lllIIl
I
9
II
9
III
I
Efficacy and safety of calcipotriol (MC 903) ointment in psoriasis vulgaris A randomized, double-blind, right~left comparative, vehicle-controlled study Louis Dubertret, MD, a Daniel Wallach, MD, a Pierre Souteyrand, MD, b Marc Perussel, MD, a Bernard Kalis, MD, c Jean Meynadier, MD, d Jacqueline Chevrant-Breton, MD, e Claire Beylot, MD, r Jacques A. Bazex, MD,g and Hans Jessen Jurgensen, M D h Paris, France
Background: The biologically active form of vitamin D3, calcitriol, may offer a new therapeutic approach to psoriasis. Calcipotriol, a new vitamin D3 analogue, is at least 100 times less calcemic than calcitriol. Objective: Our purpose was to study the efficacy and safety of calcipotriol in the treatment of psoriasis vulgaris. Methods: In a right/left comparative, double-blind study, treatment with calcipotriol ointment (50 tzg/gm) twice daily and placebo was given for 4 weeks. The preferred treatment was continued, without opening the code, for another 4 weeks. Efficacy, as measured by the Psoriasis Area and Severity Index and by the investigator's and patient's global assessment, and safety were assessed every 2 weeks. Results: The mean Psoriasis Area and Severity Index fell in 4 weeks from 14.2 to 6.3 with calcipotriol and from 14.1 to 9.2 with placebo (p < 0.001; 95% confidence interval for difference: 1.78--> 3.94). Local side effects were equally common with calcipotriol and placebo. The mean serum calcium remained unchanged. Conclusion: Topical application of up to 50 gm of calcipotriol ointment per week was found to be an effective and safe treatment of psoriasis vulgaris. (J AM ACAD DERMATOL1992;27:983-8.) Recent studies suggest that calcitriol (1,25-dihydroxy vitamin D3), the biologically active form of vitamin D3, may offer a new therapeutic approach to psoriasis. Oral administration of ealcitriol or alfacalcidol ( l a - O H vitamin D3) can improve the clinical status of patients with psoriasis. However, this effect may not become apparent for several weeks or months and the dose of vitamin D3 that can be administered is limited by its effect on the calcium From the Department of Dermatology, University Hospital of SaintLouis, Pad#; Department of Dermatology, University Hospital Clermont Ferrandb; Department of Dermatology, UniversityHospital, Reimse; Department of Dermatology, UniversityHospital, Moutpellierd; Department of Dermatology, University Hospital, Rennes~; Department of Dermatology, University Hospital, Bordeauxr; Department of Dermatology, University Hospital, Toulouseg;and Clinical Research Department, Leo Pharmaceutical Products, BalIerup, DenmarkP Supported by Leo Pharmaceutical Products, Ballerup, Denmark. Reprint requests: Louis Dubertret, Department of Dermatology, University Hospital of Saint-Louis, 2, Place Dr A Fournier, 75010Paris, France. 16/1/39498
metabolism.l-3 When administered topically, vitamin D3 has a less adverse effect on calcium metabolism, but its efficacy has not yet been fully established. 4-7 Calcipotriol ( M C 903) is a new vitamin D analogue. Its structural formula is shown in Fig. 1. Preclinical studies demonstrated that calcipotriol has a high binding affinity to the cellular receptor for calcitriols and is a potent regulator of cell differentiation and an inhibitor of cell proliferation in human keratinocytes. 9 Oral and parenteral administration of calcipotriol to rats has shown its effect on calcium metabolism to be 100 to 200 times less than that of calcitriol. 8 Dose-ranging studies showed calcipotriol ointment, 50 ~zg/gm, to be significantly more effective in treating patients with psoriasis than 25 ~ g / g m and equal in effect to an ointment containing 100 ~zg/gm of calcipotriol, l0 The aim of the present study was to study the efficacy and safety of calcipotriol ointment (50 ~zg/ gin) in a larger group of patients with psoriasis. 983
984
Journal of the American Academy of Dermatology
Dubertret et aL
OH
(
the other ointment on the opposite side of the body. Both preparations were applied twice daily. No trial medication was applied to the face or scalp. Preferredtreatmentphase. This phase consisted of an additional 4 weeks of treatment. Patients whose lesions had responded better to calcipotriol, applied calcipotriol twice daily to both sides of the body ("ealcipotriol preference" group). Patients in whom placebo was judged superior applied placebo ointment to both sides of the body ("placebo preference" group). Those patients, in whom neither ointment was judged superior, continued to apply assigned treatment as in the first 4 weeks of the study ("no preference" group).
