MC 9101 F Study Page3 ABSTRACT Background: Cyclosporin A has been shown to be an effective systemic treatment in severe psoriasis but with the disadvantage of dose-dependent toxic effects particularly on the renal and cardiovascular systems. Calcipotriol, a recently discovered vitamin D analogue, is an effective topical agent in mild to moderate psoriasis. A combination of calcipotriol with cyclosporin A in severe psoriasis could offer enhanced efficacy with the possibility of reducing the dose and therefore the toxicity of cyclosporin A. Objectives: To compare the efficacy, safety and tolerability of the combination of calcipotriol ointment and oral cyclosporin A (CSA) with that of the combination of placebo ointment (vehicle of calcipohiol) and oral cyclosporin A in patients suffering from severe psoriasis. Patients and methods: This was a multicentre, prospective, randomised, double-blind, placebo-controlled, parallel group study consisting of a 2-week wash-out phase and a 6-week treatment phase. Patients were assessed every 2 weeks. Adult patients of either sex who had a diagnosis of psoriasis vulgaris cove~g :s SO% of body surface and with a P ASI score ~ 20 were recruited by 20 dermatologists in France and Belgium. Eligible patients were treated with calcipotriol {50 J,Lg/ g) or placebo ointment together with oral CSA in a dose of 2 mg/ kg/ day. The ointment was applied twice daily without occlusion and cyclosporin A was also taken in two divided daily doses. Patients who achieved the primary criterion for response i.e.: complete clearance or a reduction in P ASI equal to or greater than 90% of their baseline value at any visit were considered to have completed the study. Results: Seventy seven patients were recruited, 69 of whom were randomised, 35 to calcipotriol + CSA and 34 to placebo + CSA. The treatment groups were comparable with respect to age, sex-ratio and history of psoriasis and the mean PAS! before treatment was 24.7 in the calcipotriol + CSA group and 25.4 in the placebo + CSA group. This document has been do\\'n loaded from ww w.teo-pharma.com subject to the terms of use state on the website. It contains data and results regarding approved and non-approved uses, formulations or treatment regimens, and it is provided for transpar ency and informational purposes only. The content does not reflect the complete results from au studies related to a product. As a docwnent of scientific nature it is not to be see:n as a recommendation or advice regarding the use of any products and you must always consult the specific prescribing information approved for the product prior to any prescription or use.
Page 4 MC 9101 F Study There were 32 patients eligible for efficacy analysis in the calcipotriol + CSA group and 34 in the placebo + CSA group. The number of patients who achieved "complete clearance" or a reduction in PASI of 01: 90% was 16 (50.0%) in the calcipotriol + CSA group and 4 (11.8%) in the placebo + CSA group (p <0.001; 95% confidence interval for between group difference 17.8% - 58.7% ). The reduction in P ASI between baseline and end of treatment was statistically significant in both groups: 20.3 (80.4%) in the calcipotriol + CSA group and 14.6 (58.3%) in the placebo+ CSA group(p = 0.004; 95% confidence interval for between group difference 7.1% - 37.0% ). In both patient and investigator overall assessments of treatment responses the results for caldpotriol + CSA were statistically significantly better than those for the placebo + CSA (84.4% v 64.7% achieving "clearance" or "marked improvement" as assessed by patients; 87.5% v 58.8% achieving "clearance" or "marked improvement" as assessed by investigators). Thirty adverse events (AE) were reported by 18 patients in the calcipotriol + CSA group and 25 AE's reported by 19 patients in the placebo+ CSA group (p > 0.50). Lesional or perilesional irritation was the most frequently encountered adverse event. It accounted for 27% of the 30 reported adverse events in the calcipotriol + CSA group and 24% of the 25 adverse events in the placebo+ CSA group. Three patients were withdrawn from the trial because of adverse events; 1 in the calcipotriol + CSA group [hypertriglyceridaemia) and 2 in the placebo + CSA group [pyelonephritis due to lithiasis (1 case) and muscular pain (1 case)). The results of the haematological and biochemical investigations did not reveal any clinically relevant unexpected outcome. Conclusions: The results obtained in this study in terms of efficacy, safety and tolerability suggest that the combination of calcipotriol and low dose cyclosporin A may be a useful treatment for severe psoriasis.
