MC 590 ABSTRACT. PageS

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1 This docwnent has OOen dov,nloaded from 'W'W'\VJ eo-pharma.c-om subject to the terms of use state on the website. It contains data and results regarding approved and non-approved uses, formulations or tre-atment regimens, and it is provided for transparency and informational purposes only. The content does not reflect the complete results from all studies related to a product. As a document of scientific nature it is notto be seen as a recommendation or advic-e regarding the use of any products and you must always consult tlle sp~ific prescribing information approved for the product prior to any prescription or use. ABSTRACT MC 590 PageS The antipsoriatic efficacy, safety and tolerability of two treatment regimens: calcipotriol ointment + PUV A and placebo ointment + PUV A were compared in a multicenter, prospective, randomised, double- blind, placebo-controlled, parallel group study. Patients with psoriasis vulgaris covering li!: 20% and s 50% of body surface area were recruited by 21 dermatologists in France and Belgium. Following a 1-2 week wash-out period, eligible patients started treatment with calcipotriol (50 ~g/ g) or placebo ointment alone for 2 weeks, both applied twice daily without occlusion. A maximum of 120 g ointment was provided for one weeks treatment Thereafter, treatment was continued with concomitant PUV A for up to 10 weeks. PUV A treatment was given 3 times weekly. The dose of UV A was increased stepwise until i) a predetermined maximum UV A dose was reached, ii) an adverse event appeared or iii) the target treatment response (ltr): >90% reduction of baseline PASI was achieved. Fifty-four patients were assigned treatment with calcipotriol ointment plus PUV A and 53 patients received placebo ointment plus PUV A. Forty-six patients in the calcipotriol group and 45 patients in the placebo group could be analysed for efficacy. The two groups were well matched at baseline for age, sex and history of psoriasis. However, mean baseline P ASI was significantly higher in the caldpotriol group than in the placebo group, 19.2 vs. 155 (p = 0.01). 71.7% (33/ 46) in the calcipotriol and 55.6% (25 I 45) in the placebo group achieved the TTR, p = 0.11 (95% confidence interval for difference % ). In this subset of patients a non-significant reduction in the need for UV A irradiation was observed in the calcipotriol group: i) 26% reduction in mean cumulative UVA dose (32.1 Joule/cm 2 for calcipotriol vs Joule/ cm 2 for placebo), p = 0.20, ii) 19% reduction in the average number of UV A irradiations given (12.5 vs. 15.4), p = 0.13 and iii) 15% reduction in average duration of PUV A treatment (31.8 days vs days), p = A statistically significant reduction in the need for UV A irradiation was observed in the total group of patients analysed for efficacy: i) 37% reduction in mean cumulative UV A dose (32.1 Joule/ c:m2 for calcipotriol vs Joule/ cm2 for placebo), p = 0.016, :ii) 26% reduction in the average number of UV A irradiations given (12.7 vs. 17.1), p = 0.01 and iii) 24% reduction in the average duration of PUVA treatment (32.0 days vs days), p = P ASI was reduced by 91% (mean) in the calcipotriol group and by 76% in the placebo group, p = 0.0~3 (95% confidence interval for difference 3-28% ). Nineteen patients treated with caldpotriol + PUV A reported a total of 28 adverse events (20 "possibly" or "probably" Ielated to treatment) as compared with 21 adverse events (14 "possibly" or "probably" related to treatment) reported by 19 patients in the placebo group. Lesional/ perilesional application

2 Page 6 MC 590 Study related irritation was the most common adverse event in both.treatment groups: 16.7% for calcipotriol and 20.8% for placebo. One patient withdrew from the calcipotriol group and 4 patients withdrew from the placebo group because of adverse events. There was no change in mean serum calcium in either treatment group. One patient was withdrawn from the calcipotriol group due to hypercalcaemia (0.11 mmol/1 above the upper limit of the reference range). It is concluded that combined treatment with calcipotriol ointment and PUV A is highly effective and is safe and well tolerated for the treatment of extensive plaque psoriasis. Pre-treatment with - and subsequent addition of - calcipotriol ointment to PUV A did not significantly reduce the cumulative dose of UV A irradiation given to the subset of patients who achieved the target treatment response. However, when all patients analysed are considered calcipotriol significantly reduced the total dose of UV A.