Evaluation of patients
HO
H
Fig. 1. Structural formula of calcipotriol (MC 903).
PATIENTS AND METHODS
Study population Patients of both sexes, older than 18 years of age, with bilateral, symmetric psoriasis of the arms, limbs, and/or trunk, which had remained stable in extent and severity during 2 weeks of treatment with art emoLlientonly, were entered into the study at eight different centers. Patients with guttate psoriasis, pustular psoriasis, psoriasis of the scalp and/or face only, or which was restricted to the elbows and/or knees were excluded. Other exclusion criteria included systemic antipsoriatic treatment or UV therapy in the previous 10 weeks and concomitant therapy with calcium or more than 400 IU of vitamin D daily, or any other medication, that might affect the course of the disease. Patients with hepatic or renal impairment and those intending to spend time in a sunny climate were also excluded.
Study design and treatment regimen The study was placebo controlled and designed as a mulficenter, randomized, double-blind, right/left comparison. It was divided into two phases, randomized treatment and preferred treatment. Randomized treatmentphase.After an initial 2-week "wash-out" phase patients were randomly assigned to 4 weeks of treatment with calcipotriol ointment (50 ~zg/ gin) on one side of the body and a placebo (vehicle) ointment on the other side. One 50 gm tube of each ointment was provided each week. Patients were instructed to apply a thin layer of one ointment onto the affected skin on one side of the body, to wash their hands, and then to repeat the process with
Patients were seen at 2-week intervals for 8 weeks. At baseline and at each subsequent visit the investigator assessed the extent of involvement and the severity of the lesions with respect to erythema, infiltration, and desquamarion. Severity was assessed on a 5-point scale and graded as follows: severest possible (4), severe (3), moderate (2), slight (1), none (0). These assessments were used to calculate a modified Psoriasis Area and Severity Index (PASI) scorer At each postrandomization control visit, the investigator recorded the response to treatment as either "complete clearance," "marked improvement," "moderate improvement," "minimal improvement," "no change," or "worse." Each patient also assessed the response to treatment on a similar basis. In addition, at the end of the initial 4 weeks of randomized treatment, investigators and patients assessed the relative response to treatment on each side of the body to decide the "preferred treatment" in each case.
The primary assessment of response was the change in PASI from baseline to the end of the initial 4-week randomized treatment phase. Other response criteria included changes in the severity of erythema, infiltration, and desquamation, the overall assessments by investigators and patients, and the treatment preference.
Recording of adverse events At each visit patients were asked about adverse events. Adverse events observed by the investigators were also recorded.
Laboratory tests The following laboratory tests were performed at baseline and every 4 weeks: hematology (hemoglobin, erythroeytes, total leukocyte and differential counts platelets) and blood chemistry (bilirubin, alkaline phosphatase, aspartate aminotransferase lAST], alanine aminotransferase [ALT], albumin, and phosphate). Serum calcium (total) was determined every 2 weeks.
Volume 27 Number 6, Part 1 December 1992
Calcipotriol to treat psoriasis vulgaris 985
Table I. P A S I during the initial 4-week randomized treatment phase I Placebo
Calcipotriol Baseline (n = 65) After 2 wk % Change from baseline (n = 62) After 4 wk % Change from baseline (n = 60)
14.2 8.6 41.2 6.3 58.6
_+ 7.5 ___7.5 + 25.7 + 6.5 + 31.7
14.1 11.3 21.4 9.2 35.4
_+ 9.9 + 9.1 _+ 24.5 + 8.3 +_. 37.2
Differencebetween treatments* --2.8 -19.8 -3.0 -23.2
+_ 4.3 _+ 24.4 _+ 4.6 _+ 30
Data are expressedas mean _+_1 standard deviation. *All differencesbetweentreatments are statisticallysignificantat p < 0.001 (paired t test).
