11 August 2000 Page 17 of 181. Subtitle A prospective, multicentre, randomised, double-blind, vehicle-controlled, parallel groupr comparative study.

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1 Study MCO 9604 DE 11 August 2000 Page 17 of SYNOPSIS Study Code MCO 9604 DE. Title Addition of Daivonex (calcipotriol) ointment (50 J.Lg!g) to fumaric acid therapy in patients with severe psoriasis vulgaris. Subtitle A prospective, multicentre, randomised, double-blind, vehicle-controlled, parallel groupr comparative study. Study objectives To investigate whether the addition of calcipotriol ointment to treatment with fumaric acid esters has a fumaric acid ester-sparing effect in patients with severe psoriasis vulgaris. To investigate the safety and tolerability of combined treatment with calcipotriol ointment and systemic fumaric acid esters. Study design A prospective, multicentre 1 randomised, double-blind, vehicle-controlled 1 parallel group comparison of the following treatments: a) fumaric acid esters+ placebo (calcipotriol ointment vehicle) b) fumaric acid esters+ calcipotriol ointment (50 J.!g/g) The study was divided into 2 phases: i) a washout I qualification phase lasting up to 2 weeks and ii) a double-blind treatment phase lasting 13 weeks. _ Number of patients A total of 150 patients was to be recruited to obtain 64 analysable patients per group. This document has been downloaded from 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 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 not to be seen as a rec-ommendation or advice regarding the use of any products and you must ahvays consult the specific prescribing information approved for the product prior to any prescription or use.

2 Page 18 of August 2000 Study MCO 9604 DE Eligibility criteria In-patients and out-patients in hospital clinics, either sex, age ~ 18 years with a clinical diagnosis of severe psoriasis vulgaris for which treatment with fumaric acid esters was deemed appropriate. Females of childbearing potential had to have a negative pregnancy test before randomisation and had to use an adequate method of contraception during the study. Excluded were patients currently undergoing treatment with fumaric acid esters; patients whose psoriasis was markedly deteriorating or spontaneously improving prior to study entry; patients with hypercalcaemia; patients with acute guttate, pustular or erythrodermic psoriasis; pregnant or breast-feeding patients; patients with impaired renal function or with severe gastrointestinal illness. Patients were not permitted to take other medication - topical or systematic - that could affect the course of the disease, with the exception of low or medium potency corticosteroid creams and I or tar based preparations for scalp and face. Study drugs and dosage schedule Calcipotriol ointment (50 llglg) was randomly assigned to one group of patients, placebo (vehicle) ointment to the other. Both ointments were applied twice daily to affected skin areas without occlusion. 120 g of ointment was provided per patient per week. Fumaric acid esters were provided in the form of tablets (Fumaderm P mite ( 105 mg per tablet) and Fumaderm P forte (215 mg per tablet)), with the starting dose being 105 mg (1 tablet Fumaderm P mite) per day. An incremental increase, depending on the patients' requirements and tolerance, took place, and a maximum dose of 1075 mg (5 tablets Fumaderm P forte) per day was not to be exceeded. An emollient cream (Abitima ) was provided for use during the wash-out I qualification and double-blind treatment phases. Primary response criterion Percentage change in Psoriasis Area and Severity Index (PASI) from baseline (visit 2) to end of double-blind treatment.

3 Study MCO 9604 DE 11 August 2000 Page 19 of 181 Assessments The PASI was assessed at each visit. Furthermore, at each postrandomisation visit the invest igator and the patient gave their assessment of the overall response to t reatment. Adverse events were recorded at all post-randomisation visits. Clinical and laboratory parameters were assessed as illustrated in the following table : I Pregnancy Test Medical history * Pregnancy * Assignment of Trial Medication Randomisation Assessment Clinical assessment/ * * * * * * * * * * PASI ( Invest igator) Overall * * * * * * * * * * Efficacy assessment (Investigator and pat ient) Laboratory Assessment s-calcium * * * * * * * * * * * * (total and adjust ed) s-al bum in * * * * * * * * * * * * s-creatinine * * * * * * * * * * * * s-alkaline phosphatase * * * * * * * * * * * * SGOT (ASAT) * * * * * * * * * * * * SGPT (ALAT) * * * * * * * * * * * * y-gt * * * * * * * * * * * * Haematology Total and differential * * * * * * * * * * * * leukocyte blood count Urine Creatinine clearance * * (24 hr urine) Urinary sediment * *

