ARTICLE
Auteur(s) : Birgitta Wilson Claréus1, Ronald
Houwing2, Jens H Sindrup3, Suzanne
Wigchert4
1Läkarhuset Farsta Centrum, Hudmottagningen,
Karlandaplan 6, 123 47 Farsta, Sweden
2Department of Dermatology, Deventer Hospital, P.O.
Box 5001, NL-7400 GC Deventer, The Netherlands
3Amagerbrogade 18 3, 2300 Copenhagen S,
Denmark
4LEO Pharma Benelux, Hoge Mosten 16, NL-4822 NH Breda,
The Netherlands
accepté le 12 Juin 2009
Psoriasis vulgaris is one of the most common chronic skin
diseases, with a prevalence of approximately 2% [1]. Psoriasis can
generally be managed by topical therapy, phototherapy, systemic
therapy and/or any combination of these. This chronic disease
requires constant disease management for many patients. Flare-ups
requiring an intensive treatment course may be alternated with
periods of less intensive treatment. Corticosteroids, vitamin D
analogues (e.g. calcipotriol) and a two-compound formulation of
calcipotriol and betamethasone are the most commonly used topical
treatments for psoriasis vulgaris. Daivobet®
(Dovobet®) ointment is a fixed combination of
calcipotriol and betamethasone dipropionate, licensed for the
treatment of psoriasis vulgaris. Due to the different mechanisms of
action of calcipotriol (normalising keratinisation and
angiogenesis) and betamethasone dipropionate (improving several
markers of inflammation), the efficacy of the combination of
calcipotriol/betamethasone dipropionate in psoriasis vulgaris is
greater than that of the individual active components and likewise,
the tolerability is increased [2].
More than 3000 patients have been treated with
calcipotriol/betamethasone dipropionate once or twice daily [3-6]
in randomised clinical trials with some patients receiving it for
up to one year [7]. Calcipotriol/betamethasone dipropionate
provides significant disease relief after 1-2 weeks of treatment.
The current labelling recommends treatment once daily for up to 4
weeks and repeated treatments can be initiated under medical
supervision. Studies have shown that plaque psoriasis has a major
impact on patients’ health-related quality of life (QoL), and that
calcipotriol/betamethasone dipropionate significantly improves the
QoL [8]. However, treatment experiences with
calcipotriol/betamethasone dipropionate in routine, real-life
clinical practice have not previously been published. The DESIRE
study (Daivobet®/Dovobet® Experience Study In
Regions of Europe), presented here, is a non-interventional study
which was designed to evaluate patients’ satisfaction after 4-week
treatment courses with calcipotriol/betamethasone dipropionate as
used in normal daily practice over a 6-month period. It is
particularly relevant to study patients’ satisfaction with
treatment since the degree of satisfaction is determined by a
multitude of factors including efficacy, tolerability, ease of use,
cosmetic acceptability, compliance, and cost burden. In addition,
the patients’ willingness to provide co-payment for a future
calcipotriol/betamethasone dipropionate treatment course within the
national health insurance systems was assessed.
Materials and methods
This study was a descriptive, international, multi-centre,
single-group, non-interventional study enrolling patients with a
calcipotriol/betamethasone dipropionate prescription prior to study
start who were followed for 6 months. All patient care was at the
discretion of the patient and the physician.
Ethics
Since this was an observational and non-interventional study, the
decision to prescribe calcipotriol/betamethasone dipropionate and
the subsequent decision to enrol the patient into the study had to
be clearly and completely independent actions.
Prior to the enrolment of patients, the study protocol was
approved/gained favourable opinion by the Ethics Committees as
applicable according to national legislation concerning
non-interventional trials in the respective countries.
All patients received written and verbal information concerning
the study and signed and dated informed consent was obtained prior
to any study-related procedure. The study was conducted in
accordance with the ethical principles that have their origin in
the Declaration of Helsinki (Edinburgh, Scotland, October
2000).
Patients
Patients eligible for the study were out-patients prescribed
calcipotriol/betamethasone dipropionate ointment for plaque
psoriasis on the trunk and/or limbs. The study was performed in the
Netherlands, Denmark, Sweden and Luxembourg in the period
2005-2007. Patients already on current calcipotriol/betamethasone
dipropionate treatment for more than 2 days prior to enrolment were
excluded.