Table II. E r y t h e m a , infiltration, and desquamation during the initial 4-week r a n d o m i z e d treatment phase
Erythema
Infiltration
Desquamation
Baseline (n = 65) 2 wk (n = 61) 4 wk (n = 60) Baseline (n --- 65) 2 wk (n = 61) 4 wk (n -- 60) Baseline (n = 65) 2 wk (n = 6O) 4 wk (n = 61)
Calcipotriol
Placebo
Difference between treaOnents*
2.48 _+ 0.64
2.48 + 0.64
--
1.87 + 0.76
2.24 _+ 0.75
-0.37 + 0.57
1.48 _+ 0.77
2.02 ___0.69
- 0 . 5 4 + 0.66
2.15 ___ 0.68
2.15 + 0.67
--
1.26 + 0.79
1.80 _+ 0.77
- 0 . 5 4 + 0.59
0.91 + 0.84
1.45 + 0.79
- 0 . 5 4 _+ 0.64
2.33 + 0.81
2.35 + 0.83
1.16 + 0.92
t.49 + 0.91
-0.31 + 0.63
0.76 + 0.72
1.21 + 0.85
- 0 . 4 2 _+ 0.71
Data are expressedas mean + 1 standard deviation. *Alldifferencesbetweentreatmentsare statisticallysignificantat p < 0.001.Scorerangesfrom0 = completelackof cutaneousinvolvementto 4 = severest possibleinvolvement.
Ethics All patients gave their informed consent. The protocol and the consent form were approved by the local Ethics Committee.
tors" overall assessment), binomial test (side preference assessment, incidence of adverse events). All p values were two-sided and 0.05 was chosen as the level of significance.
Statistical analysis
RESULTS
The calculation of sample size was based on the following assumptions: a standard deviation of 25% for the change in PASI from baseline to the end of treatment, a type I error = 0.05, a type II error --- 0.I0. To satisfy these assumptions and to detect a between-treatment dif. ference of 10% in mean change of PASI, 60 patients were to be included in the study. The following statistical tests were used: one sample t test (PASI and clinical scores, "patients and invesfiga-
Recruitment of patients took place between October 1988 and April 1989 to minimize the effect of U V radiation. Sixty-six patients, 46 men and 20 women, 21 to 84 years of a g e ( m e a n 43 years) entered the study. T h e y had a m e a n duration of psoriasis o f 13.3 years (range 0.3 to 40.0 years) and antipsoriatic treatment had been given to 64 patients (97.0%) in the previous 3 years. Thirty-six patients
986
Journal of the American Academy of Dermatology
Dubertret et al.
100
90
80
70
t • 6O ill
tla
40
30
20
10
0 CALCIPOTRIOL
PLACEBO
(n -
62)
CLEARED MARKED IMPROVEMENT SLIGHT IMPROVEMENT NO CHANGE WORSE
Fig. 2. Investigator's overall assessment of the treatment response after 4 weeksof randomized, double-blind treatment.
(54.5%) were receiving treatment of their psoriasis, mainly topical steroids, at the prestudy assessment 2 weeks before their entry into the study. Psoriatic lesions were widely distributed, affecting the trunk and both upper and lower extremities in approximately 70% of cases.
