper or lower limbs. Moderate to
severe psoriasis was defined as a minimum total score
of 6.0 out of a possible 9.0 for the combined scores
of erythema, induration and scaling (Table 1). All
patients had discontinued topical medication 2
weeks prior to the pre-trial assessment. Likewise, 4
weeks preceding the pre-trial assessment, patients
were to have stopped systemic therapy, photoche-
motherapy or other light therapy. During this pre-
trial period, patients with excessive scaling were
allowed to use salicylic acid if necessary.
Patients were excluded from the study for the fol-
lowing reasons: widespread psoriatic lesions requiring
applications of more than 50 g ointment per week,
hypercalcemia, liver or renal disease, pregnancy or
breast-feeding or the likelihood of pregnancy during
the course of the study, medications liable to affect
the course of the psoriasis, serious concomitant
medical conditions, alcohol or drug abuse, other
investigational treatments within the month preceding
the start of the study or a previous adverse response to
topical or systemic corticosteroid therapy or to topical
calcipotriol treatment.
The study protocol was approved by the relevant
Regional Ethics committee and all patients provided
their written informed consent.
2.2. Methods
2.2.1. Design
This study was a randomised, double-blind,
right- versus left-side comparison performed at five
centres in Norway. According to the randomisation
schedule, patients applied clobetasol propionate
(0.05%) ointment to one side of the body for 2
weeks followed by calcipotriol (50 mg/g) ointment
for 4 weeks. To the other side of the body patients
applied calcipotriol (50 mg/g) ointment alone for 6
weeks. Patients were instructed to apply the ointments
twice daily in a thin layer to the psoriatic lesions. The
total amount of ointment applied was not to exceed
25 g per bodyside per week. Low potency corticoster-
oids (Group I or II; British National Formulary) could
be applied to treat lesions on the scalp, as necessary.
To avoid cross-contamination, patients were in-
structed to wash and dry their hands after each appli-
cation.
Clinical examination took place at the start of the
study and then every 2 weeks during the treatment
phase. At the end of the active treatment period,
patients who were satisfied with the improvement in
their condition and who were judged by the investi-
gator to require no further active treatment on either
Table 1
Patient characteristics
All patients
No. of patients 49
Males (%) 31 (63)
Females (%) 18 (37)
Age (years) (mean (SD)) 42.4 (13.9)
Duration of psoriasis (years) (mean (SD)) 15.6 (12.3)
Duration of current episode (weeks) (mean (SD)) 32 (39)
a
Overall severity score (median (range)) 6.0 (6.0–8.0)
a
Sum of scores for erythema, thickness and scaling.
 J. Austad et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 19–24
Table 2
Global assessment of therapy response
Cleared 100% remission of signs and symptoms
Excellent At least 75% improvement
Good Between 50 and 75% improvement
Fair Between 25 and 49% improvement
Poor Less than 25% improvement
Worse Exacerbation of the disease
side of the body, entered a 4-week, treatment-free
observation period.
2.2.2. Assessments
At the first clinical examination, two lesions each
with a diameter greater than 20 mm and symmetri-
cally located on opposite sides of the body, were iden-
tified for evaluation. At each subsequent examination,
the same investigator assessed the severity of the clin-
ical symptoms (erythema, induration, scaling and
pruritis) of both target lesions. Each lesion was graded
on a 0–3 scale, according to which 0 = absent, 1 =
mild, 2 = moderate and 3 = severe. An overall sever-
ity score (sum of erythema, induration and scaling)
was calculated. Additionally, each physician made a
global assessment of response to therapy using Table
2.
Patients with an overall severity score of 0 for one
or both target lesions and whose target lesion had been
defined as cleared by the investigator, were instructed
to continue in the study but to apply ointment only to
those lesions which had not healed. Patients were to
continue their participation in the study even if all
their lesions had cleared.
Physician and patient preferences for medication
were recorded, as were all adverse events, whether
reported spontaneously by patients or in response to
specific questioning.
2.2.3. Compliance
Compliance was assessed by questioning patients at
each visit and inspecting the tubes of medication to
ascertain the amount used.
2.2.4. Analysis and sample size
The sample-size calculation was based on the over-
all severity score adjusted for the pre-treatment score.
To enable detection of a between-treatment difference
of 0.5 SD with a significance level of 5%, 42 patients
21
were required to give a power of 90%. A total of 50
patients were to be included to ensure at least 42
patients for evaluation.
Categorically-distributed variables are presented
using frequency distribution. Continuously-distribu-
ted variables are presented using mean and standard
deviation (SD).
For the overall severity score and physicians’ glo-
bal assessment of treatment, the comparison of study