Study procedures
After the prescription of calcipotriol/betamethasone dipropionate
ointment and the signing of written informed consent, the physician
made an overall clinical assessment of disease severity on the
trunk and limbs on a 6-point scale (absence of disease, very mild
disease, mild disease, moderate disease, severe disease or very
severe disease). After that, the patient attended the physician’s
office if, and when, required to do so with respect to the clinical
situation and according to standard treatment practice. During
contacts, the physician recorded treatment duration and the outcome
of the initial treatment course, the date of recurrence of
psoriasis and any subsequent treatments. Data collection did not
require any patient intervention beyond usual care, and was not to
alter the care provided.
The patients assessed treatment satisfaction at the end of each
calcipotriol/betamethasone dipropionate treatment course on a
4-point scale (very satisfied, satisfied, disappointed or very
disappointed). The patients were asked about the reason(s) for
their grading of satisfaction. Similarly, when applicable, the
physician recorded why calcipotriol/betamethasone dipropionate was
chosen for subsequent treatments. For the patients who received a
second calcipotriol/betamethasone dipropionate treatment course, it
was investigated if there was a shift in patients’ satisfaction
comparing the two treatment courses. The patients also made an
assessment on willingness for co-payments for future
calcipotriol/betamethasone dipropionate treatments (willing or not
willing to pay part of the price themselves) within their national
health insurance systems. Additional outcomes included: time to
onset of the first recurrence of symptoms, the total number of
recurrences, the number of calcipotriol/betamethasone dipropionate
treatment courses during the study period and the use of other
anti-psoriatic treatments. A 6-month follow-up report was
completed at the end of the study period.
Safety reporting
Any serious adverse events, related to calcipotriol/betamethasone
dipropionate occurring during the study had to be reported to LEO
Pharma within one working day at first knowledge of the physician.
All other drug-related adverse events had to be notified to the
National Health Authority (NHA) in accordance with applicable
national regulations.
Statistics
The primary analyses used 95% confidence interval (CI) for
proportions (percentages) assuming normal distribution. To examine
if disease severity influenced patients’ satisfaction with
treatment, the assessments were stratified into groups based on
disease severity.
The secondary analysis utilised Kaplan-Meier plots for the
outcome variable, time to recurrence. The proportion of patients
using other treatments, calcipotriol or calcipotriol plus
calcipotriol/betamethasone dipropionate and patients willing to
provide co-payment are presented by counts and/or proportions.
Results
Of the 1224 patients included in the study, 997 (81.5%) completed
the 6-month study period, 58 (4.7%) withdrew voluntarily, 86 (7.0%)
were lost to follow-up and the remaining 6.8% did not complete the
study for other reasons or did not provide data on study
completion.
Approximately half of the patients were men and the mean age was
49.4 years. At inclusion the patients had had psoriasis for 15.2 ±
14.0 years (mean ± SD). More than half of the patients (53%)
included in the study had disease of moderate severity (table 1). Disease severity was evenly distributed
over sex and age categories except for severe or very severe
disease being less common among patients aged 65 years or more.
Use of topical treatment during the 6-month period before study
start included steroids (52.5%), calcipotriol (25.8%),
calcipotriol/betamethasone dipropionate (9.2%), combination of
calcipotriol and steroids as separate products (4.2%), alternating
treatment with calcipotriol and calcipotriol/betamethasone
dipropionate (2.6%), dithranol (1.6%) and other (9.2%).
Phototherapy in the form of PUVA had been used by 2.2% of the
patients and in the form of UVB by 14.5% of the patients. Systemic
treatment during the 6-month period before study start included
methotrexate (3.0%), acitretine (1.9%), ciclosporine (1.6%),
biologicals (0.7%), fumaric acid (0.6%) and other (1.1%).
A majority of the patients (88%) had one
calcipotriol/betamethasone dipropionate treatment course during the
study, 22.9% had two courses and 4.6% had three courses or more
(the remaining did not provide start or stop data for their
course(s)).