Randomized treatment phase One of the 66 patients did not have symmetrically distributed psoriatic lesions at study entry. This left
65 patients who could be evaluated. During the initial 4 weeks of the study four patients were withdrawn; three patients defaulted and one patient left because of adverse events. The PASI values recorded during the randomized treatment phase are shown in Table I. The mean baseline PASI on the side assigned treatment with calcipotriol was 14.2 as compared with 14.1 on the side treated with vehicle alone. The PASI fell significantly on both sides of t h e body. After 4 weeks of calcipotriol treatment, t h e mean reduction in the PASI was 7.8. Placebo treatment reduced the PASI by a mean of 4.8. The difference between the two treatments is highly statistically significant (p < 0.001; 95% confidence interval for the difference is 1.78 to 3.94). There were highly significant differences in favor of calcipotriol for the reduction in the scores for erythema, inNtration, and desquamation after both 2 and 4 weeks of treatment (,p < 0.001) (Table II). Both investigators and patients judged the overall clinical response to calcipoptriol to be superior to placebo (p < 0.001). According to the investigators' assessment the proportion of patients who achieved a "marked improvement" or whose psoriasis h a d "cleared" was 74.2% for calcipotriol as compared with 17.7% for placebo treatment (Fig. 2). On completion of the initial 4-week double-blind comparison, both investigators and patients considered that the response to calcipotriol,.was better than that to placebo in 46 instances (75.4%). Placebo was judged superior in five instances (8.2%). The preference for calcipotriol was highly significant (p < 0.001). Both ointments were believed to be of equal value in 10 cases (16.4%).
Preferred treatment phase Sixty-one patients entered the second 4-week phase of the study, the preferred treatment phase, and 55 completed the full 8-week study period. Calcipotriol was applied on both sides of the body by 46 patients, 5 patients used placebo on both sides of the body, and 10 patients continued with assigned treatment as during the initial randomized treatment phase. Four patients withdrew from this part of the study: one patient was withdrawn at week 2 because of marginal hypercalcemia and three patients withdrew for "administrative" reasons as they ran out of study medication. Caleipotriol preference group. Continued treatment with calcipotriol resulted in a further reduction in the PASI and in individual scores for erythema, infiltration, and desquamation. Replacing placebo with calcipotriol resulted in a more marked response
Volume 27 Number 6, Part 1 December 1992
Calcipotriol to treat psoriasis wdgaris 987 20-
18-
16
14
12 o3 10
8' *** ~
"~,~
6.
CALCIPOTRIOL
%
4"
CALCIPOTRIOL
0
.~.
0
***
: P ,
I
9
II
9
III
I
Efficacy and safety of calcipotriol (MC 903) ointment in psoriasis vulgaris A randomized, double-blind, right~left comparative, vehicle-controlled study Louis Dubertret, MD, a Daniel Wallach, MD, a Pierre Souteyrand, MD, b Marc Perussel, MD, a Bernard Kalis, MD, c Jean Meynadier, MD, d Jacqueline Chevrant-Breton, MD, e Claire Beylot, MD, r Jacques A. Bazex, MD,g and Hans Jessen Jurgensen, M D h Paris, France
Background: The biologically active form of vitamin D3, calcitriol, may offer a new therapeutic approach to psoriasis. Calcipotriol, a new vitamin D3 analogue, is at least 100 times less calcemic than calcitriol. Objective: Our purpose was to study the efficacy and safety of calcipotriol in the treatment of psoriasis vulgaris. Methods: In a right/left comparative, double-blind study, treatment with calcipotriol ointment (50 tzg/gm) twice daily and placebo was given for 4 weeks. The preferred treatment was continued, without opening the code, for another 4 weeks. Efficacy, as measured by the Psoriasis Area and Severity Index and by the investigator's and patient's global assessment, and safety were assessed every 2 weeks. Results: The mean Psoriasis Area and Severity Index fell in 4 weeks from 14.2 to 6.3 with calcipotriol and from 14.1 to 9.2 with placebo (p < 0.001; 95% confidence interval for difference: 1.78--> 