Objectives The objectives of the study were to compare the efficacy and safety of three different strengths

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1 MC 392 Study 18 May 1998 PageS ABSTRACT Objectives The objectives of the study were to compare the efficacy and safety of three different strengths of caldpotriol cream (10, 25, 50 f!g/ g) and placebo cream (vehicle) for treating mild to moderate psoriasis vulgaris of the scalp. Methods The study was a multicentre, randomised, double-blind, parallel group, dose-ranging study. Hospital out-patients, of either sex, aged <!!: 18 years, with mild to moderate scalp psoriasis were included after giving informed consent. Excluded were patients, whose psoriasis was markedly deteriorating or improving spontaneously, those applying calcipotriol elsewhere on the body, those who required treatment for facial psoriasis or had been using systemic antipsoriatic therapy. Hypercalcaemia, impaired renal and/ or hepatic function, intake of calcium tablets or > 400 iu. vitamin D and/ or 5,000 iu. vitamin A daily were also exclusion criteria. Following a 2 week wash-out/ qualification phase patients applied either calcipotriol cream; 10 J.tg/ g, 25 J.tg/ g or 50 J.tg/ g or vehicle for upto 6 weeks, twice daily. At baseline and after 1, 2, 4 and 6 weeks, the extent and severity of scalp psoriasis, and the severity of skin flaking from the scalp, and itchiness were assessed. An overall efficacy assessment was made at 1, 2, 4 and 6 weeks. Adverse events elicited by general enquiry were recorded. Blood and serum laboratory parameters were measured at baseline and after 6 weeks (or upon withdrawal, if earlier). This document has been dov.. nloaded from ww wj eo-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 transparency 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 seem 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.

2 Page6 18 May 1998 MC 392 Study Results Primary} Response Criterion; Mean clumge ifrom baseline (visit 2) to end of treatment) in total sig11 scorev. Treatment Letters indicate statistica~ly No. of ptt~. homogen ou&:: treatments Placebo Caleipotriol 10 ~e/2 Calcipot~iol 25 pg/g Calcipot~iol 50 ~g/g ( ) -2.)8 ( ) (-9.0-J.O) ( ) A A 8 B B l) Su11 of s ores for redness, thickness and scaliness n Treatments with t he same letters are not significantly different According to the Primary Response Criterion, calcipotriol cream 50 (A.g/ g and 25 JA.g/ g were significantly different from placebo. Calcipotriol cream 50 JA.g/ g was also significantly different from placebo in reducing scores for redness, thickness, scaliness, extent of psoriasis and in the investigators' and patients' assessment of the overall treatment response. Calcipotriol cream 25 p..g/ g was significantly different from placebo in reducing scores for redness, thickness, scaliness, extent of psoriasis, and in the investigators' and patients' assessment of the overall treatment response. Calcipotriol cream 10 p..g/ g was significantly different from placebo in reducing scores for thickness and scaliness, only. Calcipotriol cream 50 J.tg/ g was significantly different from calcipotriol cream 10 JA-g/ g in reducing scores for redness, extent of psoriasis, only. Calcipotriol cream 50 p..g/ g and 25 J.tg I g were not significantly different in any respect. Adverse events, primarily lesional/ perilesional irritation and facial irritation were recorded in 31 (25.2%) patients given placebo, 37 (29.8%) patients given calcipotriol cream 10 JA.g/g, 51 (40.8%) patients given calcipotriol cream 25 JJ.g/ g, and in 64 (48.9%) patients given calcipotriol cream 50 JA.g/ g. Lesional/ perilesional irritation was recorded in 15-23% patients in all groups, whereas facial irritation was seen primarily in the calcipotriol cream 25 p..g/ g (20.8%) and 50 ~tg/ g (27.5%) groups. Adverse events caused/contributed to treatment withdrawal in 4.8% patients given placebo, in 4.0% patients given calcipotriol cream 10 llg/ g, in 8.7% patients given calcipotriol cream 25 JA.g/ ~ and in 12.9% patients given caldpotriol cream 50 p..g/ g.

3 MC 392 Study 18 May 1998 Page 7 Calcipotriol cream treatment had no effect on s-calcium levels. Conclusion In the treatment of mild/ moderate scalp psoriasis calcipotriol cream, applied twice daily for 6 weeks, was efficacious and superior to placebo, and the effect was dose-related (concentration of calcipotriol in the cream). There was a relationship between the total frequency of adverse events, and adverse events due to facial irritation, and the strength of calcipotriol cream applied. The trial medication was generally well tolerated and safe. There were no adverse events on laboratory parameters.