The median duration of calcipotriol/betamethasone dipropionate
use was 31 days for both the first and second treatment course and
27 days for the third course. The median total duration during the
complete study period was 46 days. The frequency of dosing was once
daily for 92.4% of the patients and “other” for the remaining
patients.
Satisfaction
The majority (73.6%) of the patients reported being very satisfied
(37.0%) or satisfied (36.6%) after the initial
calcipotriol/betamethasone dipropionate treatment course.
Disappointment was reported by 14.4% of the patients (12.6% were
disappointed and 1.8% were very disappointed). Assessment was
missing for 12.0% of the patients. After the second course 78.9% of
the 247 patients reported satisfaction (36.0% were very satisfied
and 42.9% were satisfied) (figure 2). After the third
course, 80.0% of the 50 patients reported satisfaction (40.0% very
satisfied, 40.0% satisfied), see figure 1.
Patient satisfaction assessments after the initial
calcipotriol/betamethasone dipropionate treatment course is based
on all 1224 patients enrolled. The patient’s satisfaction after the
second and third course is based on the 247 patients receiving a
second and the 50 patients receiving a third
calcipotriol/betamethasone dipropionate treatment course as
monotherapy, respectively. The percentages of patients with missing
data on patient satisfaction were: 12% after the initial course,
1.6% after the second course and 0% after the third course.
Among patients who were very satisfied or satisfied after the
initial calcipotriol/betamethasone dipropionate course, 167/199
(84%) were satisfied or very satisfied also after the second course
while 31 patients (16%) were disappointed and one patient (1%) was
very disappointed. Eleven (52%) of the 21 patients who were
disappointed after the initial course were also disappointed after
the second course and 1 (5%) was very disappointed, but nine (43%)
were satisfied or very satisfied after the second course.
Efficacy was the main reason for the patients’ assessment of
satisfaction, irrespective of their rating. Ease of use was also
often given as a reason for patients being satisfied or very
satisfied (table 2). The same pattern
was observed after the first, second and third treatment courses.
Efficacy was also the main reason why the physicians chose
calcipotriol/betamethasone dipropionate for the second and
subsequent treatments.
Patient satisfaction was high, regardless of the initial disease
severity. The percentage of patients who were very satisfied or
satisfied ranged from 64% to 75% among those with very mild to
severe disease (table 3). All five
patients with very severe disease were very satisfied, or
satisfied.
Table 1 Demographics and baseline characteristics
|
|
Total N = 1224
|
|
Age (years)
|
Mean
|
49.4
|
|
SD
|
15.7
|
|
Min
|
10.0*
|
|
Max
|
89.0
|
|
Gender n (%)
|
Males
|
637 (52.0%)
|
|
Females
|
587 (48.0%)
|
|
Psoriasis duration (months)
|
Mean
|
182.8
|
|
SD
|
168.2
|
|
Min
|
0
|
|
Max
|
912
|
|
Disease severity at inclusion n (%)
|
Missing observations
|
2 (0.2%)
|
|
Very mild disease
|
53 (4.3%)
|
|
Mild disease
|
398 (32.5%)
|
|
Moderate disease
|
643 (52.5%)
|
|
Severe disease
|
123 (10.0%)
|
|
Very severe disease
|
5 (0.4%)
|
Table 2 Reasons for patient satisfaction after the
initial calcipotriol/betamethasone dipropionate course
|
Very satisfied N = 453 n (%)
|
Satisfied N = 448 n (%)
|
Disappointed N = 154 n (%)
|
Very disappointed N = 22 n (%)
|
|
Efficacy
|
430 (94.9%)
|
370 (82.6%)
|
127 (82.5%)
|
19 (86.4%)
|
|
Tolerability
|
129 (28.5%)
|
118 (26.3%)