MC 9101 F Study Page 17 EXPANDED SUMMARY PROTOCOL SYNOPSIS Study objectives: To compare the efficacy, safety and tolerability of the combination of calcipotriol ointment and oral cyclosporin A (CSA) with that of the combination of placebo ointment (vehicle of calcipotriol) and oral cyclosporin A in patients suffering from severe psoriasis. Study design: A multicentre, prospective, randomised, double- blind, placebo- controlled parallel group study with 2 phases: 1) a wash-out phase lasting at most 2 weeks, and 2) a treatment phase with the combination calcipotriol (or placebo) ointment+ cyclosporin A lasting at most 6 weeks. There were assessment visits every 14 days for 6 weeks after starting double-blind treatment. Patient eligibility criteria: Out-patients or in-patients of either sex aged between 18 and 65 who presented with severe psoriasis (a PASI score of~ 20) and affected areas not exceeding 50% of the body surface and for whom treatment with cyclosporin A was indicated. Patients gave signed informed consent. Women likely to become pregnant had to use a suitable method of contraception. Patients who had guttate psoriasis, pustular psoriasis, palmar-plantar psoriasis or erythrodermic psoriasis and patients who received systemic or UV treatment for psoriasis during the previous 4 weeks were ineligible. Other reasons for exclusion were: topical treatment for psoriasis in the 2 weeks preceding visit 2,concomitant therapy likely to interfere with the study treatments or with the disease, pregnancy, breast feeding, vitamin D or calcium supplementation, intolerance to calcipotriol or cyclosporin A or exdpients, hypercalcaemia, abnormally high serum creatinine level, serum ASA Tor ALAT, alkaline phosphatase, total cholesterol or triglyceride level >2 times the upper limit of the normal range, recent or current infection, uncontrolled heart failure, neoplastic disease or immunodeficiency, weight <50 or~ 100 kg, systolic BP >160 mmhg or diastolic BP >95 mmhg, exposure to sun which might affect the course of the disease, participation in another trial in the preceding month.
Page 18 MC 9101 F Study Study drugs: Calcipotriol ointment 50 JA.g/ g and placebo ointment (vehicle of calcipotriol ointment) with identical appearance and consistency. The ointments were supplied in identical tubes of 30 g and were given to the patients at each visit in a quantity sufficient for use until the next visit. The maximum dosage was 4 tubes of 30 g of calcipobiol (or placebo) ointment per week. The ointment was uniformly applied on psoriatic lesions twice daily, in the morning and evening, with an interval of 12 hours, until there was complete clearance or a reduction in P ASI ~ 90% of baseline value or until the end of the 6-week treatment phase. No occlusion was used. The ointment was not to be applied to the face, the scalp, the genital region or skin folds. These regions could be treated with a topical corticosteroid of medium strength. Cyclosporin A 25 mg capsules, [SANDIMUN (Laboratoires SANDOZ)] were prescribed at each visit in a quantity sufficient to cover the time until the next visit. The dose of CSA prescribed was as close to 2 mg/kg/ d as possible. The capsules were taken every day, in the morning and evening, with an interval of 12 hours. The dose was kept constant throughout the 6-week treatment course, except in the case of the appearance of a side effect, which required a reduction of the dose of CSA, or the end of its administration, if necessary. An emollient [XERODERM (Laboratoires ROCHE POSAY)] in 125 g tubes was supplied at all centres for use during the wash-out phase. Sample size: The sample size calculation was based on an expected difference of 35% between the two groups in mean reduction of the P ASI (Psoriasis Area and Severity Index) between baseline and the end of the study, a standard deviation of 45% for this reduction in PASI, a type I error of 0.05 (a=5%) and a power of 80% (type II error, ~=20%) and showed that 6i patients (31 in each group) needed to be recruited to the study. Primary criterion for efficacy: The number of patients with complete clearance or with reduction in PASI equal to or greater than 90% of the baseline value.
