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Calcipotriol plus betamethasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study

European Journal of Dermatology. Volume 20, Number 4, 465-71, July-August 2010, Therapy

DOI : 10.1684/ejd.2010.0948

Summary

Author(s) : Colin Fleming, Cecilia Ganslandt, Lyn Guenther, Anders Johannesson, Colin Buckley, Jan C Simon, Helen Stegmann, Lotte Vestergaard Tingleff , Ninewells Hospital and Medical School, Dundee, United Kingdom, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark, The Guenther Dermatology Research Centre, London, Canada, Vällingby Läkarhus, Vällingby, Sweden, Waterford Regional Hospital, Waterford, Ireland, Universitätsklinikum Leipzig - Klinik für Dermatologie, Venerologie und Allergologie, Leipzig, Germany.

Summary : A two-compound ointment containing calcipotriol plus betamethasone dipropionate is an effective treatment for psoriasis vulgaris. The same active ingredients have now been combined in a gel formulation. Our objective was to compare the efficacy and safety of once daily treatment of the two-compound gel with the single components in the same gel vehicle and the gel vehicle alone, in patients with psoriasis vulgaris on the trunk and/or limbs. 364 patients received once daily treatment for up to 8 weeks with either the two-compound gel, the single components in the gel vehicle or the gel vehicle alone. The percentage of patients whose disease was clear or very mild and who had at least a two-step improvement in the Investigator's Global Assessment of disease severity at week 8, was significantly higher with calcipotriol plus betamethasone dipropionate (27.2%) than with betamethasone dipropionate (16.9%, p \= 0.027), calcipotriol (11.4%, p \= 0.006) or gel vehicle (0.0%, p <\; 0.001). This exploratory study showed that the two-compound gel was safe and more efficacious than its individual ingredients in the treatment of psoriasis vulgaris.

Keywords : betamethasone dipropionate, calcipotriol, combination therapy, psoriasis vulgaris

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ARTICLE

Auteur(s) : Colin Fleming¹, Cecilia Ganslandt², Lyn Guenther³, Anders Johannesson⁴, Colin Buckley⁵, Jan C Simon⁶, Helen Stegmann², Lotte Vestergaard Tingleff²

¹Ninewells Hospital and Medical School, Dundee, United Kingdom
²LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark
³The Guenther Dermatology Research Centre, London, Canada
⁴Vällingby Läkarhus, Vällingby, Sweden
⁵Waterford Regional Hospital, Waterford, Ireland
⁶Universitätsklinikum Leipzig - Klinik für Dermatologie, Venerologie und Allergologie, Leipzig, Germany

accepté le 29 Janvier 2010

Psoriasis vulgaris is one of the most common chronic skin diseases, with a prevalence of 1-3% of the population [1, 2]. It is characterised by sharply demarcated areas of thickened, red and scaly skin. The scalp, elbows, knees, lower back, hands, feet and nails are commonly affected sites. About 80% of affected patients complain of itching [3]. Psoriasis is a significant problem in everyday life for affected patients, and has a significant impact on their health-related quality of life – an impact that increases with increasing skin involvement [4].

There is currently no cure for psoriasis vulgaris. Treatment is targeted at reducing the signs of erythema, scaling and infiltration and associated symptoms such as itching. There is no specific limit in disease severity that would exclude a patient from topical treatment [5]. However, among patients with psoriasis, approximately 80% have mild to moderate disease, and the majority of these can be treated topically [6]. Potent corticosteroids and vitamin D₃ analogues are the most common topical treatments used for treatment of psoriasis. The efficacy of potent corticosteroids is similar to that of the vitamin D₃ analogue calcipotriol, but with a faster onset of action [7, 8]. However, topical corticosteroids are associated with a risk of steroid-related adverse effects such as skin atrophy, striae, and telangiectasia with prolonged use [3]. No such local effects are related to calcipotriol, although it may cause skin irritation [9].

A two-compound ointment containing calcipotriol 50 μg/g and the corticosteroid betamethasone 0.5 mg/g as dipropionate has been shown to be effective and safe in psoriasis vulgaris in a series of clinical trials [10-13]. These studies have demonstrated that a combination of calcipotriol and betamethasone dipropionate is more effective than either of the individual components and that once daily administration is as effective as twice daily administration. Furthermore, in long-term studies with the combination, no safety issues have arisen and use has not been associated with an increased rate of steroid-related adverse events [14, 15]. Approximately 80% of patients using the two-compound ointment in repeated courses over 6 months were satisfied or very satisfied with the treatment [16].

