ARTICLE
Psoriasis, a chronic skin disease that reportedly affects between 1 and
2% of the population of Caucasians in Europe [1, 2], is an intractable
inflammatory keratosis characterized by an abnormal proliferation of epidermal
cells. Mild to moderate cases have so far been treated with topical preparations
of vitamin D3, steroids, etc., while moderate to severe cases
are principally treated with oral medication and phototherapy.
Calcitriol, an active vitamin D3, is known as a substance
which, together with PTH, regulates calcium metabolism in the body. Its
clinical efficacy against psoriasis was first discovered by Morimoto et
al. [3], who at that time treated osteoporotic patients with complicated
psoriasis by means of oral administration of 1alpha-hydroxy-vitamin D3,
and the applicability of various active vitamin D3 topical
preparations to psoriasis has been studied since then.
Tacalcitol, one of the calcitriol derivatives, has in vitro activities
that induce differentiation and inhibit proliferation of epidermal cells,
which are equivalent to those of calcitriol [4], while its elimination
from the blood after its absorption is faster than that of calcitriol
[5, 6]. Initially, the indication of orally-administered tacalcitol to
osteoporotic patients was studied [7]. However, due to its above-mentioned
advantages, a clinical study of tacalcitol as an active vitamin D3
topical preparation in the treatment of psoriasis started in Japan in
1985, ahead of other countries, and since 1993 it has been marketed as
a tacalcitol 2 mug/g ointment. Its efficacy and safety in single daily
administration were studied in the West, where it is currently being sold
as tacalcitol 4 mug/g ointment.
Severe inflammation, eruption with marked epidermal hyperplasia, and
psoriatic eruption appearing on the elbow, knee, glutaeus and lower limbs
are generally considered to be intractable. This is why, in Japan, study
of intractable psoriasis treatment with a concentrated formulation (concentrated
ointment) of tacalcitol has been initiated. A dose finding study demonstrated
that efficacy of tacalcitol ointment was concentration-dependent in the
range of 4 to 20 mug/g for the intractable lesions of psoriasis vulgaris
that had not effectively treated with 2 mug/g tacalcitol [8]. A double-blind,
left-to-right comparative study of 4 weeks verified that 20 mug/g ointment
is an effective treatment of psoriasis vulgaris that did not satisfactorily
respond to treatment with 2 mug/g ointment [9] and no problems related
to calcium homeostasis occurred even after 28 days of treatment with doses
of up to 10 g/day [10].
The objectives of this study are to confirm the safety and efficacy
of tacalcitol 20 mug/g ointment up to 10 g daily in long-term administration.
A 26- to 54-week study was conducted on subjects with psoriasis vulgaris.
Patients and methods
Study design
A 26- or 54-week multi-center open prospective and uncontrolled study
was conducted in 59 institutions. Patients who were subjected to treatment
that could have affected the assessment of the drug efficacy, underwent
a 2-week wash-out prior to the beginning of the application. The protocol
was approved by the Institutional Review Boards of each different institution
and all the subjects were enrolled after their written informed consent
had been obtained. The study was conducted in accordance with Good Clinical
Practices.
Subjects
The subjects selected included inpatients and outpatients with psoriasis
over at least 10% of their total body area, regardless of their sex. Their
ages ranged from 16 to 79 years old. Pregnant or breast-feeding women,
patients with severe liver disease, heart disease, decreased renal function
or hypercalcemia were excluded. Treatment with systemic therapeutic drugs
of psoriasis, topical preparations containing steroids of the super-potent
or potent classes, drugs that affect calcium metabolism, PUVA or UVB were
prohibited for 2 weeks prior to the beginning of the application and throughout
the duration of the study. In addition, if the hair-covered area of the
scalp, to which application of the ointment was difficult, was not included
in the assessments, application of topical potent class steroid preparations
to this area was permitted.