MC 9101 F Study Page19 Assessments: The extent and severity of psoriasis for each patient were evaluated by the investigator at each visit using the Psoriasis Area and Severity Index (P ASI). The investigator and the patient had to give their overall evaluation of response to treatment compared to baseline after 2, 4 and 6 weeks of treatment. For the purpose of this evaluation, the patient and the investigator used a S point scale ("worse", "no change", "slight improve ment", "marked improvement", "completely cleared"). Adverse events were recorded by the investigator posing a non-leading question at visits 3, 4 and 5. Adverse events were scored for severity and estimated causal relationship to treatment with study drugs. A chest X-ray and 12-lead electrocardiogram were performed before starting treatment. Laboratory tests were performed as follows: a) serum levels of calcium (total), phosphate, creatinine, sodium, potassium, chloride, alkaline reserve, and blood urea {at all visits), b) serum levels of alkaline phosphatase, ALAT and ASAT, fasting total cholesterol and triglycerides (at visits 1, 2, 3, and 5), c) blood haemoglobin, red and white cell counts, differential wee, and platelet count at visits 1, 2 and 5. RESULTS SYNOPSIS Study population Seventy-seven patients were recruited by dermatologists in 20 centres in Belgium and France between October 27th 1991 and April 10th 1992. Eight patients were not randomised as 6 refused to continue in the study and in two others an exclusion criterion appeared during the wash-out phase. Thus, 69 patients were randomised, 35 to the caldpotriol + cydosporin A group and 34 to the placebo + cyclosporin A group.
Page 20 MC 9101 F Study Baseline characteristics of two treatment groups: The two treatment groups were comparable with respect to age, sex-ratio, duration of psoriasis, and extent and severity of psoriatic lesions evaluated using PASI as shown in the table below. Calcipotriol + CSA Placebo + CSA (n = 35) (n = 34) Age (years) Mean (SD) 44.2 (14.0) 43.3 (12.0) Range 20-67 24-76 Sex-ratio No. of men (%) 23 (65.7) 24 (70.6) No. of women (%) 12 (34.3) 10 (29.4) Duration of psoriasis (months) Mean (SD) 188.1 (123.3) 206.8 (99.1) Range 14-480 24-396 PASI Mean (SD) 24.7 (6.57) 25.4 (4.16) Range 6.20-45.50 20.40-39.60 Previous therapy for psoriasis was similar in both groups. Forty four percent of the calcipotriol + CSA group and 53% of the placebo + CSA group had been previously treated with steroids. The corresponding figures for irradiation were 38% and 47% while 38% and 41% respectively had received retinoid treatment. Three patients were ineligible for the efficacy analysis due to a P ASI of 6.2 in one case and failure to use the trial medication in two others.
MC 9101 F Study Page21 EFFICACY Number of patients with complete clearance or improved by at least 90% of baseline P ASI at the end of treatment At the end of double-blind treatment, the number of patients who achieved the primary response criterion [a) complete clearance or b) reduction in P ASI ;a: 90%] was compared between the treatment groups. In 16 patients out of 32 (50.0%) in the calcipotriol + CSA group and in 4 patients out of 34 (11.8%) in the placebo + CSA group the primary response criterion was achieved (p < 0.001; 95% confidence interval for between group difference 17.8% ~ 58.7%).