3 MC 590 Study Page9 0 EXPANDED SUMMARY AND CONCLUSIONS PROTOCOL SYNOPSIS Study objectives: To compare the efficacy, safety and tolerability of caldpotriol ointment + PUV A therapy with that of placebo ointment (i.e. vehicle of calcipotriol} + PUV A therapy in patients with psoriasis vulgaris. Study design: This was a multicenter, prospective, randomised, double-blind, placebo-controlled, parallel group comparison of calcipotriol ointment and placebo in combination with PUVA therapy. The study was divided into 3 phases: 1) a wash-out/qualification phase lasting up to 2 weeks during which patients received an emollient to use as required; 2) an initial double-blind treatment phase lasting 2 weeks during which treatment with caldpotriol or placebo ointment only was used and 3) continued double-blind treatment with calcipotriol or placebo ointment together with concomitant PUVA therapy for up to 10 weeks. Patients attended control visits at 2-week.Iy intervals throughout the study. Eligibility criteria: Hospital out-patients of either sex, aged c: 18 years with psoriasis vulgaris covering c: 20% and sso% of body surface area. Main exclusion criteria were a) systemic use of antipsoriatic treatment or UV radiation within 8 weeks prior to entry, b) acute guttate or pustular psoriasis, c) hypercalcaemia, d) impaired renal or hepatic function and e) intake of caldum tablets or >400 IU vitamin D per day. During the study patients were not permitted other topical or systemic treatment which could affect the course of the disease. All patients gave their signed informed consent to join the study. Study drugs: Calcipotriol ointment 50!J.g/ g and placebo ointment (vehicle of caldpotriol ointment). Ointments were applied twice daily without occlusion. A maximum of 120 g ointment was provided per week. PUV A therapy was given using 8-methoxypsoralen (8-MOP) 0.6 mg/ kg 2 hours before irradiation. UVA dose: UVA dose was started at 1.5 Joule/ cm 2 (skin type ll: always burn, then slight tan) or 2 Joule/ cm 2 (skin type III: sometimes burn, always tan) and increased

4 Page 10 MC 590Study by 0.5 Joule/ cm2 after every two irradiations until a) the target treatment response was achieved or b) a maximum UVA dose of 8.5 Joule/cm 2 (skin type ll) or 9 Joule/ cm 2 (skin type lll) was reached or c) an adverse event appeared. Target treatment response (TTR) was defined as: a) clearance of the patient's psoriasis or b) reduction of >90% of baseline PASJ (Psoriasis Area and Severity Index) Sample size: Based on an assumed value of 97 Joule/ cm 2 for the cumulative dose of UV A needed to reach the TIR in the control group (SD of mean dose needed in the control group = 50 Joule/ cm 2 ), it was calculated that 44 analysable patients in each group would be required to demonstrate that the true difference between the caldpotriol and placebo group is 30 Joule/cm 2 with statistical power 80% and significance level 5% (two- tailed). According to the study protocol, a total of 100 patients were to be randomised in the study. Primary response criterion: The cumulative dose of UV A necessary to achieve the TIR. Assessments: The extent and severity of patients' psoriasis was assessed by the investigator at each visit (i.e. every 2 weeks) using the PASI. The patients gave their assessment of the overall treatment response at each visit after start of double-blind treatment. Adverse events were elidted at all visits after start of treatment and routine laboratory parameters (including serum calcium (total)) were to be measured at commencement of the wash-out/ qualification phase and after 2, 4, 8 and 12 weeks treatment. RESULTS Study population: From 6 December, 1990 to 17 June, 1991, a total of 110 patients were recruited for the study. Three (2.7%) patients were withdrawn during the wash-out/ qualification phase. Therefore, 107 patients started double- blind treatment, 54 with calcipotriol and 53 with placebo.

5 MC 590 Study Page 11 Three patients (2 caldpotriol, 1 placebo) had unscheduled PUV A treatment and 1 patient (placebo) had unscheduled ointment treatment during the wash- out/ qualifi. cation phase. These four patients have been included in the analysis of safety but not in the efficacy analysis. In addition, 12 patients (6 patients on caldpotriol and 6 patients on placebo) lef the study for various reasons before starting PUV A combination therapy. These patients have been included in the safety analysis but have been excluded from the efficacy analysis. Exclusion of the patients did not influence the conclusions drawn from the study. Therefore, 107 patients have been analysed for safety and 91 patients who received combination therapy with calcipotriol (n = 46) or placebo (n = 45) ointment and PUV A have been included in the efficacy analysis. Baseline comparability of treatment groups: The two groups were well matched at baseline for age and sex, duration of psoriasis, previous/ current anti psoriatic treatment and skin type. The use of non-psoriatic drug treatment was also similar in the two groups. However, the mean P ASI at baseline was significantly higher in the calcipotriol group: 19.2 than in the placebo group: 15.5 (p = 0.01). EFFECT ON PSORIASIS Thirty-three patients (33/ 46 patients analysed for efficacy = 71.7%) in the caldpotriol group and 25 patients (25/45 patients analysed for efficacy= 55.6%) in the placebo group reached the TIR (see page 10), p = 0.11 (95% confidence interval for difference % ). Cumulative dose of UV A used, number of UV A irradiations given and duration of treatment: The table below summarizes the results in the two treatment groups fori) patients who achieved the TTR and ii) all patients analysed for efficacy.