3.94). Local side effects were equally common with calcipotriol and placebo. The mean serum calcium remained unchanged. Conclusion: Topical application of up to 50 gm of calcipotriol ointment per week was found to be an effective and safe treatment of psoriasis vulgaris. (J AM ACAD DERMATOL1992;27:983-8.) Recent studies suggest that calcitriol (1,25-dihydroxy vitamin D3), the biologically active form of vitamin D3, may offer a new therapeutic approach to psoriasis. Oral administration of ealcitriol or alfacalcidol ( l a - O H vitamin D3) can improve the clinical status of patients with psoriasis. However, this effect may not become apparent for several weeks or months and the dose of vitamin D3 that can be administered is limited by its effect on the calcium From the Department of Dermatology, University Hospital of SaintLouis, Pad#; Department of Dermatology, University Hospital Clermont Ferrandb; Department of Dermatology, UniversityHospital, Reimse; Department of Dermatology, UniversityHospital, Moutpellierd; Department of Dermatology, University Hospital, Rennes~; Department of Dermatology, University Hospital, Bordeauxr; Department of Dermatology, University Hospital, Toulouseg;and Clinical Research Department, Leo Pharmaceutical Products, BalIerup, DenmarkP Supported by Leo Pharmaceutical Products, Ballerup, Denmark. Reprint requests: Louis Dubertret, Department of Dermatology, University Hospital of Saint-Louis, 2, Place Dr A Fournier, 75010Paris, France. 16/1/39498
metabolism.l-3 When administered topically, vitamin D3 has a less adverse effect on calcium metabolism, but its efficacy has not yet been fully established. 4-7 Calcipotriol ( M C 903) is a new vitamin D analogue. Its structural formula is shown in Fig. 1. Preclinical studies demonstrated that calcipotriol has a high binding affinity to the cellular receptor for calcitriols and is a potent regulator of cell differentiation and an inhibitor of cell proliferation in human keratinocytes. 9 Oral and parenteral administration of calcipotriol to rats has shown its effect on calcium metabolism to be 100 to 200 times less than that of calcitriol. 8 Dose-ranging studies showed calcipotriol ointment, 50 ~zg/gm, to be significantly more effective in treating patients with psoriasis than 25 ~ g / g m and equal in effect to an ointment containing 100 ~zg/gm of calcipotriol, l0 The aim of the present study was to study the efficacy and safety of calcipotriol ointment (50 ~zg/ gin) in a larger group of patients with psoriasis. 983
984
Journal of the American Academy of Dermatology
Dubertret et aL
OH
(
the other ointment on the opposite side of the body. Both preparations were applied twice daily. No trial medication was applied to the face or scalp. Preferredtreatmentphase. This phase consisted of an additional 4 weeks of treatment. Patients whose lesions had responded better to calcipotriol, applied calcipotriol twice daily to both sides of the body ("ealcipotriol preference" group). Patients in whom placebo was judged superior applied placebo ointment to both sides of the body ("placebo preference" group). Those patients, in whom neither ointment was judged superior, continued to apply assigned treatment as in the first 4 weeks of the study ("no preference" group).
Evaluation of patients
HO
H
Fig. 1. Structural formula of calcipotriol (MC 903).
PATIENTS AND METHODS
Study population Patients of both sexes, older than 18 years of age, with bilateral, symmetric psoriasis of the arms, limbs, and/or trunk, which had remained stable in extent and severity during 2 weeks of treatment with art emoLlientonly, were entered into the study at eight different centers. Patients with guttate psoriasis, pustular psoriasis, psoriasis of the scalp and/or face only, or which was restricted to the elbows and/or knees were excluded. Other exclusion criteria included systemic antipsoriatic treatment or UV therapy in the previous 10 weeks and concomitant therapy with calcium or more than 400 IU of vitamin D daily, or any other medication, that might affect the course of the disease. Patients with hepatic or renal impairment and those intending to spend time in a sunny climate were also excluded.