The combination of calcipotriol and betamethasone dipropionate in a lipophilic, alcohol-free gel formulation has been demonstrated to be an effective treatment for psoriasis vulgaris on the scalp [17, 18]. The physical properties of a gel vehicle also make it suitable for use on the trunk and limbs. A calcipotriol plus betamethasone dipropionate gel could thus be a treatment alternative to the two-compound ointment, particularly in individuals seeking a less greasy formulation than an ointment.

This study was designed to investigate the efficacy and safety of a two-compound gel containing calcipotriol plus betamethasone dipropionate, when used on psoriasis on the trunk and limbs. The efficacy and safety of once daily treatment for up to 8 weeks of the two-compound gel was compared with the single components in the same gel vehicle and the gel vehicle alone. The efficacy of the study treatments was compared at two time points (week 4 and week 8) using two different assessments made by the investigator; responder analysis [patients rated as clear or very mild and who had an at least two-step improvement in the Investigator's Global Assessment of disease severity] according to the Investigator's Global Assessment of disease severity (IGA; a static measure) and change from baseline using the Psoriasis Severity and Area Index (PASI).

Materials and methods

This was an international, multicentre, prospective, randomised, double-blind, 4-arm parallel group study conducted at 19 centres in four European countries and in Canada. The study protocol was reviewed and approved by relevant Institutional Review Boards/Independent Ethics Committees. The trial conformed to the principles of the Declaration of Helsinki and was conducted in accordance with the principles of Good Clinical Practice. All patients gave signed informed consent before enrolment in the trial.

Patient selection

Patients of either sex aged 18 years or older with a clinical diagnosis of psoriasis vulgaris involving the trunk and/or arms and/or legs amenable to treatment with a maximum of 100 g of topical medication per week were suitable for inclusion. An IGA of at least mild was required. Patients with guttate, erythrodermic, exfoliative or pustular psoriasis were excluded. Also excluded were patients who had used biological therapies with a possible effect on psoriasis vulgaris within 6 months prior to randomization, other systemic antipsoriatic therapies, PUVA or Grenz ray therapy within 4 weeks prior to randomisation, and UVB therapy and topical treatment within 2 weeks prior to randomisation. Use of emollients was allowed in the wash-out period, but not during the study. However, lesions on the face, scalp and flexures could be treated with WHO group I-II corticosteroids, tar, retinoids and/or dithranol.

Treatment assignment

Patients were randomised in a 4:2:2:1 ratio according to a pre-planned, computer generated, randomisation schedule to receive once daily treatment for up to 8 weeks with either the two-compound gel containing calcipotriol 50 μg/g plus betamethasone 0.5 mg/g (as dipropionate), calcipotriol 50 μg/g gel, betamethasone 0.5 mg/g (as dipropionate) gel or gel vehicle.

The packaging and labelling of the investigational products contained no evidence of their identity, and it was not considered possible to differentiate between the investigational products solely by sensory evaluation. Therefore, it was assumed that patients and investigators remained unaware of the individual treatment assignments during the study.

Assessments

Patients were assessed at baseline and after 1, 2, 4, 6 and 8 weeks of treatment (Visits 1-6). A safety assessment was performed 2 weeks after the patient's last on-treatment visit if a treatment related adverse event (possible, probable or not assessable relationship to study medication) was ongoing. The extent and severity of psoriasis was evaluated using IGA measured with a 6-point scale (clear, minimal disease, mild, moderate, severe or very severe) and PASI. A modified PASI was used, based on an assessment of the percentage involvement of the trunk, upper and lower limbs, together with indices of erythema, induration and scaling in those areas [19]. Safety assessments were performed at every visit after baseline.

The primary response criterion was responders according to IGA at weeks 4 and 8. For patients with at least moderate disease at baseline, a responder was defined as a patient whose psoriasis was scored as either clear or minimal; for patients with mild disease at baseline, a responder had a score of clear. The IGA was chosen as the primary endpoint as this endpoint is preferred for US regulatory purposes.

Secondary response criteria included the percentage change in PASI from baseline to week 4 and 8. The percentage of patients obtaining at least 75% improvement in PASI (PASI 75) was included as a tertiary endpoint. Any reported adverse events/adverse drug reactions or reasons for withdrawal from the study were recorded.