4 MC 392 Study 18May 1998 Page 25 EXPANDED SUMMARY PROTOCOL SYNOPSIS Protocol objectives: The objectives of the study were to investigate the efficacy and safety of 3 different strengths of calcipotriol cream (10, 25 and 50 ~-tg/ g) in the treatment of mild to moderate scalp psoriasis. Study design: The study was a multicentre, randomised, double- blind, placebo (vehicle) controlled comparison of the following: i) Calcipotriol cream: 10 11g/ g ii) Calcipotriol cream: 25 11g/ g iii) Calcipotriol cream: 50 ~tg/ g iv) Vehicle of calcipotriol cream (placebo) All treatments were applied twice daily. The study comprised of 2 phases, patients being required to attend visits according to the following: PHASE I Wash-out/qualification of 2 weeks. During this phase which started at visit 1 and ended at visit 2, patients used only a non-medicated shampoo. PHASE II Randomised, double-blind treatment for 6 weeks. Parients were seen after 1 week (visit 3), 2 weeks (visit 4), 4 weeks (visit 5) and 6 weeks (visit 6).

5 Page26 18 May 1998 MC 392 Study The diagram summarises the study design: Week no Visit Sample size calculation: The protocol required a total of 480 patients to enter the study, so that 400 patients (100 per treatment group) completed the study. This would enable detection of an absolute difference in change of total sign score of 15% between any treatments. Subject eligibility criteria: Out-patients, of either sex, aged 18 years and over, with a clinical diagnosis of mild to moderate scalp psoriasis, and a history of psoriasis or psoriatic lesions elsewhere on the body, were included after giving their signed informed consent. Excluded were patients with severe scalp psoriasis, acute guttate, pustular or erythrodermic psoriasis, other dermatological conditions of the scalp, markedly deteriorating or spontaneously improving scalp psoriasis, facial psoriasis and extensive (>50% of body surface area) psoriasis on other parts of the body receiving active treatment. Also excluded were patients who had received systemic antipsoriatic treatment, PUV A or UVB in the previous 8 weeks, were receiving >400 iu vitamin D I >5,000 iu Vitamin A or calcium tablets daily, who were receiving other systemic medication which could affect the course of the disease or who were hypersensitive to components of calcipohi.ol cream. Uncooperative patients and patients with hypercalcaemia, significant renal or hepatic disease, who had received any investigational drug in the previous 3 months, who were participating in another clinical hi.al or intended to spend a time in a sunny climate and females not using adequate contraception or who were pregnant, wished to become pregnant or were breast feeding were also excluded. Treatment assignment method: At visit 1 eligible patients were assigned a patient ID number. At visit 2, patients who satisfied the protocol's inclusion/ exclusion criteria were randomised to double-blind treatment.

6 MC 392 Study 18 May 1998 Page27 Assessments: The diagram summarises the study procedures: 1) VISITS Weeks Patient history... Pregnancy test 1 ) * Randomisation * Clinical assessment: Investigator and patient * * Overall efficacy assessment: Investigator and patient * "' Laboratory examination 2 )»3) Recording of Adverse Events,.. * * Supply of test medication *.. *.. Collection of unused * * * and used tubes In female patients of child-bearing potential. 2) In case any abnormalities occur, the examination should be repeated, preferably until normalisation. 3) Or at earlier visit if patient withdraws. Medical history: At visit 1 and visit 2 the patients' suitability for the study was checked using the inclusion and exclusion criteria. The patients' medical history was taken and any concurrent medication recorded. Investigator's clinical assessments: At each visit, the investigator assessed the extent of scalp psoriasis as 0 = no involvement, 1 = s20%, 2 = 21-40%, 3 = 41-60%, 4 = 61-80% and 5 = % involvement; and the severity of redness, thickness and scaliness as 0 =absent, 1 = slight, 2 = moderate, 3 = severe, 4 = severest possible.

7 Page28 18 May 1998 MC 392 Study At visits 3-6, the investigator assessed the overall response to treatment as 1 = worse, 2 = unchanged, 3 = slight improvement, 4 = moderate improvement, 5 = marked improvement, 6 = clearance. Patient's assessments: At each visit the patient assessed the severity of skin flaking from the scalp and (non-transient post- application) itching as 0 = absent, 1 = mild, 2 = moderate, 3 = severe. At visits 3-6, the patient also assessed the overall response to treatment using the same criteria as for the investigator's assessment. Laboratory examinations: At visits 1 and 6 (or earlier if patient withdrew), blood samples were taken for determination of B-haemoglobin, B-erythrocytes, B-leucocytes, S-alkaline phosphatase, S-alanine aminotransferase, S-calcium (total), S-albumin, S-phosphate, S-creatinine. Adverse events: At visits 3-6, patients were asked if they had experienced any problems whilst using the treatment. No specific symptoms were asked for. If the response was "Yes'', the investigator recorded the nature, severity, duration and possible relationship to trial medication. Criteria for efficacy and safety: e Primary Response Criterion: Change in total sign score from baseline (visit 2) to end of double-blind treatment. Change in total sign score from baseline (visit 2) to each subsequent visit. Change in score for each of the following clinical signs: Redness, thickness and scaliness from baseline (visit 2) to end of double-blind treatment and from baseline to each subsequent visit.

