Comparative effects of calcipotriol solution (50 μg/ml) and betamethasone 17-valerate solution (1 mg/ml) in the treatment of scalp psoriasis

British Journal of Dermatology (1994) 131, 678-683. Comparative effects of calcipotriol solution (50/xg/ml) and betamethasone 17-vaIerate solution (1 mg/ml) in the treatment of scalp psoriasis M.R.KLABER. P.E.HIITCHINSON,* A.PEDVIS-LEFTICK.t K.KRAGBALLE.ij: T,L.REUNALA.§ P.CM. VAN UE KERKHOF." M.K.jOHNSSON.** L.MOLIN.tt M.S.CORBKTTti: AND N.I)OWNES§§ liroomfield Hospiuil. Chvlmsford and ihe Roiial London Hospital. U.K. 'UicesliT Rmfiil Injirmary. U.K. t Ehsabeth-liruyere lleahh Centre. Ottawa. Canada i XiarseUsbtyrg Hospital. Arhiis C. Denmark 'tiTarnpere VniwrsUi) Ihspital. Helsinki. Finland •; Kiiniek vour I luidziekten. Sijnu-jien. the \etherlands " Universitfi HospHui Trondheim. Norway ffOrebro Medicut Center. Sweden ^Aiidenbrooke's Uospital. Cambridge. U.K. eo Laboratories Ltd. U.K. Accepted for publication 22 March 1994 Summary The efficacy, tolerability and safety of calcipotriol solution and betamethasone 17-valerate solution were compared in a multicentre, prospective, randomized, double-blind, parallel group study. Four hundred and seventy-four patients with scalp psoriasis were recruited from six European countries and Canada. Following a 2-week washout period, either calcipotriol solution (50/zg/ml) or betamethasone 17-valerate solution (1 mg/ml) was applied twice daily for 4 weeks. After this time, patients who required no further active treatment were observed for relapse. Rctreatment with caicipotriol was offered to those patients who relapsed, and who were originally in the calcipotriol-treated group. The two treatment groups were well matched at baseline. At the end of treatment, the proportion of patients who had "cleared" or 'markedly improved' was statistically significantly greater in the betamethasone group (75%) than in the calcipotriol group (58%) (P < OOOl) (95% confidence interval of diflerence 25-3 -»8-6). The decrease in total sign score (sum of scores for erythema, thickness and scaliness) at the end of treatment was also statistically significantly greater in the betamethasone group (f>l %) than the calcipotriol group (45%) (P < OOOl) i9S% confidence interval of difference 9-7 -* 23-1). Adverse events were reported by 87 patients in the calcipotriol group, and 31 patients in the betamethasone group: the most common was lesional or perilesiona! irritation, which occurred significantly more frequently with calcipotriol (2fiTo) than with betamethasone (8';^.) (P < OOOl). Fifteen patients (6%) in the calcipotriol group and four (1%) in the betamethasone group withdrew from thestudy because ofadverse events or unacceptable treatment response (P — 0 017). There was no statistically significant change in serum total calcium in either treatment group. There was no significant difference in the rate of relapse between the two treatment groups. In the 69 calcipotriol-treated patients who relapsed, re-treatment with calcipotriol was effective and well tolerated. Calcipotriol solution was effective in treating mild to moderate scalp psoriasis. However, betamethasone solution was significantly more effective, and was associated with statistically significantly less local irritation on the scalp and face. Psoriasis is one of the most common chronic skin diseases, with a prevalence in the general population of between 1-4 and 2-9%.^"^ Involvement of the scalp is extremely common, and in some patients the scalp j .. n t-. I- .* .1 „ _ . ,. c ij Correspondence: M.R.Klaber. Dermatology Department, Broomfield Hospital, Broomfieid.Chdmsford. Essex CMl 5ET. U.K. may be the only site affected.^ j J K K CalcipotrioI (MC 9 0 3 : Daivonex ; Dovonex ) is a 678 COMPARISON OF CALCIPOTRIOL AND BETAMETHASONE IN SCALP PSORIASIS vitamin Dj analogue which is available for the treatment of chronic plaque psoriasis. Calcipotriol induces difierentiation and inhibits proliferation of keralinocytes in vivo.'' Its effect on calcium metabolism in rats in vivo is 100-200 times less than 1.25 dihydroxyvitamin D,.'' Several large-scale clinical studies'""'" have demonstrated the safety iind efficacy of treatment with calcipotriol in an ointment formulation. Indeed, calcipotriol has been shown to be at least as effective as betamethasone 17-valerate ointment.'" and more effective than a short-contact dithranol regimen. Presently available treatments for scalp psoriasis leave much to be desired; they are either messy, malodorous, oily, inconvenient to use or. as is the case with topical corticosteroids. restricted to short-term use. There is a need for a safe and effective alternative. This study compared the efficacy and safety ofa solution of calcipotriol |S()/ig/ ml) with the most frequently prescribed topical treatment for scalp psoriasis, betamethasone 17-valerate solution (1 mg/ml). 