6 Page 12 MC 590 Study Effed of treatment with calcipotriol + PUV A and placebo + PUV A on patients' need for UV A irradiation The was no significant difference in the need for UV A irradiation between the two treatment groups for the patients who achieved TIR. When all patients eligible for efficacy analysis are included, the caldpotriol group required a 37% lower cumulative dose of UV A (32.1 Joule/ cm 2 for caldpotriol vs for placebo), p = 0.016, 26% fewer irradiations (12.7 vs. 17.1), p = 0.01, and 24% shorter duration of treatment (32.0 vs days), p = 0.02, than the patients in the placebo group. PASI: The change in PASI from start of treatment with caldpotriol or placebo ointment alone to end of combi~ed treatment with ointment plus PUV A is presented in the table below for all patients analysed for efficacy:

7 MC 590 Study Page 13 Change in PASI from baseline to end of combined treatment (phase Ill) The reduction in PASI between baseline and end of combined treatment was significant in both treatment groups (17.3, 91.4% in the caldpotriol group and 11.4, 75.7% in the placebo group). The reduction was significantly greater in the calcipotriol group, p = (95% confidence interval for difference %). Patient's overall assessment of treabnent response: The patient gave his/her overall assessment of the treatment response at each visit following start of randomised treatment.

8 Page 14 MC 590 Study Ninety-one per cent of the caldpotriol treated patients reported "marked improvement" or "complete clearance" as against 76% in the placebo group. AMOUNT OF OINTMENT USED The mean amount of ointment used in the caldpotriol group varied from 62.1 g per week during weeks 0-2 and 37.5 g per week during weeks 6-8. SAFETY Adverse events: A total of 28 adverse events (20 of which were considered "possibly" or "probably" related to the assigned treatment) were reported by 19 (35.2%) calcipotriol + PUVA treated patients. Nineteen (35.8%) placebo + PUV A treated patients reported a total of 21 adverse events (14 of which were considered to be "possibly" or "probably" related to the study treatment), p = Virtually all adverse events were "skin and appendage disorders" (according to "WHO System Organ Oass"): 23/28 reports in the calcipotriol group and 21/21 reports in the placebo group. Percentage patients reporting adverse events after randomisation

9 MC 590 Study Page 15 The following adverse events caused withdrawal from the study: "Burning sensation" (placebo, 2patients), "eczema" (caldpotriol, 1 patient), "burning sensation/ulceration" (placebo, 1 patient) and "mild irritation at application" (placebo, 1 patient). Laboratory examinations: There was no evidence that haemopoietic, hepatic or renal functions were adversely affected by either treatment. There was no change in mean serum calcium in either treatment group. One patient in the calcipotriol group was withdrawn because hypercalcaemia (0.11 mmol/1 above the upper limit of the reference range). Patients withdrawn from randomised treabnent: A total of 23 (21.5%) out of the 107 patients starting randomised treatment were withdrawn from the study. Ten patients withdrew from the caldpotriol group (6 prior to and 4 after starting PUV A therapy} and 13 patients withdrew from the placebo group (6 prior to and 7 after starting PUV A therapy). Deterioration of patients' psoriasis was the most common reason for withdrawal (3 calcipotriol and 4 placebo}, followed by adverse events (1 caldpotriol and 4 placebo), bad compliance (2 caldpotriol and 1 placebo), default (1 caldpotriol and 2 placebo), voluntary withdrawal (2 calcipotriol and 1 placebo), and hypercalcaemia (1 caldpotriol and 0 placebo). One patient in the placebo group left the study because of hospitalisation unrelated to the study. CONCLUSIONS The present study demonstrated that combined treatment with calcipotriol ointment and PUV A is highly effective and is safe and well tolerated for the treatment of extensive plaque psoriasis. Pre-treatment with - and subsequent addition of - caldpotriol ointment to PUV A did not significantly reduce the cumulative dose of UV A irradiation given to the subset of patients who achieved the target treatment response (>90% reduction of PASI). However, when all patients analysed are considered caldpotriol significantly reduced the total dose of UV A.