8 MC 392 Study 18 May 1998 Page 29 Change in score for extent of psoriatic involvement from baseline (visit 2) to end of double-blind treatment and from baseline to each subsequent visit. e e Investigator's overall assessment of treatment response from baseline (visit 2) to end of double-blind treatment and from baseline to each subsequent visit. Change in score for skin flaking and itching from baseline (visit 2) to end of double-blind treatment and from baseline to each subsequent visit. Patient's overall assessment of treatment response from baseline (visit 2) to end of double- blind treatment and from baseline to each subsequent visit. e e Any reported adverse events. Any changes in the laboratory parameters from visit 1 to end of double-blind treatment.

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10 MC 392 Study 18 May 1998 Page 31 RESULTS SYNOPSIS The study commenced on 14 October 1992 and was completed on 9 June A total of 538 patients was recruited by 83 investigators in Belgium, Canada, France, Ireland, and the United Kingdom. 506 patients were randomised to double-blind comparative treatment. There were 234 males (46.2%). Randomised patients had a mean age of 44.0 years (range 18 to 88 years), with a mean history of scalp psoriasis of 12.5 years (range 1 month to 61 years). The four treatment groups, placebo, calcipotriol cream 10 11g/ g, 25 JA.g/ g, and 50 t-tg/ g were well matched at baseline in respect of sex distribution, history of scalp psoriasis, extent and severity of scalp psoriasis. The mean total sign scores at baseline and at subsequent visits are shown below. Mean total sign score 1 > at baseline (visit 2) and at subsequent uisits Placebo + Calcipotriol 1 0 IJg/g -;~~ Calcipotriol 25 IJg/g...,_ Calcipotriol 50 IJg/Q r r---r--o Weeks 4 6 l) Sum of scores for redness, thickness and scaliness.

11 Page32 18 May 1998 MC 392 Study Primary Response Criterion The Primary Response Criterion was the change in total sign score (sum of scores for redness, thickness and scaliness) from baseline (visit 2) to end of double-blind treatment. There were significant differences between treatments with respect to the Primary Efficacy Criterion. Treatments differing from each other were delineated by Duncan multiple-range tests. The results are shown below, which lists the mean changes and indicates the homogeneous subsets, ie not significantly different treatments. Primary Response Criterion; Mean chnnge (from baseline (visit 2) to end of treatment) in total sign score 1 ). Treatnent Placebo Ca1cipotriol 10 ~g/g Calcipotriol 25 ~g/g Calcipotriol 50 ~g/g Mean change (r:ange) ll Sum of scores for redness. thickness and scaliness ~ Treatments with the same letters are not significantly different letters indieate ~tatis t iea~ly No. of ptts. homogeneous treatments Z A A B B B The mean change in the total sign score from baseline to end of double-blind treatment in the calcipotriol 50 J.t.g/ g group was statistically significantly different from that observed with placebo. The mean change in the calcipoh:iol 25 J.t.gl g group was statistically significantly different from that observed with placebo.

12 MC 392 Study 18 May 1998 Page 33 The mean change fn scores for the individual signs (redness, thickness, scaliness) are shown below. Mean score for redness 1 > at respective control visits during double-blind treatment. Score - -Placebo + Calcipotriol 1 o IJQ/g * Caleipotriol 25 IJQ/g o Calcipotriol o;---~--~--~ , Weeks 1 ) Absent = 0, Slight = l, Moderate = 2, Severe = 3. Severest ~ssible = 4 Mean score for thickness 1 ) at respective control visits during double-blirld treatment. Score --Placebo + Calcipotriol 10 IJQ/9 m Calcipotriol 25 IJg/g... Calcipotriol 50 IJQ/Q ~--~--~------,---,--,,--, Weeks 4 6 l ) Absent = 0, Slight = 1, Moderate = 2, Severe = 3, Severest possible = 4