679 Procedures Following a 2-week washout period, when only a mild, non-medicated shampoo was used, patients were randomized to receive double-blind treatment with either calcipotriol (50/xg/mi) solution or betamethasone 17valerate (1 mg/ml) solution, applied twice daily for 4 weeks. The maximum amount allowed was 60 ml/ week. Patients were fol!owed-up at 1, 2 and 4 weeks of treatment. The same investigator assessed the extent of scalp psoriasis (graded 0-5) and the severity of the cfinical signs, [erythema, thickness and scaliness (each graded 0-4): Table 1]. An overafi assessment of treatment response from the start of active treatment was made by both investigators and patients, using a fivept)int scale (Table 1). Patients also assessed scalp fiaking and itching (each graded 0-3). and acceptability (graded 1-5: Table 1) for the following aspects of treatment: greasiness. ease of application, whether treatment caused dryness of the scalp and odour. Any adverse events were documented, following an open question to the patient. A blood sample for haematology and serum biochemistry (including serum total cal- Methods Study design The study was a multicentre. randomized, double-blind, prospective, parallel group comparison, and was performed in 68 centres in Canada. Denmiirk, Finland, the Netherlands, Norway, Sweden and the United Kingdom. Patients Adult patienLs with a clinical diagnosis of stable, mild to moderate scalp psoriasis who also had a history of psoriasis on the body, were recruited for the study. Patients with severe (thick) scalp psoriasis, seborrhoeic dermatitis ofthe face and scalp, or any established or suspected bacterial or fungal infection of the scalp, were excluded. Other exclusion criteria were systemic antipsoriatic treatment or UV light within the previous 8 weeks, extensive psoriasis (> 50% of the body being actively treated), concurrent medication with > 4(H) i.u. vitamin D daily, calcium tablets, or any other medication which could affect the course of the disease (e.g. lithium, potent topical or systemic corticosteroids), significant hepatic or renal disease, or hypercalcaemia. Pregnant or breast-feeding women were excluded, and women of child-bearing potential were required to have a negative pregnancy test, and to use adequate contraception. The study protocol was approved by local ethics committees, and aU patients gave written informed consent. Table 1. l';irameters assessed in this study Assessment of extent of scalp psoriasis 0. no involvement 1. < 20% 2. 2 0 - 39% 3, 40-59% 4, f)0-79% 5. H0-U10% Assessment of clinical signs/symptoms (erythema, scaiiness, thickness. flaking, itching) 0, absent 1, slight 2, moderate 3, severe 4, severest possible Overall assessment of treatment response 1. worse 2, no change 3, .slight improvement 4, marked improvement 5. cleared Assessment of acceptability 1. very poor 2. poor 3. atceptablf 4. good excellent 680 M.R.KLABER etal cium) was taken for analysis at the local laboratory, at the first visit and after 1 and 4 weeks' treatment. Compliance was assessed by questioning the patients at each visit, and collecting and weighing the bottles of medication to ascertain the amount used. Post-treatment foUoW'Up and re-treatment At the end of the double-blind period, patients who required no further active treatment entered an optional observation period for 4 weeks. For those patients who relapsed during this period, the treatment code was broken, and patients who originally received calcipotriol were offered re-treatment with calcipotriol for a further 6 weeks. Sample size and statistics The study was designed to detect an absolute difference of \()% with a power of H()% and a significance level of 5% (two-tailed) between the two treatment arms, with respect to the proportion of patients who. at the end of treatment, had attained either 'clearance' or 'marked improvement' according to the investigators' overall assessment. With respect to total sign score and score for individual signs, statistical analysis was performed using the paired t-test, to evaluate the significance of mean changes within each treatment group between baseline and subsequent visits. Between-group differences were evaluated using I-tesls. Chi-squared tests were used to compare treatments with respect to investigator and patient overall assessment, and frequency of adverse events. Results Double-blind comparison Four hundred and eighty-one patients entered the washout phase of the study, and 474 were randomized (240 to the calcipotriol group. 