Page 22 MC 9101 F Study Change in PASI PAS I: The change in P ASI from start of treatment with calcipotriol + CSA or placebo + CSA to the end of treatment is presented in the table below for all patients analyzed for efficacy. Reduction in PASI from baseline to end of treatment Calcipobiol + CSA (n = 32) Placebo +CSA (n = 34) P value Diff. in mean change (95% conf.int) VISIT 2 (BASELINE) PASI Mean (SD) Range Number 25.25 (5.90) 20.0-45.5 32 25.35 (4.16) 20.4-39.6 34 END OF TREATMENTPASI Mean (SD) Range Number 4.88 (6.79) 0.0-25.7 32 10.71 (8.98) 0.0-41.0 34 Mean reduction (SO) Range Number Prob of change within group 1 > Number Equality between treatments 2 l 20.37 (8.55) 23.4 17.2 <0.001 32 14.64 (8.58) 17.6 11.6 <0.001 34 0.008 5.73 9.94 1.51 Mean percentage reduction (SD) Upper CL Lower CL Prob of change within group 1 > Number Equality between treatments 2 > 80.45 (27.52) 90.3 70.5 <0.001 32 58.35 (32.84) 69.8 46.8 <0.001 34 0.004 22.09 37.04 7.15 1) 2) -. One sample t-test Two sample t-test Overall assessment of response to treabnent by patients and investigators Patient's overall assessment of treatment response: The patient gave his/her overall assessment of the treatment response at each visit following start of randomised treatment. Patients' overall assessments at the end of treatment in both treatment groups are as follows:
MC 9101 F Study Page23 Patient's overall assessment of response at end of treatment Calcipotriol Placebo PI) + + CSA CSA (n = 32) (n = 34) Worse 0 4 No change 2 1 0.005 Slight improvement 3 7 Marked improvement 14 18 Completely cleared 13 4 Not assessed 0 0 l) Wilcoxon test, exact p-value, excluding "not assessed" At the end of the trial84.4% of patients considered themselves "completely cleared" or "marked improvement" in the calcipotriol + CSA group versus 64.7% in the placebo+ CSA group. Investigator's overall assessment of response at end of treatment I Calcipobiol Placebo PI) + + CSA CSA (n = 32) (n = 34) Worse 0 3 No change 2 2 0.001 Slight improvement 2 9 Marked improvement 16 17 Completely cleared 12 3 Not assessed 0 0 t) Wilcoxon test, exact p-value, excluding "not assessed" At the end of the trial, 87.5% of patients were assessed by the investigators as "completely cleared" or "marked improvement" in the calcipotri.ol + CSA group versus 58.8% in the placebo group. These figures are consistent with the patients' assessments. Two patients in the placebo + CSA group were withdrawn from the study due to worsening of their psoriasis.
Page 24 MC 9101 F Study SAFETY AND TOLERABILITY Adverse Events Thirty adverse events (AE's) were reported by 18 patients in the calcipotriol + cyclosporin A group and 25 adverse events were reported by 19 patients in the placebo+ cyclosporin A group. In the reported AE's there is no difference between the groups as regards the number of patients, the types of reactions reported, or whether the reactions were observed by the patient or the investigator. Lesional or perilesionaj irritation was the most frequently reported adverse event. It accounted for 27% of the 30 reported adverse events in the calcipotriol + CSA group and 24% of the 25 adverse events in the placebo+ CSA group. Three patients were withdrawn from the trial because of the occurrence of adverse events: 1 in the calcipotriol + CSA group [hypertriglyceridaemia] and 2 in the placebo + CSA group [pyelonephritis due to lithiasis (1 case) and muscular pain (1 case)]. Laboratory Results The results of the haematological and biochemical investigations did not reveal any clinically relevant unexpected outcome. Statistically significant elevations in mean creatinine, urea, potassium, cholesterol and ASA T levels were seen at some visits.
MC 9101 F Study Page 25 CONCLUSIONS Caldpotriol ointment (50 11g/ g) applied twice daily in combination with cyclosporin A orally (2 mg/kg/ d) over 6 weeks resulted in: complete clearance or a reduction in PASI of:~: 90% in 50.0% of caldpotriol + CSA treated patients compared to 11.8% in patients treated with placebo + CSA, a mean reduction in PASI of 80.4% in the active group as compared to 58.3% in the placebo group. The adverse event profile seen with the combination of caldpotriol + cyclosporin A is not significantly different from that expected from the known profile of these drugs used individually. No potentiation of adverse events was observed. The results obtained in this study in terms of efficacy, safety and tolerability suggest that the combination of caldpotriol and low dose cyclosporin A may be a useful treatment for severe psoriasis.