Calcitriol ointment and clobetasol propionate cream: a new regimen for the treatment of plaque psoriasis

ARTICLE

Auteur(s) : Morad LAHFA¹, Ulrich MROWIETZ², Miriam KOENIG³, Jan C SIMON³

¹ Hôpital Saint-Louis,1 avenue Claude Vellefaux, 25015 Paris, France
² Department of Dermatology, University of Kiel, Kiel, Germany
³ Albert-Ludwigs-Universität, Freiburg Universitäts-Hautklinik, Freiburg, Germany

Article accepted on 11/03/2003

Psoriasis is a chronic skin disorder characterized by an epidermal hyperproliferation and dermal inflammation. An exaggerated and inappropriate immune response to the diseased tissue also contributes to the clinical manifestations of the condition [1]. The physiopathology of this disorder is still unknown.
Because of the chronic nature of the disease, relapse is a relatively common problem when topical anti-psoriatic treatments are discontinued. While the incidence of relapse following steroid withdrawal may be reduced by intermittent treatment, the well-documented side-effects profile of corticosteroids precludes either extensive or extended use. As reported by Ruzicka and Lorenz [2] combination therapy reduces the hazards associated with the long-term use of topical corticosteroids (atrophy, rebounds), while reducing side effects caused by calcipotriol, possibly due to the synergy of corticosteroids and vitamin D analogue and leads to an additive clinical effect in terms of reducing psoriatic symptoms.
Calcipotriol is an analogue of vitamin D that is used for the treatment of chronic plaque psoriasis and has minimal effects on calcium metabolism. The therapeutic efficacy of calcipotriol has been demonstrated in numerous clinical studies [3-7].

Calcitriol (1 α, 25-dihydroxyvitamin D₃) is the hormonally active metabolite of vitamin D₃. Apart from its well-known role in calcium homeostasis, it has been shown to both inhibit proliferation and induce differentiation of keratinocytes, as well as modulating the immune response in skin tissue.[8] A number of clinical trials have demonstrated that topical calcitriol is effective in the treatment and control of psoriasis [9-11].

The vitamin D₃ analogue calcitriol may present an attractive alternative to calcipotriol for the control of psoriasis in a regimen with clobetasol propionate 0.05% a super potent topical corticosteroid [12-13].

Therefore, the aim of this study was to evaluate a regimen strategy composed by a 2 to 4 weeks bitherapy with clobetasol propionate and calcitriol or calcipotriol to achieve marked improvement in each patient’s lesions followed by a 8 to 10 weeks maintenance monotherapy with either calcitriol or calcipotriol. Such a regimen would also closely mimic the clinical real life situation where, once an acute episode is under control, the patients wish to sustain the level of improvement in their psoriasis with continuing effective and well tolerated therapy.

Methodology

Study design and treatments

The aim of the trial was to assess the efficacy and safety of the following treatment regimens: Calcitriol 3μg/g ointment (Silkis^® ointment, Galderma Laboratories) and calcipotriol 50 μg/g ointment (Dovonex^® ointment, Leo Pharmaceuticals) used as part of an initial bitherapy alongside clobetasol propionate 0.05% cream followed by a monotherapy with vitamin D compounds. This randomized, investigator-blinded, parallel group study was conducted at 14 centres in France and Germany. 
To be considered for the study, patients had to be suffering from mild to moderate chronic plaque-type psoriasis affecting up to 30% of their body surface area. All provided written informed consent and were given a clinical examination to confirm their suitability for the study. Among the exclusion criteria were: skin conditions that could interfere with study drug assessments, any clinical condition that might put the patient at risk during the study, severe forms of psoriasis such as erythrodermic psoriasis and pregnancy or breast-feeding (women of child bearing age were required to be using effective contraception). Also excluded were those who had been using therapies which might have interfered with psoriasis without respecting a sufficient washout period (2 weeks for topical treatments and UVB, 4 weeks for PUVA therapy and 8 weeks for retinoids such as: acitretin, etretinate or isotretinoin and for other therapies such as methothrexate, ciclosporin, tacrolimus, interferon, fumaric acid compounds, betablockers or lithium). 
At the start of the study patients were screened for suitability then randomised to either the calcitriol or the calcipotriol regimen group. During the bitherapy phase patients were instructed to apply study drugs (either calcitriol 3 μg/g ointment or calcipotriol 50 μg/g ointment) once in the evening and clobetasol propionate 0.05% cream once in the morning. When the patient’s skin had cleared or improved (after 2 or 4 weeks), the steroid was discontinued and the patient entered the maintenance phase where either calcitriol or calcipotriol was applied as monotherapy twice daily until week 12 (endpoint). To qualify for the maintenance phase after 2 weeks of bitherapy, patients had to have achieved at least a marked global improvement (grade 3) in their psoriasis. Patients who did not qualify after 2 weeks continued the bitherapy 2 more weeks before entering the monotherapy phase. During the maintenance phase, relapse was defined as a return to a lesser degree of global improvement (grade 2 – moderate improvement); relapsing patients were not necessarily dropped from the study.