234 to the betamethasone group). The groups were well matched at baseline with respect to age. sex, history of psoriasis, and extent and severity of scalp psoriasis (Table 2). Twenty-nine patients (20 in the calcipotriol group and nine in the betamethasone group) withdrew from the study, leaving 445 patients (220 in the calcipotriol group and 225 in the betamethasone group) who completed 4 weeks of double-blind treatment. Withdrawals in the calcipotriol group were due to adverse events (11 patients), unacceptable treatment response Table 2. Demographic data al baseline Calcipotriol (fi - 2 4 0 ) Betamethasone (n-234) Age (years) Mean (SD) Range 45-2(15-9) 18-»90 42-9(15-5) Sex Males (%) Females (%) 53-3 46-7 49-6 50-4 Duration of scalp psoriasis (years) Mean (SD) Range Score for extent Mean (SD) Range Total sign score* Mean (SDI Range 13-1 (U'U) O'l -* 52'() 18-83 13-1 ai'3) 0-1 -.67'0 l-»5 2-8(1-3) 1 -»5 6-4 (1'7) J-> 12 6-6(1-7) 2-12 2-7(1-3) * Sum of scores for erythema, thickness and scaliness. (four), and default (five). In the betamethasone group, they were due to adverse events (two patients), unacceptable treatment response (two) and default (five). Compliance was good in both groups, and more than 90% of patients were fully compliant at each follow-up visit. Patients used a mean (+SD)of 31-5 (± 169) ml per week in the calcipotriol group, and 27-1 ( ± 17-5) ml per week in the betamethasone group (P ~ 0-014). The investigators' and patients' overall assessments of treatment response at the end of treatment are shown in Figure 1. Betamethasone was statistically significantly superior to calcipotriol—75-4% of investigator assessments and 73-7% of patient assessments in the betamethasone group and 58-5% of investigator assessments and 57-6% of patient assessments in the calcipotriol group were 'marked improvement' or 'cleared' ( P < 0 0 0 ] ) (95% confidence interval of difference 25-3 -» S-b for investigators. 24-6 -• 7-6 for patients). The total sign score (sum of scores for erythema, thickness and scaliness) decreased significantly from baseline at al! time points in both treatment groups (Fig. 2). The mean percentage reduction in the total sign score from baseline to the end of treatment was statistically significantly greater in the betamethasone group (61-6%) than the calcipotriol group (45 2%; P < 0-001) (95% confidence interval of difference 9-7-» 231). The scores for the individual signs of erythema, thickness and scaliness reflected this pattern of response. COMPARISON OE CALCIPOTRIOI, AND BETAMETHASONE IN SCALP PSORIASIS 5- Figure 1. O\'erall assessment of treatment response at the end of Ireatment. (a) Investigators: (b| patienis. Q . worse; Q . no change; Q . slight impnn'fment; [^, marked improvement; I . cleared. 40 • Calcipotriol Similarly, ihe score for extent decreased significantly from baseline at ail subsequent assessments in bolb treatment groups (Fig. 2). The reduction in score for Calcipotriol Betamethasone 1 681 2 Weeks Figure 2. ia) The total sign score, and (bl score For extent during douhle-hlind treatment. Betamethasone Calcipoinoi Betamethasone extent was statistically significantly greater in the betamethasone group at the end of treatment (P < OOOl). The distribution of the patients' assessments of scalp flaking and itching at the end of treatment are shown in Figure 1 Both treatments signiiicantly reduced the incidence and severity of scalp llaking and itching throughout the study (P < OOOl}. but betamethasone was statistically significantly superior to calcipotriol (P < 0-OOi). The patients found both treatments equally acceptable in terms of greasiness. ease of application and odour, with over 9S'X. of patients finding both "acceptable", "good" or 'excellent'. However. Ireatment with calcipotriol tended to cause more 'dryness of the scalp" with 21 % of paUents rating acceptability as 'very poor' or 'poor', compared with 11% in the betamethasone group {P — 0-()02|. Adverse events reported during the study are