Statistical methods

For the primary response criterion at week 8 a sample size of a total of 360 patients was calculated to give the comparison of the two-compound gel versus betamethasone dipropionate gel and the two-compound gel versus calcipotriol gel, 80% power in each of the comparisons if the proportion achieving “controlled disease” was 48% in the two-compound gel arm and not more than 28% in the comparator arms. The comparison of the two-compound gel versus the gel vehicle would have at least 98% power if the proportion of responders at week 8 in the gel vehicle arm was not more than 15%. Thus, overall, approximately 60% power would be achieved to reject the combined null hypothesis. The calculations were based on a two group chi-squared test and a two-sided 5% significance level. This study had two primary endpoints; responders at weeks 4 and 8. Since the study was intended as exploratory, there was no pre-planned adjustment of significance levels for multiple testing, i.e. a significance level of 5% was used in testing both endpoints.

The primary efficacy analyses for the primary response criteria were based on the full analysis set. The proportion of responders according to IGA at weeks 4 and 8 was compared between the treatment groups using the Cochran-Mantel-Haenszel test adjusting for the effect of centre. The proportion of responders was evaluated at weeks 4 and 8 with last observation carried forward (LOCF). In addition, a post-hoc analysis of responders according to IGA at week 4 and week 8, excluding patients with severe or very severe disease at baseline, was performed.

Analysis of variance (ANOVA) was used to compare the percentage change from baseline in PASI between the treatment groups including centre and treatment in the model as design variables. In addition, post-hoc analyses were conducted of patients obtaining PASI 75 at week 8 (Cochran-Mantel-Haenszel test) and of the percentage change in PASI at weeks 4 and 8, excluding patients with severe or very severe disease at baseline (ANOVA).

Safety analysis was carried out based on the safety analysis set. The proportions of patients who experienced adverse events were compared between the treatment groups, using the chi-squared test.

Results

Patients

A total of 374 patients were enrolled from 19 centres in 5 countries (Canada: 6; Germany: 4; Ireland: 1; Sweden: 3; United Kingdom: 5). Ten patients did not continue in the study after the washout period and 364 patients were thus randomised in the study (162 to the two-compound gel, 83 to betamethasone dipropionate gel, 79 to calcipotriol gel and 40 to the gel vehicle). Two patients withdrew at or just after baseline and did not provide any post-baseline efficacy or safety data. In total, 90% of all randomised patients attended the week 8 visit. The percentage of patients withdrawing during the study was 8.0% in the two-compound gel group, 6.0% in the betamethasone dipropionate gel group, 7.6% in the calcipotriol gel group and 30.0% in the gel vehicle group, respectively. Withdrawals due to “unacceptable treatment efficacy” occurred more frequently in the gel vehicle group (25.0% of the patients) compared with the other treatments groups (between 2 and 4% of the patients).

All 364 randomised patients were considered and included in the full analysis set. The safety analysis set consisted of the 362 patients for whom post-baseline safety data were available.

At baseline, the treatment groups were well balanced with regards to demographics and disease severity (table 1). The mean duration of psoriasis was 19 years and 59% of all patients had moderate disease.

Most patients (between 73.5% and 80%) in the four treatment groups were fully compliant and applied the treatment once daily as instructed. Most patients who were not fully compliant missed less than 10% of applications. The mean weekly use of medication was 22.7 g in the two-compound gel group, 25.9 g in the betamethasone dipropionate gel group, 22.4 g in the calcipotriol gel group and 26.1 g in the gel vehicle group.
Table 1 Demographics and baseline characteristics of all randomised patients

	Two-compound gel	Betamethasone	Calcipotriol	Vehicle
	(n = 162)	(n = 83)	(n = 79)	(n = 40)
Mean age ± SD, years	50.1 ± 14.9	51.4 ± 14.5	52.6 ± 15.2	51.4 ± 13.4
Males, %	57.4	57.8	60.8	62.5
Caucasians, %	97.5	100	97.5	97.5
Mean duration of psoriasis ± SD, years	18.5 ± 13.8	18.8 ± 14.0	19.5 ± 14.8	19.2 ± 11.5
IGA, No. of patients (%) [PASI range]
Mild	31 (19.1) [1-8]	25 (30.1) [1-10]	17 (21.5) [2-8]	9 (22.5) [3-6]
Moderate	95 (58.6) [2-23]	43 (51.8) [2-19]	50 (63.3) [1-16]	26 (65.0) [3-22]
Severe	34 (21.0) [3-25]	14 (16.9) [6-21]	12 (15.2) [6-23]	5 (12.5) [9-18]
Very severe	2 (1.2) [6-11]	1 (1.2) [14]	0 (0)	0 (0)
Mean PASI ± SD	7.7 ± 4.6	7.8 ± 4.4	7.9 ± 3.9	7.9 ± 4.7