|
9 (5.8%)
|
1 (4.5%)
|
|
Cosmetic acceptability
|
126 (27.8%)
|
93 (20.8%)
|
9 (5.8%)
|
1 (4.5%)
|
|
Ease of use
|
147 (32.5%)
|
123 (27.5%)
|
5 (3.2%)
|
0
|
|
Patient costs
|
17 (3.8%)
|
6 (1.3%)
|
7 (4.5%)
|
1 (4.5%)
|
|
Societal costs
|
8 (1.8%)
|
2 (0.4%)
|
0
|
0
|
|
Missing observations
|
6 (1.3%)
|
11 (2.5%)
|
12 (7.8%)
|
1 (4.5%)
|
Table 3 Patient satisfaction after the initial
treatment course by psoriasis severity at baseline
|
Psoriasis severity at baseline
|
Patient’s satisfaction after the initial calcipotriol/
betamethasone dipropionate treatment course
|
|
Missing (n %)
|
Very satisfied (n %)
|
Satisfied (n %)
|
Disappointed (n %)
|
Very disappointed (n %)
|
|
Missing
|
0
|
2 (100%)
|
0
|
0
|
0
|
|
Very mild disease
|
10 (18.9%)
|
16 (30.2%)
|
18 (34.0%)
|
7 (13.2%)
|
2 (3.8%)
|
|
Mild disease
|
48 (12.1%)
|
155 (38.9%)
|
141 (35.4%)
|
47 (11.8%)
|
7 (1.8%)
|
|
Moderate disease
|
71 (11.0%)
|
240 (37.3%)
|
242 (37.6%)
|
80 (12.4%)
|
10 (1.6%)
|
|
Severe disease
|
18 (14.6%)
|
37 (30.1%)
|
45 (36.6%)
|
20 (16.3%)
|
3 (2.4%)
|
|
Very severe disease
|
0
|
3 (60.0%)
|
2 (40.0%)
|
0
|
0
|
Follow-up therapy
Follow-up therapy was prescribed at the first visit for 60.4% of
the patients. The most common therapy was topical treatment (96%).
44.8% of the patients were prescribed a combination of calcipotriol
on weekdays, alternating with calcipotriol/betamethasone
dipropionate in the weekend. Other prescriptions included
phototherapy (12.8%) and systemic treatment (5.9%), usually in
combination with a topical treatment.
Recurrence
During this 6-month study, 45.3% of the patients did not experience
any recurrence of psoriasis, 26.9% had one recurrence, 7.2% had two
and 4.1% had three or more (16.5% of the patients had missing or
incomplete data).
The Kaplan-Meier curve of time in days from the end of the first
calcipotriol/betamethasone dipropionate treatment to first
recurrence of psoriasis plaques showed that the probability of
experiencing a first re-occurrence within 50 days was approximately
20-25%, while the probability of experiencing a first recurrence
within 150 days was between 40% and 45% (figure 2).
The Kaplan-Meier analysis is based on data from 886 evaluable
patients (patients with missing or incomplete data have been
excluded).
Co-payment
After the first treatment course 59.6% of patients answered that
they were willing to provide co-payment for
calcipotriol/betamethasone dipropionate while 20.6% were not
willing to do that (the remaining did not provide any answer). The
percentage of patients willing to provide co-payment increased with
the increasing number of treatment courses and was 78.6% after the
third course.
Safety
No drug-related serious adverse event occurred during the study.
Discussion
Studies presenting patient-related study outcomes are scarce and
use in daily practice may give results different from those in well
controlled clinical trials in which patient populations are
generally more homogenous. Although non-interventional studies
cannot be blinded and are subject to patient-, observer- and
analyst bias, it is particularly important to study patients’
satisfaction with treatment in daily practice. This is particularly
important since not only efficacy and safety but also factors such
as tolerability, ease of use, cosmetic acceptability, compliance,
and cost burden affect the use and compliance and thereby the
treatment outcome. In line with this, patient-reported outcomes
regarding effectiveness endpoints in clinical trials are becoming
increasingly accepted as support for claims in product labelling
[9].