Treatment
Tacalcitol 20 mug/g ointment, provided by Teijin Ltd., was applied once
daily, for 26 weeks, at a maximum daily dose of 10 g, to all skin lesions
of psoriatic patients. Based on the attending physician's judgement and
the subject's consent, the application could be extended to 54 weeks.
If the eruption cleared, application was stopped and if the disease was
exacerbated, the treatment could be re-started. On each visit to the hospital,
the compliance was evaluated based on records of the number of ointment
tubes used and adherence to the application instructions. The use of any
topical preparation other than the study drug to any area studied, except
for the hair-covered part of the scalp, was prohibited for the study period.
Assessments
Clinical observations and laboratory tests were conducted at the beginning,
every week until the 4th week, then every other week until the 10th week
and then every 4 weeks until the 26th to 54th week. On each observation
day, the same physician assessed the severity of the psoriasis based on
the Psoriasis Area and Severity Index (PASI) score system [11]. The severity
of the psoriatic area was assessed using 5 degrees (absent, trace, slight,
moderate and severe) with respect to erythema, thickness and scaling.
The global improvement rating was assessed, based on improvement of the
disease in comparison with the baseline condition, using 6 degrees (aggravated,
not changed, slightly improved, moderately improved, markedly improved
and cleared).
Adverse events were examined on every visit to the hospital. In addition
to systemic and local adverse events, the laboratory test results of hematological
tests (red blood cell count, white blood cell count, platelet count, hemoglobin,
hematocrit), blood biochemical tests (calcium, inorganic phosphorus, albumin,
total protein, total bilirubin, urea nitrogen, creatinine, GOT/AST, GPT/ALT,
alkaline phosphatase, LDH, intact PTH) and urinalysis (glucose and protein)
were measured at the beginning and during every visit to the hospital,
and abnormal changes in the laboratory test results were assessed. In
addition, the serum tacalcitol and 1alpha,25-(OH)2D3
levels were measured at the beginning and in the 2nd, 4th, 8th, 14th,
26th, 38th and 54th weeks.
Adverse events, for which a causal relationship with the study drug
could not be ruled out by the physician, were determined to be adverse
drug reactions.
Statistical tests
The primary endpoint of this study is safety assessment.
The 1-sample Wilcoxon test was used to test the PASI score and the laboratory
test results.
In addition, the final global improvement ratings were summed up and
the effective rate (the ratio of cases in which the final global improvement
rating was cleared, markedly improved or moderately improved) and its
95% confidence interval were calculated.
Results
Patients' details
One hundred and sixty subjects were enrolled in this study.
The safety analysis was conducted using a full analysis set. Six subjects
were excluded because they were determined to be unsuitable for assessment,
and the remaining 154 subjects were analyzed. The efficacy analysis was
conducted using a per-protocol set. The number of subjects who observed
the study protocol and were analyzed, was 115 for the 26-week application
and 74 for the 54-week application. Since the subjects who were deemed
to be eligible for further treatment after 26 weeks of the application
continued the application for a total of 54-weeks, the 115 subjects included
the 74 subjects. Those who did not comply with the administration method
or dose, or who took contraindicated drugs for concomitant use or missed
the observation of the primary endpoint were not included in the analysis.
The patient profiles are shown in Table
I.
Efficacy
The mean changes in the PASI scores of the 115 subjects of 26-week application
and 74 subjects of 54-week application, who complied with the study protocol,
are shown in Figure 1.
For the 115 subjects of 26-week application, a significant decrease (p
< 0.001) in the mean PASI score was seen after 1 week of application,
compared with the score before the beginning of the study (application),
from 21.38 ± 10.56 (mean ± SD) at baseline to 5.17 ± 5.54
after 26 weeks. For the 74 subjects having the 54-week application, the
mean PASI score before the beginning of the study was 22.49 ± 10.20,
which decreased to 5.73 ± 6.04 after 54 weeks. The PASI score remained
almost constant after 18 weeks through to 54 weeks. In addition, the baseline
PASI score ranged from 7.2 to 57.6. Moreover, the effective rate of final
global improvement rating of "moderately improved" or higher was 93.0%
after 26 weeks and 93.2% after 54 weeks. The specific results of the final
global improvement rating are shown in Table
II. The photographs of the cases with improvement in dermatological
findings are shown in Figure
2.