4 Page 20 of August 2000 Study MCO 9604 DE Supply of * * * * * * * * * * Trial medication Collection of * * * * * * * * * * Unused and used Trial medication Adverse Events Recording of adverse * * * * * * * * * * events 1) If the investigator could verify that a patient fulfilled all Inclusion and Exclusion Criteria in all respects, including the necessity of being free of the confounding influence of previous treatment for psoriasis before commencement of the st udy treatment, she/he was allowed to randomise the patient and begin study treatment before the 2-week wash-out period had elapsed. 2) In female patients of child-bearing potential. Results A total of 143 patients were recruited to the study. Nine pat ients were withdrawn before being randomised because they failed one or more criteria for entry to the randomised phase. Therefore 134 patients were include.d in the randomised patient population - 68 to calcipotriol, 66 to vehicle. Subsequent data are available on all 134 patients which comprised the safety population. Two of these patients did not provide efficacy data; the intention-to-treat population therefore comprised 132 patients (68 calcipotriol, 64 vehicle). Eight patients violated one or more eligibility criteria; the per-protocol population therefore includes 124 patients (64 calcipotriol, 60 vehicle). A total of 34 (25.4 %) patients withdrew during the study, 14 (20.6 %) in the calcipotriol group, 20 (30.3 %) in the vehicle group.

5 . i!. '. r ',_,;.. ~. Study MCO 9604 DE 11 August 2000 Page 21 of 181 At baseline the treatment groups were well matched for mean age (43.4 years in the calcipotriol group, 43.6 years in the vehicle group). The proportion of male patients was slightly greater in the vehicle group (64.7% calcipotriol, 75.8% vehicle). The two treatment groups were similar with respect to the distribution of skin type (skin type II or III in 73.5 % of patients in the calcipotriol group and in 72.7 % of patients in the vehicle group). The mean duration of history of psoriasis was also similar between the groups (duration of psoriasis greater than 10 years in 69.1 % of patients in the calcipotriol group and in 68.2 % of patients in the vehicle group). The two treatment groups were also well matched for the percentage change in PASI during the wash-out period between visits 1 and 2 and for PASI at baseline (visit 2). In the calcipotriol group the mean PASI at baseline was 17.4 and in the vehicle group it was 17.7 (intention-to-treat population, see Table 51). Table 51: Percentage change in PAS! score from baseline to end of treatment : intention-to-treat population Calcipotriol (n=68) Vehicle (n=64) Difference between Treat:mant groups' Difference (95% CI) P-value PASI score at baseline MeaD SD Min MaX NUmber Percentage change in PASI at end of treatment Lsmaan Mean SD Minimum MaXimum NUmber LoWer 95% CL Opper 95% CL (-34.2 to ) P< ) Difference between treatments (calcipotriol minus vehicle) and least squares means with respect to percentage change in PASI adjusted for effect of PASI at visit 2 anci centre by analysis of covariance. Data from centres - and were pooled for the analysis.