Efficacy; IGA

Figure 1 shows the percentage of responders according to IGA over time by treatment group. At week 4 the percentage of responders in the two-compound gel group was 16.0%, compared with 9.6% in the betamethasone dipropionate gel group (OR 2.02; 95% CI 0.84 to 4.82; p = 0.11), 3.8% in the calcipotriol gel group (OR 5.98; 95% CI 1.53 to 23.34; p = 0.006) and 2.5% in the gel vehicle group (OR 10.83; 95% CI 1.04 to 112.73; p = 0.027). At week 8 the percentage of responders in the two-compound gel group was 27.2%, compared with 16.9% in the betamethasone dipropionate gel group (OR 2.40; 95% CI 1.11 to 5.20; p = 0.027), 11.4% in the calcipotriol gel group (OR 2.89; 95% CI 1.31 to 6.38; p = 0.006) and 0.0% in the gel vehicle group (p < 0.001).

A post-hoc analysis of responders according to IGA at weeks 4 and 8, excluding patients with severe or very severe disease at baseline, was also performed (figure 2). In patients with mild to moderate disease, 20.6% of the patients in the two-compound gel group were responders at week 4 compared with 10.3% in the betamethasone dipropionate gel group (OR 2.52; 95% CI 1.01 to 6.29; p = 0.039), 4.5% in the calcipotriol gel group (OR 6.67; 95% CI 1.71 to 26.03; p = 0.003) and 2.9% in the gel vehicle group (OR 21.50; 95% CI 1.29 to 358.02; p = 0.012). At week 8, 31.7% of the patients in the two-compound gel group were responders compared with 19.1% in the betamethasone dipropionate gel group (OR 2.61; 95% CI 1.10 to 6.17; p = 0.030), 13.4% in the calcipotriol gel group (OR 2.85; 95% CI 1.25 to 6.47; p = 0.009) and 0.0% in the gel vehicle group (p < 0.001).

Efficacy; PASI

Figure 3 shows the mean percentage change in PASI over time by treatment group. At week 4 the mean percentage change in PASI in the two-compound gel group was – 48.1%, compared with – 40.9% in the betamethasone dipropionate gel group (difference – 7.85; 95% CI – 15.2 to – 0.5; p = 0.04), – 32.7% in the calcipotriol gel group (difference – 15.4; 95% CI – 22.8 to – 7.9; p < 0.001) and – 16.9% in the gel vehicle group (difference – 30.8; 95% CI – 40.4 to – 21.2; p < 0.001). At week 8 the mean percentage change in PASI in the two-compound gel group was – 55.3%, compared with – 49.8% in the betamethasone dipropionate gel group (difference – 6.16; 95% CI – 14.2 to 1.9; p = 0.13), – 41.2% in the calcipotriol gel group (difference – 13.9; 95% CI – 22.0 to – 5.7; p < 0.001) and – 11.9% in the gel vehicle group (difference – 43.1; 95% CI – 53.6 to – 32.6; p < 0.001).

The percentage of patients achieving PASI 75 at week 8 was 35.8% in the two-compound gel group, compared to 28.9% in the betamethasone dipropionate gel group (p = 0.18), 17.7% in the calcipotriol group (p = 0.003) and 0% in the gel vehicle group (p < 0.001).

As for IGA, a post-hoc analysis of percentage change in PASI to weeks 4 and 8, excluding patients with severe or very severe disease at baseline, was performed. In patients with mild to moderate disease, the mean percentage change in PASI from baseline to week 4 was – 50.2% in the two-compound gel group, compared with – 40.8% in the betamethasone dipropionate gel group (difference – 8.79; 95% CI – 17.0 to – 0.6; p = 0.037), – 32.1% in the calcipotriol gel group (difference – 16.7; 95% CI – 25.0 to – 8.5; p < 0.001) and – 17.0% in the gel vehicle group (difference – 31.1; 95% CI – 41.6 to – 20.7; p < 0.001). The mean percentage change in PASI from baseline to week 8 was – 58.8% in the two-compound gel group, compared with – 51.8% in the betamethasone dipropionate gel group (difference – 6.30; 95% CI – 15.2 to 2.6; p = 0.17), – 40.8% in the calcipotriol gel group (difference – 16.5; 95% CI – 25.5 to – 7.5; p < 0.001) and – 11.1% in the gel vehicle group (difference – 45.9; 95% CI – 57.2 to – 34.5; p < 0.001).