Adverse events
Serious adverse events reported included 1 case of bac-terial pneumonia
and 1 case of rectal carcinoma, but neither of them was life-threatening,
and no causal relationship with the study drug was determined. Ninety-seven
systemic adverse events were seen in the 154 subjects, but no causal relationship
with the study drug was found in any of the events. A total of 102 local
adverse events (cumulative 111 events) were reported in 58 subjects. Of
these, causal relationship with the study drug was determined for 25 local
adverse drug reactions (cumulative 29 events) in 16 subjects. The symptoms
of the 25 events reported included 6 events of itching, 5 events of application
site irritation, 5 events of feeling irritated, 4 events of application
site redness, 4 events of swelling and 1 event of pigmentation. The severity
was mild to moderate in all events. The number of days until the onset
of each of the local adverse drug reactions is shown in Table
III. Twenty-three of the cumulative 29 events (79.3%), including itching,
feeling irritated, application site irritation, application site redness
and swelling, appeared within the first 21 days of the application.
Laboratory parameters
The changes in the mean corrected serum calcium level of all the subjects
are shown in Figure 3.
Compared with the levels before the beginning of the study (baseline level),
a statistically significant increase was found in the 1st, 26th, 38th
and 42nd weeks. Compared with a mean baseline level of 9.27 mg/dL, the
levels after 1, 26, 38 and 42 weeks were 9.32, 9.35, 9.36 and 9.35 mg/dL,
respectively (standard level: 8.7 to 10.1 mg/dL). A significant decrease
was also noted in 1alpha,25-(OH)2D3 and intact PTH,
which regulate calcium metabolism (Fig.
4). A significant decrease in intact PTH levels was noted after 1
to 14, 26, 42, 46 and 54 weeks, and a significant decrease in 1alpha,25-(OH)2D3
levels was noted after 2 to 54 weeks. The serum tacalcitol level was measured
8 times at the beginning and after 2, 4, 8, 14, 26, 38 and 54 weeks, and
in 48 of the 154 subjects, tacalcitol was detected in at least 1 of these
measurements.
In the laboratory tests, 155 abnormal changes were noted in 85 of the
154 subjects (55.2%). Of these, a causal relationship with the study drug
was determined for GPT increase in 1 event and decrease in the serum intact
PTH in 5 events.
In 1 subject in whom the corrected serum calcium level reached the discontinuation
criteria (11.0 mg/dL or higher) and in 5 subjects whose serum creatinine
level reached the discontinuation criteria (1.5 mg/dL or higher), the
study (the treatment application) was discontinued. However, since the
increase was small in each case, these changes were not determined to
be abnormal changes. No causal relationship between the increase and the
study drug was determined.
Discussion
High efficacy of tacalcitol 20 mug/g ointment in long-term topical administration
was demonstrated by means of assessments using the PASI score and the
global improvement rating. In the 74 subjects who applied the ointment
once daily for 54 weeks and who were subjected to the efficacy analysis,
the mean PASI score decreased from a baseline of 22.49 ± 10.20 (mean
± SD) to 8.17 ± 6.04 after 8 weeks of application, a decrease
of approximately 60%, and was 5.73 ± 6.04 at the end of the study,
after 54 weeks. In long-term repeated administration of topical steroid
preparations, tachyphylaxis, i.e., gradual decrease in drug effect
due to long-term administration of the same drug, has been reported, but
no tachyphylaxis was observed in 54-week application of the 20 mug/g tacalcitol
ointment.