In this 6-month non-interventional study enrolling 1224
patients, approximately 75% of patients who used
calcipotriol/betamethasone dipropionate indicated that they were
satisfied or very satisfied with the initial treatment course. The
Kaplan-Meier plot on time from end of first
calcipotriol/betamethasone dipropionate treatment course to first
re-occurrence showed that the probability of experiencing a first
re-occurrence of psoriasis plaques within 5 months was 40-45%. The
relapse rate is much higher when psoriasis is treated with topical
steroids alone [10]. From this study it also appeared that
follow-up therapy prolongs the time that the disease remains in
remission. Recurrent calcipotriol/betamethasone dipropionate
courses were prescribed for approximately one fifth of the
patients, i.e. to approximately half of the patients who
experienced a recurrence, and patient satisfaction rates remained
equally high (about 80%) with repeated treatment. These data
support the findings from a large-scale clinical trial of
calcipotriol/betamethasone dipropionate ointment in which
approximately 80% of the patients were satisfied with the efficacy
of this treatment, used as required, for up to 52 weeks [7]. The
current study shows that a majority of patients who were satisfied
or very satisfied after the initial calcipotriol/betamethasone
dipropionate course, remained satisfied or very satisfied after the
second course. Almost half of the 14% of patients who were
disapppointed after the initial course, were satisfied or very
satisfied after the second course, supporting the use of an
additional course or prolonged treatment with
calcipotriol/betamethasone dipropionate. There was a wide range in
the duration of the calcipotriol/betamethasone dipropionate courses
with a mean duration of 55 days for the initial course. The long
duration of use in many patients in the current study is in
agreement with the positive results on disease control observed
with longer term use in the 52-week study [7]. Follow-up therapy
was prescribed at the first visit for 60.4% of the patients.
Importantly, patient satisfaction was high, regardless of the
initial psoriasis severity. Systemic treatment is commonly
prescribed for patients with severe disease but the current study
supported earlier studies [11, 12] showing that
calcipotriol/betamethasone dipropionate is efficacious also in the
treatment of severely affected patients.
The majority of the patients in this study were willing to
provide co-payment for calcipotriol/betamethasone dipropionate. The
willingness-to-pay for treatment is relatively large in patients
with skin diseases, including scalp psoriasis [13]. A Swedish
study from 1999 reported that on average, patients were willing to
pay between 1253 and 1956 Swedish crowns (SEK), or between 132 and
206 EUR, per month for a psoriasis treatment [14]. A patient’s
willingness to pay is an individual decision and not necessarily
associated to the cost-effectiveness of a treatment. The
cost-effectiveness is a measure made for the authorities to make
reimbursement decisions and therefore corresponds to a “Society
Willingness to Pay”. Several studies have shown that
calcipotriol/betamethasone dipropionate is a cost-effective
treatment [15-17].
No drug-related serious adverse event occurred during the study.
Calcipotriol/betamethasone dipropionate has been shown to be safe
for long-term management of psoriasis. Kragballe et al. [18]
showed that treatment with calcipotriol/betamethasone dipropionate,
once daily as required for up to 52 weeks, was related to
significantly fewer adverse drug reactions compared with treatment
with calcipotriol/betamethasone dipropionate (4 weeks) alternating
with calcipotriol ointment (48 weeks).
A benefit with non-interventional studies is that the
investigator observes and evaluates the results of ongoing medical
care without controlling the therapy beyond normal medical
practice. This non-interventional study on the clinical practice of
calcipotriol/betamethasone dipropionate treatment supports the
results from clinical trials by showing that patient satisfaction
was high both in the initial treatment and after repeated treatment
courses, regardless of the initial disease severity.
Acknowledgements
This study was financially supported by LEO Pharma A/S, producer of
Daivobet®/Dovobet®. We would like to thank
the participating investigators. We also thank Karin Gewert,
Writewise, for medical writing services and the Pharma Consulting
Group for biostatistical service.
Conflict of interest: Suzanne Wigchert is an employee of LEO
Pharma.
References
1 Menter A, Gottlieb A, Feldman SR, et al.
Guidelines of care for the management of psoriasis and psoriatic
arthritis: Section 1. Overview of psoriasis and guidelines of care
for the treatment of psoriasis with biologics. J Am Acad Dermatol
2008; 58: 826-50.
2 Guenther L. Fixed-dose combination therapy for psoriasis.
Am J Clin Dermatol 2004; 5: 71-7.
3 Douglas WS, Poulin Y, Decroix J, et al. A
new calcipotriol/betamethasone formulation with rapid onset of
action was superior to monotherapy with betamethasone dipropionate
or calcipotriol in psoriasis vulgaris. Acta Derm Venerol 2002; 82:
131-5.