treatments was performed on within-subject differ-
ences in changes from the pre-treatment assessment
values using Wilcoxon signed rank test [7]. Pairs with
equal right-left values were excluded. Treatment com-
parisons for patients’ and physicians’ preferences
were analysed using the sign test [8] and ignoring
the ties (i.e. ‘no preference’).
All tests were performed two-sided at a significance
level of 5%.
3. Results
3.1. Subjects
The elbows, knees and lower legs were the body
area sites most frequently affected and treated: 43
patients (87.8%), 32 patients (65.3%) and 25 patients
(51%), respectively.
Three patients withdrew from the study, two of
whom failed to return after 2 and 4 weeks, respec-
tively, and a third who withdrew after 4 weeks
because all lesions had almost cleared. Concurrent
medication was recorded by 16 patients, predomi-
nantly hydrocortisone butyrate, which was used by
six patients for treatment of scalp psoriasis.
3.2. Overall severity score
The overall severity score decreased from baseline
values at all time-points on both treatments (Fig. 1).
However, after the initial 2-week therapy, the median
overall severity score was significantly lower for clo-
betasol propionate than for calcipotriol (P , 0.0001).
After the subsequent 4-week treatment with calcipo-
triol, the lesions which had been treated for 2 weeks
with clobetasol propionate had significantly lower
severity scores than the lesions which had received
continuous treatment with calcipotriol (P , 0.0001).
22 J. Austad et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 19–24
Fig. 1. Overall median symptom score (combination of erythema,
induration and scaling). *Statistically significantly different; P ,
0.0001 at 2, 4 and 6 weeks and P = 0.0002 at 10 weeks; n = ≥ 46
during the 6-week treatment period; n = 25 during the 4-week
follow-up period. Abbreviations: calcipotriol (6w), calcipotriol
for 6 weeks; clobetasol propionate (2w)/calcipotriol (4w), clobeta-
sol propionate for 2 weeks followed by calcipotriol for 4 weeks;
calcipotriol (follow up pat.), observations made during a 4-week
follow-up period of patients who had received calcipotriol for 6
weeks; clobetasol prop./calcipotriol (follow up pat.), observations
made during a 4-week follow-up period of patients who had
received clobetasol propionate for 2 weeks followed by calcipotriol
for 4 weeks.
Scores for the individual signs of erythema, thickness
scaling and pruritus reflected the same pattern of
response.
3.3. Physicians’ global assessment of treatment
The physicians strongly favoured the 2-week treat-
ment with clobetasol propionate (P , 0.0001 for
treatment difference) and subsequent 4-week treat-
ment with calcipotriol (P , 0.0001 for treatment dif-
ference) rather than 6 weeks of calcipotriol treatment
alone (Fig. 2).
3.4. Treatment preferences
Eighty percent of physicians and 82% of patients
judged the lesions which were treated initially for 2
weeks with clobetasol propionate to have had a better
treatment response than those treated with calcipotriol
over the same period. This was in contrast to the 8% of
physicians and 6% of patients who favoured the initial
2 weeks with calcipotriol (P , 0.0001 for treatment
difference) (Table 3). After a subsequent 4-week per-
iod using calcipotriol on both sides of the body, 61%
of physicians and patients judged the lesions which
had been treated with clobetasol propionate to have
had a better treatment response (Table 3). This is in
contrast to the 11% of physicians and patients who
judged continuous calcipotriol therapy to be the better
treatment (P , 0.0001 for treatment difference).
3.5. Adverse events
Four patients reported a total of seven adverse
events, principally local skin reaction, (five reports)
which were judged to be related to study medication.
One report of influenza and one report of bronchitis
were considered to be unrelated to study medication.
The local skin reactions included one report of
increased skin irritation which occurred only on the
calcipotriol-treated side and three cases of pruritis
occurring on both sides of the body. There was also
one report of reddish discoloration in one patient,
which occurred with both treatments.
3.6. Post-treatment follow-up
At the end of the active-treatment period, 25
patients fulfilled the criteria to enter a 4-week treat-
ment-free observation period. These were all patients
who were satisfied with the improvement in their con-
ditions and who were judged by the investigator to
require no further active treatment on either side of
the body. At the end of the observation period, the
lesions which had been treated with 2 weeks of active
treatment with clobetasol propionate followed by 4
weeks with calcipotriol had significantly lower overall
severity scores than the lesions which had received 6
weeks of continuous treatment with calcipotriol (P =
0.0002). (Fig. 1).
There was no rebound effect after cessation of treat-
ment. At the end of this treatment-free observation
period, the median severity score for the lesions
which had received clobetasol propionate followed
 J. Austad et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 19–24 23