Study design and treatment regimen The study was placebo controlled and designed as a mulficenter, randomized, double-blind, right/left comparison. It was divided into two phases, randomized treatment and preferred treatment. Randomized treatmentphase.After an initial 2-week "wash-out" phase patients were randomly assigned to 4 weeks of treatment with calcipotriol ointment (50 ~zg/ gin) on one side of the body and a placebo (vehicle) ointment on the other side. One 50 gm tube of each ointment was provided each week. Patients were instructed to apply a thin layer of one ointment onto the affected skin on one side of the body, to wash their hands, and then to repeat the process with
Patients were seen at 2-week intervals for 8 weeks. At baseline and at each subsequent visit the investigator assessed the extent of involvement and the severity of the lesions with respect to erythema, infiltration, and desquamarion. Severity was assessed on a 5-point scale and graded as follows: severest possible (4), severe (3), moderate (2), slight (1), none (0). These assessments were used to calculate a modified Psoriasis Area and Severity Index (PASI) scorer At each postrandomization control visit, the investigator recorded the response to treatment as either "complete clearance," "marked improvement," "moderate improvement," "minimal improvement," "no change," or "worse." Each patient also assessed the response to treatment on a similar basis. In addition, at the end of the initial 4 weeks of randomized treatment, investigators and patients assessed the relative response to treatment on each side of the body to decide the "preferred treatment" in each case.
The primary assessment of response was the change in PASI from baseline to the end of the initial 4-week randomized treatment phase. Other response criteria included changes in the severity of erythema, infiltration, and desquamation, the overall assessments by investigators and patients, and the treatment preference.
Recording of adverse events At each visit patients were asked about adverse events. Adverse events observed by the investigators were also recorded.
Laboratory tests The following laboratory tests were performed at baseline and every 4 weeks: hematology (hemoglobin, erythroeytes, total leukocyte and differential counts platelets) and blood chemistry (bilirubin, alkaline phosphatase, aspartate aminotransferase lAST], alanine aminotransferase [ALT], albumin, and phosphate). Serum calcium (total) was determined every 2 weeks.
Volume 27 Number 6, Part 1 December 1992
Calcipotriol to treat psoriasis vulgaris 985
Table I. P A S I during the initial 4-week randomized treatment phase I Placebo
Calcipotriol Baseline (n = 65) After 2 wk % Change from baseline (n = 62) After 4 wk % Change from baseline (n = 60)
14.2 8.6 41.2 6.3 58.6
_+ 7.5 ___7.5 + 25.7 + 6.5 + 31.7
14.1 11.3 21.4 9.2 35.4
_+ 9.9 + 9.1 _+ 24.5 + 8.3 +_. 37.2
Differencebetween treatments* --2.8 -19.8 -3.0 -23.2
+_ 4.3 _+ 24.4 _+ 4.6 _+ 30
Data are expressedas mean _+_1 standard deviation. *All differencesbetweentreatments are statisticallysignificantat p < 0.001 (paired t test).
Table II. E r y t h e m a , infiltration, and desquamation during the initial 4-week r a n d o m i z e d treatment phase
Erythema
Infiltration
Desquamation
Baseline (n = 65) 2 wk (n = 61) 4 wk (n = 60) Baseline (n --- 65) 2 wk (n = 61) 4 wk (n -- 60) Baseline (n = 65) 2 wk (n = 6O) 4 wk (n = 61)
Calcipotriol
Placebo
Difference between treaOnents*
2.48 _+ 0.64
2.48 + 0.64
--
1.87 + 0.76
2.24 _+ 0.75
-0.37 + 0.57
1.48 _+ 0.77
2.02 ___0.69
- 0 . 5 4 + 0.66
2.15 ___ 0.68
2.15 + 0.67
--
1.26 + 0.79
1.80 _+ 0.77
- 0 . 5 4 + 0.59
0.91 + 0.84
1.45 + 0.79
- 0 . 5 4 _+ 0.64
2.33 + 0.81
2.35 + 0.83
1.16 + 0.92
t.49 + 0.91
-0.31 + 0.63
0.76 + 0.72
1.21 + 0.85
- 0 . 4 2 _+ 0.71
Data are expressedas mean + 1 standard deviation. *Alldifferencesbetweentreatmentsare statisticallysignificantat p < 0.001.Scorerangesfrom0 = completelackof cutaneousinvolvementto 4 = severest possibleinvolvement.
Ethics All patients gave their informed consent. The protocol and the consent form were approved by the local Ethics Committee.
tors" overall assessment), binomial test (side preference assessment, incidence of adverse events). All p values were two-sided and 0.05 was chosen as the level of significance.