4 Guenther L, Cambazard F, Van de Kerkhof PC,
et al. Efficacy and safety of a new combination of
calcipotriol and betamethasone dipropionate (once or twice daily)
compared to calcipotriol (twice daily) in the treatment of
psoriasis vulgaris: a randomized, double-blind, vehicle-controlled
clinical trial. Br J Dermatol 2002; 147: 316-23.
5 Kaufmann R, Bibby AJ, Bissonnette R,
et al. A new calcipotriol/betamethasone combination is an
effective once-daily treatment for psoriasis vulgaris. Dermatology
2002; 205: 389-93.
6 Kragballe K, Noerrelund KL, Lui H, et al.
Efficacy of once-daily treatment regimens with
calcipotriol/betamethasone dipropionate ointment in psoriasis
vulgaris. Br J Dermatol 2004; 150: 1167-73.
7 Kragballe K, Austad J, Barnes L, et al.
Efficacy results of a 52-week, randomised, double-blind, safety
study of a calcipotriol/betamethasone dipropionate two-compound
product (Daivobet®/Dovobet®/Taclonex) in the
treatment of psoriasis vulgaris. Dermatology 2006; 213: 319-26.
8 van de Kerkhof PC. The impact of a two-compound product
containing calcipotriol and betamethasone dipropionate
(Daivobet®/ Dovobet®) on the quality of life
in patients with psoriasis vulgaris: a randomized controlled trial.
Br J Dermatol 2004; 151: 663-8.
9 U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER),
Center for Biologics Evaluation and Research (CBER), Center for
Devices and Radiological Health (CDRH). Guidance for Industry.
Patient-Reported Outcome Measures: Use in Medical Product
Development to Support Labeling Claims. Draft guideline. Feb 2006.
http://www.fda.gov/CDER/guidance/5460dft.pdf
10 Koo JK, Lebwohl M. Duration of remission of
psoriasis therapies. J Am Acad Dermatol 1999; 41: 51-9.
11 Anstey AV, Kragballe K. Retrospective assessment of
PASI 50 and PASI 75 attainment with a calcipotriol/betamethasone
dipropionate ointment. Int J Dermatol 2006; 45: 970-5.
12 van de Kerkhof PC, Wasel N, Kragballe K,
et al. A two-compound product containing calcipotriol and
betamethasone dipropionate provides rapid, effective treatment of
psoriasis vulgaris regardless of baseline disease severity.
Dermatology 2005; 210: 294-9.
13 Schiffner R, Schiffner-Rohe J, Gerstenhauer M,
et al. Willingness to pay and time trade-off: sensitive to
changes of quality of life in psoriasis patients? Br J Dermatol
2003; 148: 1153-60.
14 Lundberg L, Johannesson M, Silverdahl M,
et al. Quality of life, health-state utilities and willingness
to pay in patients with psoriasis and atopic eczema. Br J Dermatol
1999; 141: 1067-75.
15 Bottomley JM, Auland ME, Morais J, et al.
Cost-effectiveness of the two-compound formulation calcipotriol and
betamethasone dipropionate compared with commonly used topical
treatments in the management of moderately severe plaque psoriasis
in Scotland. Curr Med Res Opin 2007; 23: 1887-901.
16 Peeters P, Ortonne JP, Sitbon R, et al.
Cost-effectiveness of once-daily treatment with
calcipotriol/betamethasone dipropionate followed by calcipotriol
alone compared with tacalcitol in the treatment of Psoriasis
vulgaris. Dermatology 2005; 211: 139-45.
17 Augustin M, Peeters P, Radtke M, et al.
Cost-effectiveness model of topical treatment of mild to moderate
psoriasis vulgaris in Germany. A comparison of
calcipotriol/betamethasone
(Daivobet®/Dovobet®/Taclonex) once daily and
a morning/evening non-fix combination of calcipotriol and
betamethasone. Dermatology 2007; 215: 219-28.
18 Kragballe K, Austad J, Barnes L, et al. A
52-week randomized safety study of a calcipotriol/betamethasone
dipropionate two-compound product
(Dovobet®/Daivobet®/Taclonex®) in
the treatment of psoriasis vulgaris. Br J Dermatol 2006; 154:
1155-60.
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