Pharmacology and Treatment Dermatology 2002;205:46–53 Received: January 4, 2002 Accepted: January 12, 2002 Topical Calcipotriol plus Oral Fumaric Acid Is More Effective and Faster Acting than Oral Fumaric Acid Monotherapy in the Treatment of Severe Chronic Plaque Psoriasis vulgaris H. Gollnick a P. Altmeyerb R. Kaufmann c J. Ringd E. Christopherse S. Pavelg J. Zieglerf aDepartment of Dermatology and Venereology, Otto von Guericke University, Magdeburg, bDepartment of Dermatology, Ruhr University, Bochum, cDepartment of Dermatology and Venereology, J.W. Goethe University, Frankfurt/Main, dDepartment of Dermatology and Allergy, Biederstein, Technical University, Munich, eDepartment of Dermatology, University of Kiel, and fLeo Pharma GmbH, Neu-Isenburg, Germany; gDepartment of Dermatology, Leiden University Medicel Centre, Leiden, The Netherlands Key Words difference between treatments was –24.2% (95% CI from Psoriasis vulgaris W Calcipotriol W Fumaric acid esters –34.2 to –14.2%; p ! 0.001). Group B responded more (FAEs) W Clinical trial W Pharmacoeconomics rapidly to treatment. Investigators’ and patients’ overall efficacy assessments were significantly more favourable for group B (p ^ 0.001). Group B was prescribed less FAE Abstract than group A. This difference was greatest at the last visit Background: Calcipotriol is an established topical thera- (mean daily dose 529 and 685 mg, respectively; p = py for psoriasis vulgaris. Objective: This study aimed to 0.006). Overall adverse events in the two groups were investigate whether the addition of calcipotriol to fu- similar. Conclusion: This study shows that the combina- maric acid ester (FAE) monotherapy had an additive effi- tion of calcipotriol and FAEs is significantly more effec- cacy and an FAE-sparing effect in patients with severe tive and faster acting than FAE monotherapy in the treat- plaque psoriasis. Methods: This multicentre, random- ment of severe plaque psoriasis. The combination has a ised, double-blind, vehicle-controlled study included 143 slight FEA-sparing effect and therefore a superior bene- patients for up to 13 weeks treatment. Group A received fit/risk ratio. FAE tablets (Fumaderm®) with an increasing daily dos- Copyright © 2002 S. Karger AG, Basel age from 105 to 1,075 mg + ointment vehicle. Group B received FAE tablets + calcipotriol ointment (50 Ìg/g). Ointments were applied twice daily. Clinical response Introduction was assessed using percentage changes in the Psoriasis Area and Severity Index (PASI), from baseline to treat- Psoriasis is a very common chronic relapsing skin dis- ment end. Results: The mean percentage change in the ease with a prevalence in central Europe of about 2–3% PASI was –76.1% in group B and –51.9% in group A, the [1, 2]. Today, its aetiology can be much better explained, © 2002 S. Karger AG, Basel Prof. Dr. Harald Gollnick ABC 1018–8665/02/2051–0046$18.50/0 Department of Dermatology and Venereology, Otto von Guericke University Fax + 41 61 306 12 34 Leipziger Strasse 44, D–39210 Magdeburg (Germany) E-Mail [email protected] Accessible online at: Tel. +49 391 67 15249, Fax +49 391 67 15235 www.karger.com www.karger.com/journals/drm E-Mail [email protected] but as a polygenic disease with an autoimmune patho- Patients and Methods mechanism involving both the epidermal/dermal com- partments and the T-cell-immune system koebnerized by Study Design The study was a prospective, multicentre, randomised, double- internal and external factors it is far away from being fully blind, vehicle-controlled, parallel-group, comparative study on the understood [1–7]. The therapeutic armamentarium most- efficacy and safety of the combination of FAEs and calcipotriol. ly comprises topical and systemic drugs or methods Patients received FAEs + placebo (calcipotriol ointment vehicle) or affecting both or alone the processes of epidermal hyper- FAEs + calcipotriol ointment (50 Ìg/g). The study was divided into two phases: the initial wash-out and qualification phase with emol- proliferation and differentiation, and the epidermal tro- lient cream took place over a 2-week period and was followed by a pism of T cells and polymorphonuclear granulocytes. double-blind treatment phase of 13 weeks’ duration. Vitamin D3 derivatives and fumaric esters are both involved in inhibiting these pathways. Calcipotriol has Study Population been demonstrated to be equivalent to or more effective A total of 143 patients with severe psoriasis vulgaris were than dithranol [8], coal tar [9] and at least as effective as recruited into the study. Recruits were hospital in-patients and out- patients, aged 618 years and with a clinical diagnosis of severe pso- steroids [10, 11]. It is effective in the long term [12] and riasis vulgaris for whom treatment with FAEs was deemed appro- has been successfully used in combination with systemic priate. Standard exclusion criteria applied. treatments [13, 14] and, as well as other vitamin D3 deriv- atives, with phototherapy [15–17]. Calcipotriol