Efficacy measures

Overall global improvement in psoriatic lesions was used as the primary efficacy measure. Investigators noted changes from baseline in disease status at weeks 2, 4, 6, 8, 10 and 12 using the following scale:  
–1 = worse
0 = no change 1 = minimal improvement (~ 25%; not clinically significant) 
2 = moderate improvement (~ 50%; significant, but many symptoms remaining) 
3 = marked improvement (~ 75%; majority of symptoms resolved)
4 = almost clear (~ 90%; only minimal symptoms remaining) 
5 = clear (100% from baseline; condition resolved). 
Patients’ assessments of global improvement scores were also requested as a secondary efficacy measure, and to enable their perceptions to be compared with those of the investigator. 
To determine the secondary efficacy criterion, the psoriasis area severity index (PASI), a lesion was selected from three separate body areas (trunk, upper and lower limbs), and the severity of erythema, scaling and plaque elevation were estimated; the PASI was then calculated based on the formula of Fredriksson and Petterson [14]. The proportion of the body surface area (BSA) affected by psoriasis was also used as a secondary criterion, being determined at baseline, weeks 2, 4 and at endpoint using the method of Ramsay et al (rule of nines) [15].

Safety assessments and adverse events

At each visit, the areas selected for the PASI assessment were examined to gauge cutaneous safety. Peri-lesional erythema, scaling, oedema, itching, burning/stinging, and soreness were evaluated (using a 4-point scale ranging from none to severe), with the last three parameters also being assessed within the lesions. In addition, global cutaneous safety was assessed by the investigator, and scored as poor, good or excellent. Patients were asked whether they had experienced any problems during treatment and the onset, nature, severity, outcome, and possible relationship to test products, of any adverse events were recorded.

Statistical methods

Global assessments and cutaneous safety were subjected to Cochran-Mantel-Haenszel analysis using the row mean score statistic to assess significance at the 5% level. PASI and BSA score were submitted to analysis of covariance at each visit, using the baseline corresponding variable as covariate, with centre and treatment as factors. Least- square means were estimated from this model; 95% confidence intervals for the difference in least-square means between treatments were then calculated. 
A statistical hypothesis of non-inferiority at a probability level of 5% was the basis for this study, which sought to demonstrate that the difference in least-square means between the two treatment groups was greater than or equal to – 15% of the average baseline PASI. The principal timepoints were week 2 and week 12. Given an average baseline PASI of 6.77 for the enrolled population, the 15% margin translates into – 1.01 point of PASI, which was from a medical point of view not assessable. The lower limit of the 95% confidence interval for the difference between the two treatment regimen was therefore required to be greater than or equal to – 1.01 in order to show non-inferiority of one treatment regimen over the other.

Results

The study was conducted between March and July 2000; 125 patients were recruited, of whom 61 were enrolled in the calcitriol regimen group and 64 in the calcipotriol regimen group. The two groups were well matched with regards to age (50 and 49 years, respectively), to mean weight (73 kg and 69 kg, respectively) and to mean duration of psoriasis (16.0 years and 17.3 years, respectively). No significant difference between the two treatment groups was noted for previous psoriasis treatment (Table I). Baseline characteristics of psoriasis were also comparable between the two groups. The mean percent BSA affected by psoriasis was 13.0 ± 7.5% in the calcitriol and 13.3 ± 7.4% in the calcipotriol regimen group, while the mean PASI at baseline was 6.86 and 6.68, respectively.

Table I. Demographic Data

* most reported treatments

Eight patients from each drug regimen group withdrew from the study once treatment had started, the main reasons being subject’s request (1 patient undergoing the calcitriol regimen (for personal reasons) and 4 patients undergoing the calcipotriol regimen (for worsening on untreated areas, wishing to stop protocol or for leaving for holidays) and lost to follow-up (2 patients of the clacitriol group and 3 patients of the calcipotriol group).

Efficacy evaluation

Global assessment of improvement

No significant differences between the two regimen groups in the investigator’s global assessment of improvement (Table II) were detected at any of the study time points (all P values > 0.05). Over the first 2-4 weeks of the study clobetasol propionate cream was used in conjunction with either calcitriol 3 µg/g ointment or calcipotriol 50 µg/g ointment. The clinical response during this phase for both groups was similar, with 54% (33 patients) of the calcitriol regimen group and 59% (37 patients) of the calcipotriol regimen group being able to enter the maintenance phase at week 2.

Table II. Global improvement scores during treatment (Intent to Treat Population)

The global assessment by investigators at endpoint revealed a successful clinical response (marked improvement, almost clear or clear) for 48 patients (79%) of the calcitriol regimen group compared with 56 patients (88%) of the calcipotriol regimen group. At study endpoint there was complete clearing of psoriasis lesions for 16 patients (26%) in the calcitriol regimen group and for 16 patients (25%) in the calcipotriol regimen group. Relapse during the maintenance phase (grade 2 or lower) resulted in study withdrawal for two patients undergoing the calcitriol regimen and for four patients undergoing the calcipotriol regimen.
Likewise, no significant difference between the groups was detected at any of the study times in global improvement as assessed by the patients, showing a marked similarity to the investigators’ assessments. By the end of the maintenance phase (week 12), 48 patients (79%) of the calcitriol group and 56 patients (88%) of the calcipotriol group reported at least marked improvement in their condition.