The main concern in the use of the tacalcitol 20 mug/g ointment is the
possibility of hypercalcemia, induced when tacalcitol is transferred into
the blood. A constant calcium concentration in the blood is strictly maintained,
principally by PTH and 1alpha,25-(OH)2D3, through
promotion of bone resorption, renal excretion, and intestinal absorption
of calcium and inorganic phosphorus and so forth. In this study, the maximum
daily dose of tacalcitol was restricted to 200 mug. Because tacalcitol
was detected in the blood of some subjects and because a decrease in the
serum levels of intact PTH and 1alpha,25-(OH)2D3
was observed, it seems that tacalcitol was percutaneously absorbed and
transferred into the blood, resulting in activation of the calcium regulatory
mechanism. Nevertheless, the mean level of the serum calcium remained
within the standard level (8.7 to 10.1 mg/dL) and even the maximum level
of 9.36 ± 0.36 mg/dL (mean ± SD), seen in the 38th week, did
not significantly deviate from the mean baseline calcium level of 9.27
± 0.39 mg/dL. It seems, therefore, that the homeostasis of the serum
calcium could be maintained. However, if the dose applied exceeds 10 g/day,
the serum calcium level may naturally increase. Increase in the applied
dose of a similar drug, calcipotriol 50 mug/g ointment, was reported to
induce a decrease in intact PTH and 1alpha,25-(OH)2D3
and a tendency toward loss of calcium homeostasis, and the dosage should
be cautiously monitored [12-16]. In a similar manner, the daily dose of
tacalcitol 20 mug/g ointment should also be restricted to a maximum of
200 mug tacalcitol. In addition, the present study revealed that the dose
decreased along with study duration.
Because regulation of calcium metabolism may be inadequate in some patients
with impaired renal function, increase in the blood calcium may occur
in such cases. No patients with moderately or severely impaired renal
function were included in this study, and application of the ointment
was discontinued if the creatinine level exceeded 1.5 mg/dL. In the review
of laboratory test results in each subject after the end of the study,
the application at 10 g/day was found to affect the serum calcium level,
although the change remained within the standard range, in the subjects
with mildly reduced renal function. Moreover, it is clinically predictable
that the renal function has decreased in patients who are under concomitant
use or have a history of use of drugs known to cause renal dysfunction,
such as cyclosporine. In such cases, laboratory tests should be conducted
before and during the treatment with tacalcitol 20 mug/g ointment, and
the renal function and serum calcium should be intensively monitored.
The adverse drug reactions seen in this study were symptoms known to
be associated with conventional tacalcitol topical preparations [17] (ointment,
cream and lotion), such as itching, feeling irritated, application site
irritation, redness, swelling and pigmentation, all of which were mild
to moderate. In clinical studies of calcipotriol conducted in Japan, folliculitis
[18], which was not reported in connection with tacalcitol 20 mug/g ointment,
and severe symptoms of skin irritation (irritation, itching [19]) were
reported. Moreover, the irritancy of calcipotriol is so severe that it
is generally believed that, because of the high incidence of adverse events,
it should not be applied to the face [20]. On the other hand, tacalcitol
20 mug/g ointment was applied to the scalp of 74 out of 154 subjects in
this study. Since there was no particular difference in the severity of
the irritation symptoms that appeared on the scalp and on other areas,
it is considered that, as with tacalcitol 2 mug/g ointment, the 20 mug/g
ointment can also be applied to the scalp (face). More-over, no area-specific
symptoms were observed and the severity was area-independent.
As shown in Table III,
23 of the cumulative 29 events (79.3%) of adverse drug reactions, such
as itching, feeling irritated, irritation, redness and swelling, appeared
within the first 21 days of the treatment, which tended to decrease with
the improvement in the eruption. Neither unknown adverse events due to
long-term administration nor increase in the incidence of known adverse
events was observed.
No abnormal laboratory change was found in any of the subjects. In 1
subject, the corrected serum calcium level increased from 10.0 mg/dL at
baseline to 11.6 mg/dL after 10 weeks, and the treatment was discontinued
in accordance with the discontinuation criteria (11.0 mg/dL or higher).