is well tol- Study Medication Ì erated, even in children [18], with no effect on hepatic or Treatment with either calcipotriol ointment (50 g/g) or placebo (vehicle ointment) was randomly assigned to each patient. The oint- renal function or calcium haemostasis [19]. Calcipotriol ments were similar in appearance, smell and texture. They were and other vitamin D3 derivatives act via the 1,25(OH)2 applied twice daily without occlusion to affected skin areas, up to a ® D3 receptor of keratinocytes and lymphocytes in differen- maximum of 120 g per patient per week. FAEs (Fumaderm , Fume- tiation and proliferation with little effects on calcium dica GmbH) were provided in the form of tablets, and all patients ® metabolism [20] and are well established, effective and started with a dose of 105 mg/day (1 tablet Fumaderm P mite; week 0). The dose was increased weekly as far as possible, reaching safe treatment options. 645 mg/day (3 tablets Fumaderm® P forte) by week 5, after which the Systemic treatment with fumaric acid esters (FAEs) dose was individualised for each patient at the physician’s discretion. has also been shown to be effective in clinical studies, elic- A maximum daily dose of 1,075 mg was not exceeded. An emollient iting an improvement in up to 75% of patients [21–23]. cream (Abitima®, Dumex GmbH) was additionally provided during the wash-out/qualification period and double-blind treatment Its mode of action most probably leads to a switch of Th1 phases. to Th2 T cell activity (IL-10D) on the one hand [24–27], and, on the other hand, to keratinocyte proliferation [28]. Clinical Assessments Studies have shown superior improvement when a combi- Response was assessed using percentage changes in the Psoriasis nation of FAEs was used, but several reversible side- Area and Severity Index (PASI), from baseline (at visit 2) to the end of treatment. The PASI was assessed at each visit. Investigator and effects were seen in these studies, including eosinophilia patient also gave an assessment of overall response to treatment at and leukopenia [22, 23, 29]. Up to 25% of patients treated each postrandomisation visit, grading the overall response on a 6- with FAEs withdrew from studies due to adverse events. point scale of cleared, marked improvement, moderate improve- There have been reports on nephro- and hepatotoxicity ment, slight improvement, unchanged or worse. Adverse events were [30–32] which, however, could not be confirmed in con- recorded and clinical and laboratory parameters assessed. trolled studies with larger patient collectives [22, 23]. Statistical Evaluation FAEs are considered to be an effective long-term treat- Approximately normally distributed data on an interval scale are ment for severe psoriasis, but it is recommended that described by the mean, standard deviation, minimum and maximum patients be regularly monitored [33, 34]. The threat of values. For data on a nominal or ordinal scale, the number and per- side-effects can influence compliance in patients taking centage of patients in each category are presented. The results of all statistical analyses are presented as the estimate of treatment effect, FAEs, so monotherapy with FAEs is not necessarily 95% confidence interval (CI) and p values. adopted. The aim of this study was to determine whether the addition of calcipotriol to the treatment with FAEs may have an additive therapeutic and an FAE-sparing effect in patients with severe chonic plaque psoriasis and to assess the efficacy, safety and tolerability of this therapeutic combination. Calcipotriol plus Fumaric Acid Esters in Dermatology 2002;205:46–53 47 Psoriasis Fig. 1. Schematic presentation of patient populations. Results tion group and 17.7 in the FAE monotherapy group; intention-to-treat, ITT, population). Patient Numbers and Demographics In total, 143 patients were recruited into the study Change in PASI from Baseline to End of Treatment from 16 centres in Germany and 1 centre in the Nether- In both treatment groups the PASI was lower at the lands. The patient population as included in the study is end of treatment compared with baseline (fig. 2). The schematically represented in figure 1. During the course mean percentage change in the PASI adjusted for the of the study, a total of 34 (25.4%) patients withdrew, 14 effect of centre and baseline PASI was –76.1% in the (20.6%) in the combination group and 20 (30.3%) in the combination group and –51.9% in the FAE monothera- FAE monotherapy group (table 1). The combination and py group (ITT population). The difference between treat- monotherapy groups were well matched at baseline for ments (calcipotriol – vehicle) was –24.2% (95% CI from age (43.4 vs. 43.6 years, respectively), the proportion of –34.2 to –14.2%), which is statistically significant (p ! patients with a duration of psoriasis 110 years (69.1 and 0.001). 68.2%, respectively) and distribution of skin type (73.5 and 72.7% of patients, respectively, had skin type II or Treatment Response III).