Tolerability and safety

Safety data were contributed by 362 of the 364 randomised patients.

The proportion of patients with at least one adverse event was not statistically significantly different in the two-compound gel group (42.5%) compared with the betamethasone dipropionate gel group (48.2%; p = 0.60), the calcipotriol gel group (35.4%; p = 0.49) and the gel vehicle group (55.0%; p = 0.39). Most adverse events were considered “not related” to study treatment and were of mild or moderate intensity.

Lesional/perilesional adverse events on the trunk or limbs occurred in 12 patients (7.5%) in the two-compound gel group, 7 (8.4%) in the betamethasone dipropionate gel group, 8 (10.1%) in the calcipotriol gel group versus 10 (25.0%) in the gel vehicle group (table 2). No serious adverse events related to study treatment were reported.
Table 2 Lesional/perilesional adverse events on the body by MedDRA primary system organ class and preferred term: safety analysis set

System organ class^a	Two-compound gel (n = 160)	Betamethasone (n = 83)	Calcipotriol (n = 79)	Vehicle (n = 40)
Preferred term	No. of patients (%)	No. of patients (%)	No. of patients (%)	No. of patients (%)
General disorders and administration site conditions
Application site burning	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Application site inflammation	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Application site pruritus	0 (0.0)	1 (1.2)	1 (1.3)	0 (0.0)
Pain	2 (1.3)	1 (1.2)	2 (2.5)	0 (0.0)
Infections and infestations
Eczema infected	0 (0.0)	0 (0.0)	1 (1.3)	0 (0.0)
Folliculitis	1 (0.6)	1 (1.2)	0 (0.0)	0 (0.0)
Injury, poisoning and procedural complications
Blister	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Musculoskeletal and connective tissue disorders
Arthralgia	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Nervous system disorders
Burning sensation	2 (1.3)	0 (0.0)	0 (0.0)	1 (2.5)
Skin and subcutaneous tissue disorders
Alopecia	0 (0.0)	1 (1.2)	0 (0.0)	0 (0.0)
Dry skin	3 (1.9)	0 (0.0)	0 (0.0)	1 (2.5)
Eczema	0 (0.0)	0 (0.0)	1 (1.3)	1 (2.5)
Erythema	1 (0.6)	0 (0.0)	2 (2.5)	0 (0.0)
Pain of skin	1 (0.6)	0 (0.0)	1 (1.3)	0 (0.0)
Pruritus	1 (0.6)	2 (2.4)	3 (3.8)	7 (17.5)
Psoriasis	1 (0.6)	2 (2.4)	1 (1.3)	2 (5.0)
Skin burning sensation	0 (0.0)	0 (0.0)	2 (2.5)	0 (0.0)
Skin fissures	0 (0.0)	0 (0.0)	1 (1.3)	0 (0.0)
Total number of adverse events^b	16	8	15	12
Total number of patients	12 (7.5)	7 (8.4)	8 (10.1)	10 (25.0)

Discussion

A two-compound ointment has been shown to be efficacious in the treatment of psoriasis vulgaris on the body [10-13]. This two-compound ointment contains the same concentrations of calcipotriol and betamethasone dipropionate as the gel investigated in the current study. A gel formulation of calcipotriol plus betamethasone dipropionate has previously been demonstrated to be an effective treatment for psoriasis vulgaris on the scalp [17, 18]. Cosmetically convenient formulations have been identified as an important aspect when developing topical treatments as it may impact patient adherence, which in turn will affect treatment efficacy [20, 21]. The physical properties of the two-compound gel suggest that it may be a more cosmetically acceptable formulation for use on psoriasis on trunk and limbs, since it is less greasy than the ointment formulation [2]. However, evaluation of cosmetic acceptability was not part of the present study.

The combination of a vitamin D₃ analogue and a topical steroid is often used in the treatment of psoriasis. Clinical studies with the two-compound ointment have shown an additive effect on the trunk and limbs, and a safety profile similar or even better than for the mono-components [10-13]. The betamethasone dipropionate counteracts the local skin irritation that some patients treated with calcipotriol experience. Calcipotriol may, on the other hand, reduce the amount of corticosteroid required due to the additive effect and thus reduce the risk of steroid-related adverse effects. In this study, the amount of gel used was slightly lower in the two-compound gel group than in the betamethasone dipropionate gel group. It remains to be confirmed whether this will be the case in clinical practice.