shown in Table 3. I^esionai or perilesional irritation was the most common, and was reported by statistically significantly more patients in the calcipotriol group (2 5-7%) than the betamethasone group (8-1%) ( P < 0-001). Facial irritation was also statistically significantly greater in the caicipotriol group (11-3%I than the betamethasone group (0-4%) (P < 0 001). However, only 1 1 patients (4-6%) in the calcipotriol group und two patients (()'9'}(.) in the betamethasont' group withdrew because of adverse events (P — 0O17). There were no con.sistent or clinically important differences between the calcipotriol- and betametbasone-treated groups with regard to haemopoietic. liver or renal function. In particular, tbere was no change in the mean serum total calcium in either group during double-blind treatment. 682 M.R.KLABER etal. 100 Betamethasone {n=232) Calcipotriol (/7=236) Calcipotriol (/7=236) Post-treatment follow-up and re-treatment Ninety-nine patients from the calcipotriol group and 129 patienls in the betamethasone group, who attained a satisfactory treatment response, entered the posttreatment follow-up phase of the study. After 4 weeks' observation, there was no statistically significant difference between the two groups in terms of relapse rate (defined as an increase in total sign score to at least 50% of the score at the start of douhle-biind treatment). Seventy-five patients (75-8%) in the calcipotriol group and 102 patients (79-1%) in the betamethasone group relapsed according to this definition. Sixty-nine patients received re-treatment with calcipotriol solution for 6 weeks. The mean percentage Table 3. Adverse events Calcipotriol n-240 No. of adverse events (%) Betaraethasone n-234 No, ofadverse events (%) P Lesional or perilesional irrilatlon 62 (25-8) 19(8-1) < 0 001 Facial irritation 27(11-3) 1 (0-4) < 0-001 Various skin reactions 6(2-5) 9(3-08) NS Non-cutaneous 3 (1-2) 6(2-5) NS No. of patients reporting one or more adverse events 87{36'3) 31(13-2) < 0-001 NS, not significant. Betamethasone (/?=232) Figure 3, Patients' assessment at the end of treatment, (a) Scalp llaking: (b) itching. D . severe: • • moderate; [ j . mild: • . absent. reduction in the total sign score from relapse was 60-1% (95% Cl 51-8 -* f)8-4). This result was reilected in highly statistically significant reductions in extent, and erythema, thickness and scaliness during re-treatment (P < 0-001). At the end of re-treatment 82-6% of patients reported a 'marked improvement' or 'clearance'. There was also a highly statistically significant reduction in scores for skin Haking and itching (P < 0-001). There was no change in serum calcium during retreatment. Discussion This study has shown that twice daily application of calcipotriol (50 //g/ml) solution for 4 weeks is effective in treating mild to moderate scalp psoriasis. However, it is statistically significantly less effective than betamethasone 17-vaierate (0-1%) solution. This was demonstrated in all efficacy parameters measured: extent, the clinical signs (erythema, thickness, scaliness). and the investigators' and patients' overall assessment of treatment response. Betamethasone was also found to be statistically significantly superior to calcipotriol in reducing the problems of scalp llaking and itching. Post-treatment relapse rates were similar for betamethasone- and calcipotriol-treated patients, and re-treatment with calcipotriol was effective and well tolerated. There have been two other randomized, double-bbnd studies of calcipotriol solution for the treatment of scalp psoriasis. Both were small, placebo-controlled studies in which calcipotriol solution was compared with its vehicle. A total of 48 patients received calcipotriol solution, and the reduction in total sign score was 3-2 COMPARISON OF CALCIPOTRIOL AND BETAMETHASONE IN SCALP PSORIASIS and 3-3. respectively, in the two trials, which compares well with a reduction of 3-2 in the present study, from the same baseline score. Calcipotriol solution was less well tolerated than betamethasone solution, with local irritation on the scalp and face being signiiicantly more common. This facial irritation could have been caused by the solution running on to the face, despite the fact that the patients were told to try to avoid this. Possibly an instruction to tip the head back during application, or a solution containing a lower concentration of calcipotriol. might solve this problem. However, the high compliance