6 Page 22 of August 2000 Study MCO 9604 DE The primary response criterion was the percentage change in PASI from baseline to end of double-blind treatment. For the intention to treat population, percentage in PASI from baseline to end of treatment is shown in Table 51 and Figure 51. PA5I was lower at the end of treatment compared to baseline in both treatment groups. The mean percentage change in PA51 adjusted for the effect of centre and baseline PASI was -76.1% in t he calcipotriol group compared to -51.9% in the vehicle group. The difference (95% CI) between treatments (calcipotriol minus vehicle) was (-34.2 to -14.2) %which is statistically significant (P<O.OOl). Figure 51: Percentage change in PAS! at each visit and end of treatment: intention-to-treat population Vehicle Calcipolriol Ci) -30 ~ CL.5.. Cll -40 c:... r. C> & -so... D c.. ~ "' a. c:... "' -60 :! End of Time (weeks) Treatment

7 Study MCO 9604 DE 11 August 2000 Page 23 of 181 The distribution of investigators' overall efficacy assessment at the end of treatment is shown in Table 52. The odds ratio (95% CI) for calcipotriol relative to vehicle was 3.06 (1.57 to 5.95) indicating that investigators' assessment was statistically significantly more favourable for the calcipotriol group compared to the vehicle group (P<O.OOl). Table S2: Investigators assessment of overall efficacy at end of treatment: intention-to-treat population Investigators overall Calcipotriol Vehicle Treatment CClii!Pa.rison efficacy assessment (n=68) (n 64) NUmber of NUmber of Odds ratio' (95% CI) P-value Patients % Patients % END OF TREATMENT Clearance (1.57 to 5.95) P<O.OOl Marked i.jiiprovement Moderate improvment Slight tmprovement Condition unchanged condition worse Total ) Odds ratio for the comparison of calcipotriol relative to vehicle by logistic regression using cumulative l ogits. The results of patients' self-assessments were similar to those of the investigators' assessments (see Table 53). Table S3: Patients assessment of o.vera/1 efficacy at end of treatment: intention-totreat population Patients overall Calcipotriol Vehi cle Treatment compar ison efficacy assessment <n=68) <n=64) Number of Number of Odds ratio' (95% CI) P-value Patients % Patients % END OF TREATMENT Clearance (1.52 to 5.68) P=O. OOl Marked i.jiiprovement Moderate improvment Slight improvement Condition unchanged condition worse Total ) Odds ratio for the comparison of calcipotriol relative to vehicle by logistic regression using cumulative logits.

8 Page 24 o/ August 2000 Study MCO 9604 DE The mean dose of fumaric acid esters prescribed across the entire course of the study and the mean at the last visit is shown in Table 54 (intention-totreat population). In total, the calcipotriol group were prescribed 4.5 g less fumaric acid esters, than the vehicle group (95% CI 11.6 g less to 2.5 g more, P=0.20). At the last visit that fumaric acid esters were prescribed, the calcipotriol group were prescribed a mean of 154 mg less than the vehicle group (95% CI -262 mg to -45 mg, P=0.006). Table 54: Total dose of fumaric acid esters across all visits and at the last visit: intention-to-treat population Total dose prescribed (mg) Cal cipotriol (n 68) Vehicle (n 64) Difference between treatment groups Difference ( 95% CI) P -value TOTAL Vl:SITS 1 Mean SD Min Max Number ( to 2472) P 0.20 LAST Vl:SI:T Mean SD Min Max Number (-262 to -45) P ) Total visits is the total amount of fumaric acid esters prescribed throughout the study. ~) Some patients had incomplete prescribed drug data and were therefore excluded from the calculations. ~) Difference between treatments (calcipotrio1 minus vehi cle) adjusted for effect of centre by analysis of variance. Data from centres - and - were pooled for the analysis. Safety results