13 Page34 18May 1998 MC 392Study Mean score for scaliness1) at respective control visits during double-blind treatment. 2.5 Score Placebo +Calcipotriol 10 JJg/g..;r~ Calcipotriol /9 --Calcipotrlol 50 pg/g 0.5 o+---~--~----~~~--~--~--~ Weeks 4 6 l ) Absent = 0, Slight = 1, Moderate = 2, Severe = 3, Severest possible = 4 The mean score for extent of scalp psoriasis during double-blind treatment is shown below. Mean score for extentl) of scalp psoriasis at respective control visits during double-blind treatment Placebo +calcipotriol 10 #JQ/g -m Calcipotrlol 25 JJQ/g... Calcipotriol 50 #JQ/g ~--~--~--~--~--~--~~ weeks 4 6 l )No involvement= 0, s 20%= 1, 21-40% = 2, 41-60% = 3, 61-80% "' % = 5

14 MC 392 Study 18 May 1998 Page 35 The mean change in the score for extent of scalp psoriasis from baseline to end of double-blind treatment in the calcipotriol 50 ~-tg/ g group was significantly different from that observed with placebo, and calcipotriollo IJ.S/g. The mean change in the calcipotriol 25 fag/ g group was significantly different from that observed with placebo. The investigators' and the patients' overall assessment of the treatment response at end of double-blind treatment are shown below. Investigators' overall assessment of treatment response at end of treatment clearance Marked improvement Moderate improvement ffil Slight improvement 0 Condition unchanged 0 Condilion worse 10 0 Placebo Calcipotriol Calcipotriol Calcipotriol 10 pg/g 25 pg/g 50 IJQ/9 The distribution of the investigators overall assessment of the treatment response at the end of treatment in the 25!Ag/ g and 50!Ag/ g calcipotriol treated groups was significantly different from that in the placebo group (p <0.0083).

15 Page36 18 May 1998 MC 392 Study Patients' overall assessment of the treatment response at end of treatment. CI&arance Marked Improvement Moderate improvement Ill Slight improvement 0 Condition unchanged 0Condition worse Placebo Calcipotriol Calcipotriol Calcipotriol 10 pg/g 25 pg/g 50 IJg/g The distribution of the patients' overall assessment of the treatment response at the end of treatment in the 25 t-tg/ g and 50 t-tg/ g calcipotriol treated groups was significantly different from that in the placebo group (p <0.0083). Patients' assessment of skin flaking from the scalp and itching (non-transient postapplication) during double-blind treatment are shown below.

16 MC 392 Study 18 May 1998 Page 37 Patients' assessment of skin Jlaking1) at respective control visits during double-blind treatment Score 2.51 t Placebo + Calcipotrlol 10 pg/g ~" Calcipotriol 25 pg/g --carclpotriol 60 pg/g r-~--r-,--r-~---r--, Weeks 1 ) Absent ~ 0, Mild ~ 1, Moderate ~ 2, Severe ~ 3. Patients ' assessment of itchingl> at respective control visits during double-blind treatment 2.5 Score Placebo + Calcipotriol ; ~ Calcipotriol o- Calcipotriol 50 IJQ/Q ~--.---~--~--r---~~r-~ Weeks l) Absent = 0, Mild = 1, Moderate = 2, Severe = 3. There was no significant differences between the treatments with respect to the mean change in the score for skin flaking and with respect to the mean change in the score for itching.

17 Page38 18 May 1998 MC 392Study The proportions of patients experiencing adverse events, skin and appendages disorders, in the four treatment groups were: calcipotriol 10 ~-tg/g (29.8%), calcipotriol25 ~-tg/g (40.8%), calcipotriol50 ~J.g/g (48.9%) and placebo (25.2%). Adverse events were primarily lesional/ perilesional irritation or facial irritation. Frequency of facial irritation appeared dose related; calcipotriol 10 JA,g/ g (16 reports), calcipotriol25 ~-tg/g (26 reports), calcipotriol50 taglg (36 reports) and placebo (4 reports). Adverse events conbibuted to treatment withdrawal in 5 patients (4.0%) given calcipotriol10 11g/ g, in 11 patients (8.7%) given calcipotriol 25 t-tg/ g, in 17 patients (12.9%) given calcipotriol 50 t-tg/ g and in 6 patients {4.8%) given placebo. Treatment with caldpotriol cream or placebo had no adverse effect on the indices of haematological and biochemical function monitored. No patient given calcipotriol cream had a corrected serum total calcium above the upper limit of the normal reference interval at the end of treatment. Conclusion In the treatment of mild/ moderate scalp psoriasis calcipotriol cream, applied twice daily for 6 weeks, was efficacious and superior to placebo, and the effect was doserelated (concentration of calcipotriol in the cream). There was a relationship between the total frequency of adverse events, and adverse events due to facial irritation, and the strength of calcipotriol cream applied. The trial medication was generally well tolerated and safe. There were no adverse events on laboratory parameters.