Table 3 propionate followed by 4 weeks treatment with calci-

Physician and patient treatment preferences potriol, was maintained for a further 4 weeks after the
Week 2 Week 6
n = 49 (%) n = 46 (%)

Physicians
No preference 12 28
Calcipotriol 8 11
Clobetasol propionate 80 n.a.
Clobetasol propionate n.a. 61
followed by calcipotriol
Patients
No preference 12 28
Calcipotriol 6 11
Clobetasol propionate 82 n.a.
Clobetasol propionate n.a. 61
followed by calcipotriol

n.a., not applicable.

by calcipotriol was 3.0 and for the lesions which had

received calcipotriol alone it was 3.5.
At the end of this 4-week observation period, the
physicians’ global assessment of treatment continued
to favour the combination treatment (P = 0.008 for
treatment difference; Fig. 2). Combination treatment
remained the preferred option for 40% of physicians
and 44% of patients, whereas 8% of both physicians
and patients preferred treatment with calcipotriol
alone (P = 0.04 and 0.02, respectively, for treatment
differences).

4. Discussion

This study has shown that over a 2-week period,

twice daily applications of clobetasol propionate oint-
ment succeeded in clearing the symptoms of moderate
to severe plaque psoriasis more rapidly than equiva-
lent applications of calcipotriol ointment. The super-
ior efficacy of clobetasol propionate in this respect
was maintained over a subsequent 4-week treatment
period with calcipotriol ointment twice daily. The
same pattern of response was observed in all measures
of efficacy, including symptoms of erythema, indura- Fig. 2. Physicians’ global assessment of treatment after (a) 2 weeks
tion, scaling and pruritis, physicians’ overall assess- treatment with clobetasol propionate or calcipotriol, (b) after a
ment of treatment, and patients’ and physicians’ treat- subsequent 4-week treatment period with calcipotriol and (c)
after a 4-week post-study, observation period with no treatment.
ment preferences. Furthermore, in patients who Abbreviations: CAL, calcipotriol; CP, clobetasol propionate; CP/
showed a satisfactory treatment response, the superior CAL, clobetasol propionate for 2 weeks followed by calcipotriol
effect of 2 weeks initial treatment with clobetasol for 4 weeks.
24 J. Austad et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 19–24
cessation of active treatment. During this treatment-
free observation period symptom scores remained low
and there was no evidence of a rebound effect.
This study did not measure the effects of clobetasol
propionate and calcipotriol on laboratory parameters,
in particular, serum calcium and serum cortisol. How-
ever, the published findings of a trial lasting up to 1
year, have shown that calcipotriol has no effect on
serum calcium [9]. Some previous studies have
shown that clobetasol propionate was associated
with depressed plasma cortisol levels. However, the
levels returned to normal even with continued treat-
ment and were, all within normal ranges 1 week after
the end of therapy [10,11]. Both treatments were, in
fact, well tolerated. A small number of patients
reported a similar incidence of minor local skin irrita-
tions in both treatments.
Clobetasol propionate is the most potent of the cur-
rently available topical steroids and is effective in the
treatment of psoriasis. Furthermore, it has been found
that clobetasol propionate is faster in restoring barrier
function than calcipotriol [12]. The present study, like
others before it, has shown clobetasol ointment to be
rapid and effective in clearing moderate to severe
psoriasis. when used over a 2-week period [2,3].
In order to optimise the treatment efficacy and
safety in long term treatment, the combination of clo-
betasol propionate for 2 weeks to induce rapid healing
of the psoriatic lesions followed by a non-steroidal,
antipsoriatic treatment for maintenance therapy is rea-
sonable, and would certainly minimise the risk of
unwanted corticosteroid side effects. Rapid healing
and reduction of the length of treatment periods is
of high importance in patients with chronic psoriasis.
5. Conclusion
This study has demonstrated that the particular
combination of twice daily clobetasol propionate oint-
ment for 2 weeks followed by calcipotriol ointment
twice daily for 4 weeks, is an effective treatment regi-
men for moderate to severe plaque psoriasis, and is
superior to calcipotriol ointment alone.
Acknowledgements
This study was supported by a grant from Glaxo
Wellcome Research and Development Norway.
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