Statistical analysis
RESULTS
The calculation of sample size was based on the following assumptions: a standard deviation of 25% for the change in PASI from baseline to the end of treatment, a type I error = 0.05, a type II error --- 0.I0. To satisfy these assumptions and to detect a between-treatment dif. ference of 10% in mean change of PASI, 60 patients were to be included in the study. The following statistical tests were used: one sample t test (PASI and clinical scores, "patients and invesfiga-
Recruitment of patients took place between October 1988 and April 1989 to minimize the effect of U V radiation. Sixty-six patients, 46 men and 20 women, 21 to 84 years of a g e ( m e a n 43 years) entered the study. T h e y had a m e a n duration of psoriasis o f 13.3 years (range 0.3 to 40.0 years) and antipsoriatic treatment had been given to 64 patients (97.0%) in the previous 3 years. Thirty-six patients
986
Journal of the American Academy of Dermatology
Dubertret et al.
100
90
80
70
t • 6O ill
tla
40
30
20
10
0 CALCIPOTRIOL
PLACEBO
(n -
62)
CLEARED MARKED IMPROVEMENT SLIGHT IMPROVEMENT NO CHANGE WORSE
Fig. 2. Investigator's overall assessment of the treatment response after 4 weeksof randomized, double-blind treatment.
(54.5%) were receiving treatment of their psoriasis, mainly topical steroids, at the prestudy assessment 2 weeks before their entry into the study. Psoriatic lesions were widely distributed, affecting the trunk and both upper and lower extremities in approximately 70% of cases.
Randomized treatment phase One of the 66 patients did not have symmetrically distributed psoriatic lesions at study entry. This left
65 patients who could be evaluated. During the initial 4 weeks of the study four patients were withdrawn; three patients defaulted and one patient left because of adverse events. The PASI values recorded during the randomized treatment phase are shown in Table I. The mean baseline PASI on the side assigned treatment with calcipotriol was 14.2 as compared with 14.1 on the side treated with vehicle alone. The PASI fell significantly on both sides of t h e body. After 4 weeks of calcipotriol treatment, t h e mean reduction in the PASI was 7.8. Placebo treatment reduced the PASI by a mean of 4.8. The difference between the two treatments is highly statistically significant (p < 0.001; 95% confidence interval for the difference is 1.78 to 3.94). There were highly significant differences in favor of calcipotriol for the reduction in the scores for erythema, inNtration, and desquamation after both 2 and 4 weeks of treatment (,p < 0.001) (Table II). Both investigators and patients judged the overall clinical response to calcipoptriol to be superior to placebo (p < 0.001). According to the investigators' assessment the proportion of patients who achieved a "marked improvement" or whose psoriasis h a d "cleared" was 74.2% for calcipotriol as compared with 17.7% for placebo treatment (Fig. 2). On completion of the initial 4-week double-blind comparison, both investigators and patients considered that the response to calcipotriol,.was better than that to placebo in 46 instances (75.4%). Placebo was judged superior in five instances (8.2%). The preference for calcipotriol was highly significant (p < 0.001). Both ointments were believed to be of equal value in 10 cases (16.4%).
Preferred treatment phase Sixty-one patients entered the second 4-week phase of the study, the preferred treatment phase, and 55 completed the full 8-week study period. Calcipotriol was applied on both sides of the body by 46 patients, 5 patients used placebo on both sides of the body, and 10 patients continued with assigned treatment as during the initial randomized treatment phase. Four patients withdrew from this part of the study: one patient was withdrawn at week 2 because of marginal hypercalcemia and three patients withdrew for "administrative" reasons as they ran out of study medication. Caleipotriol preference group. Continued treatment with calcipotriol resulted in a further reduction in the PASI and in individual scores for erythema, infiltration, and desquamation. Replacing placebo with calcipotriol resulted in a more marked response
Volume 27 Number 6, Part 1 December 1992
Calcipotriol to treat psoriasis wdgaris 987 20-
18-
16
14
12 o3 10
8' *** ~
"~,~
6.
CALCIPOTRIOL
%
4"
CALCIPOTRIOL
0
.~.
0
***
: P ,