PASI

In each of the treatment groups, the beneficial effect of treatment on the severity of psoriasis was detected by a marked decrease in PASI, particularly during the first 2-4 weeks of the study (Fig. 1). No significant differences between the two regimen groups were detected at any of the study time points. At week 2, mean PASI had fallen from baseline by 56% and 63% for the calcitriol and for the calcipotriol regimen groups, respectively (Table III). Analysis of percent changes from baseline in the mean PASI throughout the study provided a similar pattern to that seen for the analysis of global assessment by the investigator.

Evaluation of safety and adverse events

No significant differences were seen between the 2 regimens for the areas of psoriasis monitored for cutaneous safety, as shown by an analysis of the worst score seen at any time point post-baseline (Table IV). Likewise, the global cutaneous safety assessment by investigators revealed no significant differences between the regimen of calcitriol and that of calcipotriol. Poor safety was recorded for only 1.6% of patients undergoing calcitriol regimen and for 3.1% of those patients undergoing calcipotriol regimen; at endpoint week 12, excellent safety was recorded for 89% patients treated with calcitriol and for 95% of those patients treated with calcipotriol.

Twelve patients from each treatment group reported a total of 42 adverse events; these were generally mild to moderate. Dermatological events that were rated possibly, probably or definitely related to study treatment occurred in 4 (6.6%) patients (5 events) following the calcitriol regimen and 3 (4.7%) patients (6 events) following the calcipotriol regimen; one patient following the calcitriol regimen withdrew from the study after experiencing irritation in and around psoriatic lesions.

Discussion

As described by Lebwohl [16] the treatment of psoriasis with a corticosteroid alone is accompanied by several drawbacks and side effects, such as cutaneous atrophy, formation of telangiectasia and striae.
These side effects may be reduced while maximizing the beneficial effects in a concurrent administration with a vitamin D3 analogue.
To confirm this, different treatment combination regimens have been studied in the past, such as vitamin D preparations in the morning and class II steroids in the evening or vitamin D preparations applied on weekdays and class I steroids applied during weekends [16]. 
Ruzicka and Lorenz [2] reported that a combination therapy reduces the hazards associated with the long-term use of topical corticosteroids (atrophy, rebounds), while reducing side effects caused by calcipotriol, possibly due to the synergy of corticosteroids and vitamin D analogue and leads to an additive clinical effect in terms of reduced psoriatic symptoms.
The present trial confirmed the efficacious and safe role of vitamin D₃ and corticosteroids as a first line therapy and underlined the safe maintenance effect of vitamin D₃ derivates as a maintain monotherapy in the treatment of psoriasis. 
In fact more than 50% of the patients in each group experienced improvement of psoriasis after 2 weeks of combination treatment and a high proportion of patients continued to see a marked improvement in their psoriatic lesions during maintenance with monotherapy; at endpoint week 12, 83% of all patients fell within this category. In addition 26% of all patients in the calcitriol group and 25% of those in the calcipotriol group achieved complete clearance of lesions at the end of the maintenance phase. Throughout the study the global improvement of psoriasis relative to the baseline was used as the primary efficacy variable; it showed that with no statistically significant differences calcitriol and calcipotriol were comparable in controlling the disease. It is notable also, for a disease where the symptoms are so clearly evident to patients, that the views of the patients on the effectiveness of the medications closely matched those of their physicians. 
Global improvement scores provide a good overall picture of the disease status. The PASI, however, may provide a more sensitive measure of drug effectiveness. The marked decrease in PASI scores achieved in both groups reflected the effectiveness of both regimens adopted for this two-phase trial. 
Issues of treatment acceptability and tolerance are key considerations for topical treatments of a chronic disease such as psoriasis. No significant differences in cutaneous safety were noted between the calcitriol and calcipotriol, and the number of patients reporting adverse events was the same for both groups. 
Concomitant and sequential treatments are tested means of controlling psoriasis, a disease that is characterised by the problem of recurrence. While topical corticosteroids have an important part to play in initial symptom control, their well-documented side-effects profile precludes either extensive or chronic use [16]. The current study therefore suggests a real versatile role for either calcitriol or calcipotriol in maximising the therapeutic potential of steroids while minimising exposure, by using an initial monotherapy followed by a maintenance period with a vitamin D₃ compound alone.

Conclusions

In the present study the treatment regimen including 2 to 4 weeks therapy with clobetasol propionate cream and calcitriol ointment followed by a maintenance monotherapy with calcitriol for 8 to 10 weeks was shown to be safe and very effective. Both calcitriol and calcipotriol can be proposed as a maintenance therapy in mild to moderate plaque-type psoriasis. n

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