There were no particular clinical symptoms, and 2 weeks after the discontinuation
of the study drug, the corrected serum calcium level returned to within
the standard level. This patient was concomitantly treated with a digestant
containing precipitated calcium carbonate, and the increase in the corrected
serum calcium level might result from interactions with the concomitantly
used drugs.
CONCLUSION
In conclusion, tacalcitol 20 mug/g ointment, applied once daily at doses
of up to 10 g (200 mug tacalcitol), is safe and effective, even for long-term
administration, in the treatment of patients with psoriasis vulgaris.
Serum calcium should be monitored in patients with decreased renal function
and other suspected impairment of calcium metabolism, before and during
the treatment with tacalcitol 20 mug/g ointment.
Acknowledgements
We gratefully acknowledge Dr. Masataka Shiraki for his advice.
The following investigators also participated in the study: H. Iizuka,
Y. Hashimoto, M. Kinouchi, H. Shimizu, H. Kobayashi, T. Matsumura, T.
Kawashima, K. Tamai, J. Kimura, T. Akasaka, T. Sato, S. Mayama, H. Tagami,
H. Ozawa, M. Funayama, Y. Mitsuhashi, M. Kawaguchi, F. Kaneko, K. Iwatsuki,
F. Ohtsuka, H. Fujisawa, O. Ishikawa, K. Ohnishi, M. Abe, T. Morishima,
Z. Yamaguchi, S. Watanabe, T. Nakagomi, H. Mori, M. Iijima, H. Sueki,
A. Igarashi, H. Kitahara, M. Kawashima, N. Kanda, Y. Igarashi, R. Okamoto,
T. Nishikawa, M. Tanaka, T. Murata, M. Koga, T. Ohi, Y. Okubo, Y. Umezawa,
H. Suzuki, S. Uchigasaki, M. Tan, T. Eto, Y. Todoroki, S. Kawana, E. Aoki,
H. Ogawa, H. Yaguchi, M. Komine, N. Hayashi, A. Asahina, K. Nishioka,
K. Otoyama, M. Niimura, R. Kamide, A. Kitada, K. Katsuoka, T. Ohkawa,
A. Ozawa, J. Sugai, K. Iwashita, M. Mizoguchi, M. Ito, S. Ohhashi, H.
Nakajima, N. Ishii, M. Ito, K. Ito, M. Minagawa, M. Morohashi, T. Seki,
M. Toyoda, K. Takehara, S. Kawara, M. Inaoki, H. Ishizaki, T. Mochizuki,
K. Takeda,S. Shimada, A. Saito, Y. Kitajima, H. Aoyama, M. Takigawa, S.
Moriwaki, H. Wakita, Y. Tomita, Y. Matsumoto, T. Tsuji, A. Morita, M.
Shimizu, H. Mizutani, K. Isoda, M. Uehara, K. Danno, H. Yasuno, K. Yamanishi,
K. Toda, M. Ishii, H. Kobayashi, K. Fukai, K. Yoshikawa S. Sano, T. Horio,
H. Okamoto, T. Tezuka, H. Endo, M. Ichihashi, S. Harada, M. Oka, M. Kitano,
M. Natsuaki, J. Arata, W. Fujimoto, H. Ueki, M. Kohda, M. Yamaguchi, S.
Yamamoto, O. Kohro, Y. Yamamura, S. Arase, Y. Nameta, Y. Kubota, T. Moriue,
K. Hashimoto, Y. Shirakata, H. Kodama, M. Ikeda, T. Hashimoto, N. Yamamoto,
J. Nakayama, Y. Kubota, Y. Egami, M. Furue, S. Yasumoto, H. Terao, T.
Ono, Y. Inoue, T. Kanzaki, S. Yotsumoto, K. Usuki.
Article accepted on 13/7/02
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