and low withdrawal rate indicates that the sideeffects were generally mild. Treatment with calcipotriol solution had no effect on the laboratory values measured, in particular serum total calcium. This is in agreement with numerous other studies,"^"'" which have shown no statistically significant changes in serum calcium in trials lasting up to 1 year. At first sight, these results do not appear to be at all impressive. Caicipotriol solution is less effective and less well tolerated than betamethasone. Does it have a place in the cfinical treatment of scalp psoriasis? Most patients with psoriasis have involvement of the scalp, either continuously or intermittently.' AU currently available treatments have significant drawbacks, which make them far from ideal. Successful tar preparations, such as Ung.Cocois Co. or coal tar and salicylic acid ointment, are messy, malodorous and greasy. Application is compficated and time-consuming, and because they are cosmetically unacceptable, they need to be removed later by shampooing. Dithranol preparations may be used on the scalp, but are even more didicult to use than tar products, with the additional problem of staining of hair and scalp margins. They are mainly used in hospital practice. However, in most countries, topical corticosteroids are preferred in general practice, because they are much more pleasant to use. Betamethasone is the most widely prescribed topical agent for the treatment of scalp psoriasis. Nevertheless, long-term use may give rise to typical corticosteroid side-effects, especially atrophy. Thus, it would appear that calcipotriol solution has a place in the treatment of scalp psoriasis, as it is neither messy nor malodorous, and does not have significant side-effects. Acknowledgments This study was sponsored by U'o Pharmaceutical 683 Products. Denmark. Statistical analysis was performed by Mr F.Jensen MSc. Tech. of Leo Pharmaceutical Products. Denmark. In addition to the authors, the following investigators participated in the trial. Canada: I.E.Adam. M.L.Baxter. R.P.Haydey. R.S.Lester. R.A.Miller, K.Moses, A.H.Murray. E.Murray, S.J.Murray. C.Ramsay, D.Schachter. R.Schachter. N.H.Shear. S.A.Swiggum. Denmark: F.Brandrup. F.Da Cunha Bang. T.Karlsmark, F.G.Larsen. T.Menne. J.Roed-Petersen. S.UlIman. I.L.Wildfang. Finland: L.R.Forstrom. LA.Helander. T.T.Juvakoski. U.O.Kiistala. A.Vaalasti. Netherlands: P.Arnold. M.T.liousema. M.J.T.B.van de Broek. W.R.Faber. J.Fiinterman, F.Heule, D.de Hoop, H.A.M.Neumann. T.T.Tio, A.R.van de Wateren. Norway: J.Bull-Berg. O.Fyrand, B.T.Gjertsen. L.I.Hanssen, T.Morken. E.J.Nordal. Sweden: G.Brundin. L.Gip. R.Hornqvist, B.Kristensen, O.Kristensen, E.Nilsson. E.NylanderLundqvist. I.Reidhav. (J.Skold-Nordstrom. A.Svensson. United Kingdom: A.C.Chu. I.H.Coulson. W.J.Cunliffe. J.P.Ellis, D.Goldin. M.Goodfield. W.A.D.GrifRths. P.V.Harrison. C.R.I^vell. J.A.Miller. R.Pye. References 1 ll.S.NaUonal Health Survey 1971-74. Vital and HealthStaUslics. Series U No. 212. 2 Brandrup F. Green A. The prevalence of psoriasis in t)enmark. Ada Derm VenereoUSlockh) 1981:61: 344-6. 3 Dawber. R. Diseases involving the scalp. In: Diseases of the Hair and Scalp (Rook A. Dawber R. cdsl. Oxford: Blackwell Scientiiic Publications, 1991: SOf> 9. 4 Kragballe K. Beck HI, Sogaard H. Improvement of psoriasis by a topical vilamin Dj analogue (MC 903) In a double-blind study. Br JDermatol 1988: 119: 223-JO. 5 Binderup L. Bramm H.. Effects of a novel vitamin D analogue MC 903 on cell proliferatjon and diSerentiatlon in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988: 37: 8 8 9 95. 6 Duberlret I., Wallach I), Souteyrand P et al. Efficacy and safety of calcipotriol (.MC9O3) ointment In psoriasis vulgaris. / Am Acad Dermatol 1992: 27; 983-8. 7 CuntifTe W|, Berth-jones J, Claudy A et al. Comparative study of calcipotriol (MC9O3) ointment and betamethasone 17-valerate ointment in patienis with psoriasis vuigaris. / Am Acad Dermatol 1992:26: 7 3 6 - 4 3 . 8 Kragballe K. Gjerlsen BT. De Hoop D et al. Double-blind lefl/right comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. iMncei 1991: 331: 19J-6. 9 Berth-)ones |. Chu AC. DtHld VVAH ei al. A multicentre. parallelgroup comparison of calcipntriol ointment and short-contact dithranot therapy in chronic plaque psoriasis. Br / Dermatol 1992: 1 2 7 : 2 6 6 - 7 1 . 10 Klaber MR, Hutchinson PK. Holden C et at. Long lerm treatmcnl of psoriasis with calcipotriol. Or / Dermaiol 1992: 127 (Suppi. 40J: 17 (Abstr.).