The study population comprised patients amenable to topical therapy with an IGA score ranging from mild to very severe. It should be noted that the IGA does not take extent of psoriasis into account. It is likely that the patients included with severe or very severe disease according to the IGA had very red, thick and scaly lesions but their body surface area involvement was still within a range for which topical monotherapy was feasible. This is further supported by the mean baseline PASI score, which was 7.7-7.9 in the four treatment groups. The actual body surface area involved was however not recorded.

This study was intended as exploratory and there was thus no pre-planned adjustment of significance levels for multiple testing (responders at both weeks 4 and 8), i.e. a significance level of 5% was used in testing both endpoints. The two-compound gel showed increasing efficacy at each post randomisation visit and it was statistically significantly more efficacious than calcipotriol and the gel vehicle at week 4 and 8, but the study was not sufficiently powered to show statistical significance over betamethasone dipropionate in all comparisons. However, a statistically significant benefit over betamethasone dipropionate was shown at week 8 for the primary response criterion (IGA) and at week 4 for the secondary response criterion of PASI.

The results are in accordance with those of previous studies, in which the two-compound ointment containing betamethasone dipropionate plus calcipotriol was superior to each active component and to vehicle alone in the treatment of psoriasis vulgaris [11-13].

A post-hoc analysis of responders according to IGA at weeks 4 and 8, excluding patients with severe or very severe disease at baseline, showed a statistically significantly better effect with the two-compound gel than with the mono-components and the gel vehicle alone at both week 4 and 8. The efficacy level in this study was lower than reported for the ointment formulation in a previous study, i.e., the mean reduction in PASI from baseline to the end of 8 weeks of treatment was 55.3% for the two-compound gel and 73.3% for the two-compound ointment [22]. Although the gel and ointment have not been tested head to head, the above data suggest that the ointment is likely more efficacious than the gel. The higher efficacy of the ointment would most probably be due to its occlusive effect and the resulting enhanced penetration of its active components. A mean reduction of PASI of 22.7% from baseline to the end of 4 weeks of treatment has been reported for the ointment vehicle [11]. The corresponding figure for the gel vehicle in this study was 16.9%, which suggests that the higher efficacy level for the ointment may partly be due to the vehicle itself.

Ongoing improvement of psoriasis after week 4 was noted suggesting that 8 weeks of therapy is more optimal than 4 weeks (figure 1).

The two-compound gel was well tolerated during the study. The common (≥ 1%) lesional/perilesional AEs associated with the two-compound gel were dry skin, pain and burning sensation. Lesional/perilesional adverse events occurred with similar frequency in the two-compound gel and betamethasone dipropionate gel groups and were lower than observed in the calcipotriol gel and the gel vehicle groups. The adverse event profile in the present study is in accordance with that seen for the ointment formulation in 4-week studies [11-13]. Fifty-two week long-term studies with calcipotriol plus betamethasone in ointment (on the body) and gel (on the scalp) formulations did not show any long-term safety concerns [14, 15, 23]. All available data support that the use of the two-compound gel in psoriasis vulgaris is safe.

In conclusion, this exploratory study showed that the two-compound gel was safe and effective in the treatment of psoriasis vulgaris.

Acknowledgements

Financial support: This study was sponsored by LEO Pharma A/S. Calcipotriol plus betamethasone dipropionate ointment and gel are approved/marketed under the trade names Daivobet^®/Dovobet^®.

Conflicts of interests: Colin Fleming has served as international coordinating investigator and presenter for LEO Pharma. Lyn Guenther has served as researcher, presenter and consultant for LEO Pharma. Colin Buckley and Jan C. Simon have served as investigators for LEO Pharma. Anders Johannesson reports no conflicts of interest. Cecilia Ganslandt, Helen Stegmann and Lotte Vestergaard Tingleff are fully salaried employees of LEO Pharma.

Acknowledgements: The authors would like to thank Eva Johansson (EKJ Consulting, Sweden) for writing assistance, and the following participating investigators: Dr. Beatrice Gerlach, DE; Dr. Yves Poulin, CA; Dr. Georg Popp, DE; Prof. Kristian Reich, DE; Dr. Kim Papp, CA; Dr. Alexander Anstey, UK; Dr. Ingela Flytström, SE; Dr. Lena Lindberg, SE; Dr. Raj Tuppal, CA; Dr. Catherine Maari, CA; Dr. Richard Langley, CA; Dr. David Burden, UK; Dr. John Lear, UK; Dr. Colin Holden, UK.

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