9 Study MCO 9604 DE 11 August 2000 Page 25 of 181 Adverse events were categorised according to the WHO Adverse Reaction Dictionary (1992) to obtain the preferred term and System Organ Class. In the calcipotriol group 56 (82.4 %) patients reported adverse events compared to 52 (78.8 %) patients in the vehicle group (see Table 55). There was no statistically significant difference between the treatment groups with respect to the proportion of patients who reported adverse events (P=0.60). The odds ratio for the calcipotriol group relative to vehicle group was 1.26 (95% CI 0.53 to 2.96). Table 55: Number of patients with adverse events by WHO System Organ Class: safety population $yseam Organ Classificaeion 1 C&lcipoeriol Vehicle (n=68) (n 66) NUmber of Number of patienes % paeienes % Body as a whole - general disorciers Cardiovascular, general Central and peripheral nervous system Gastro-intestinal system Heart rate and rhythm 0 o.o Metabolic and nutritional Musculo-skeletal system Psychiatric Reproductive, female o.o Reproductive, male 0 o.o Resistance mechanism Respiratory system Skin and appendages Special senses other, o.o Urinary system 0 o.o Vascular (extracardiac) Vision White cell and res Total number of patienes (%) ) Classification according to the WBO Adverse Reaction Dictionary (1992). The most common adverse events were diarrhoea (22 calcipotriol patients, 24 vehicle patients), flushing (23 calcipotriol patients, 17 vehicle patients),

10 Page 26 of August 2000 Study MCO 9604 DE abdominal pain (16 calcipotriol patients, 14 vehicle patients) and pruritus (10 calcipotriol patients, 14 vehicle patients). The intensity of adverse reactions to calcipotriol (defined as an event considered as "possibly" or "probably" related to calcipotriol) is listed in Table 56. Patients randomised to calcipotriol experienced 25 adverse reactions (16 mild, 5 moderate, 4 severe), patients randomised to vehicle experienced 16 adverse reactions (4 mild, 7 moderate, 5 severe). Table 56: Intensity of adverse drug reactions: safety population Calcipotriol Vehicle (n.. 68) (n 66) Mild Moderate Severe Mild Moderate Severe Number of adverse drug reactions NUmber of adverse drug reactions Abscess l 0 Allergic reaction J Conjunctivitis l Dermatitis contact 0 0 l Diarrhoea l l 0 Eczema J Eosinophilia l Folliculitis J Headache l ~ection fungal J. 0 0 Paraesthesia l 0 0 J. 0 0 Pruritus 3 J Rash l Rash erythematous J. l 0 l 0 Rhinitis ' 0 l 0 0 l 0 Skin discoloration sweating increased tlrticaria Total number of adverse drug reactions ' 7 5 Only one serious adverse event was reported (patient randomised to calcipotriol, CRF IIIII The event was hospitalisation for lower abdominal pain, the subsequent diagnosis was adnexitis. It was considered as unlikely to be related to study medication; the patient continued the study. No patients were above the upper limit of the reference range for albumin adjusted calcium at the end of treatment in either group.

11 Study MCO 9604 DE 11 August 2000 Page 27 of 181 For all clinical chemistry parameters categorised as low, normal or high, the majority of patients was in the same category at baseline and end of treatment. Three patients (2 calcipotriol, 1 vehicle) were withdrawn from the study due to increasing values for liver enzymes under fumaric acid esters therapy. The mean leucocyte count decreased by 13% in both treatment groups. Lymphocytes decreased from normal at baseline to low at end of treatment in 6 patients (9.7 %) in the calcipotriol group and 9 patients (15.3 %) in the vehicle group. Eosinophiles increased from normal at baseline to high at end of treatment in 6 patients (9.7 %) in the calcipotriol group and 7 patients (11.9 %) in the vehicle group. Four patients (2 calcipotriol, 2 vehicle) were withdrawn from the study due to eosinophilia emerging during fumaric acid esters therapy. No other clinically important changes were seen for any clinical chemistry, haematology or urinalysis parameters. Conclusions The combination of calcipotriol ointment and fumaric acid esters is significantly more effective in the treatment of patients with severe psoriasis vulgaris than fumaric acid esters alone. Whilst providing better efficacy the combined use of calcipotriol and fumaric acid esters results in a slight fumaric acid ester-sparing effect. The risk/benefit ratio of this combination treatment is superior to fumaric acid esters monotherapy.