Page 6 of6 5 January MCO 953 INT Study weeks. Throughout all phases of the study the interval between control visits was3weeks. Number of patients A total of patients was to be recruited to obtain 4 evaluable patients per group. Eligibility criteria Out-patients in hospital clinics, either sex, 8 years of age or above, who had chronic plaque psoriasis, who had been on maintenance therapy for psoriasis with methotrexate tablets for at least 6 months and whose psoriasis had been in a stable satisfactory condition for at least 3 months. Females of childbearing potential had to use an adequate method of contraception during the study and within 6 months thereafter, and males had to be aware that they were not allowed to make a partner pregnant during the study and within 3 months thereafter (within 6 months thereafter for Ireland and the United Kingdom). Excluded were patients who were pregnant or breast-feeding, patients with acute guttate, pustular or erythroderrnic psoriasis, those who had previously been treated with. arsenic derivates or who had been treated with systemic. antipsoriatics (other than methotrexate), PUV A or UVB within 6 weeks prior to study entry or topical antipsoriatics on the trunk and/ or limbs within weeks prior to study entry or who intended to use systemic corticosteroid or folic acid during the study. Patients with unacceptable blood tests within the last 3 months, that indicated that methotrexate therapy should not be continued, patients with hypercalcaemia, ulcerative disorders of the gastrointestinal tract, any chronic infectious disease likely to exacerbate due to methotrexate therapy, lung toxicity due to methotrexate, history of severe psoriatic arthropathy or known hypersensitivity to components of calcipotriol ointment were excluded. Finally, patients who were known or suspected of not being able to comply with a study ' protocol, who were participating in any other clinical trial, who had been treated with an investigational drug within 3 months prior to study entry or who had previously been randomised in this trial were to be excluded.
MCO 953 INT Study 5 January Page 7 o/6 Shtdy drugs At the beginning of Phase I patients were randomly assigned to either calcipotriol ointment 5 J.!g/ g or vehicle. The ointment was applied to affected areas twice daily during the entire study. During Phase II, methotrexate tablets, (.5 mg), were administered weekly, starting on half the maintenance dose used at baseline then titrated upwards until the target :tvpss has been achieved or downwards if there are adverse events attributable to the methotrexate. During Phase Ill the treatment was continued as in Phase II, the methotrexate dose being the same as at the end of Phase II or lower. Primary response criterion I Mean weekly dose of methotrexate used from the start of Phase I to the end of Phase II. Assessments The extent and severity of psoriasis were assessed at each visit, using a Modified Psoriasis Severity Score (MPSS) (4). Furthermore, at each post-randomisation visit both the investigator and the patient assessed the overall response to treatment. Adverse events were elicited at all post-randomisation visits and a laboratory examination carried out at the first two visits during Phase I and at every visit during Phase II and Ill
Page 8 of6 5 January MCO 953 INT Study The diagram surrunarises the study procedures: PHASE I PHASE II PHASE ill Methotrexate free and Methotrexate titration Follow-up: double-blind topical and double-blind Methotrexate and treatment period topical treatment double-blind topical period treatment period VISITS Fl F -Fnn Tl - 7> FU -FU3 Weeks Every 3 weeks Every 3 weeks Every 3 weeks Med ical history.. Pregnancy test3).. Cessation of methotrexate an d.. randomisation to calcipotriol or vehicle Clinical assessment (MPSS): *.. *.. Investigator Overall efficacy assessment:...... Investigator and patient Laboratory examination4) * *5).. * Recording of adverse events *.... Supply of tria l medication6>.. *.. * Collection of unused and used * * * trial medication ) Patients enter Phase II when relapse occurs as d efined in Section 3. ) Patients enter Phase Ill when target response is reached as defined in Section 3. 3) In female patients of child-bearing potential. 4) In case any clinically significant abnormality occurs at withdrawal, the exai.junation was repeated, preferably until normalisation. 5) A t visit F only. 6) No trial medication was supplied at the last visit.
MCO 953 INT Study 5 January Page 9 o/6 Results One hundred and one out-patients were recruited from seven countries. Ninety-eight patients were randomised: 5 to calcipotriol and 46 to vehicle. All 98 randomised patients are included in the safety analysis; one patient (randomised to calcipotriol) withdrew and supplied no efficacy data, hence the intention-to-treat analyses include 97. patients. Baseline demographics were similar in each treatment group (Table ).. Table I: Baseline demography for all randomised patients. All randomised patients Calcipotriol Vehicle (n 98) (n=5) (n=46) Age (years} Mean 57. 57.7 56.4 SD 3. 5 5.. 7 Minimum 9 9 9 Maximum 85 85 8 Number 98 5 46 Number of Number of Number of Sex patients % patients ts patients % Male 5 53. 8 53.8 4 5. Female 46 46.9 4 46. 47.8 Total 98. 5. 46. Number of Number of Number of Race patients % patients patients % Caucasian 95 96.9 5. 43 93.5 Negro/Black o.o. o.o Oriental/Asian 3 3.. 3 6.5 Other.... Total 98. 5. 46. '" There were some differences in demography between countries (8% of Finnish patients were male whilst only 5% of French patients were male compared to 53% overall). Within each country, there were no differences between the treatment groups.
Page of 6 5 January MCO 953 INT Study Baseline disease severity as measured by weekly dose methotrexate and modified MPSS score was also similar between treatment groups (Table II). Table.II: Baseline disease severity for all randomised patients All randomised patients Calcipotriol Vehicle (n=98) <n=5) <n =46) Methotrexate dose (mg/weelt) Mean.9 3.. 7 so 6.3 7. 5.4 Minimum. 5.5.5 Maximum 35. 35. 5. Number 98 5 46 Modified MPSS score Median 3 3 Minimum Maximum 36 36 5 Number 98 5 46 Again there were some differences between countries: in Belgium the mean weekly dose of methotrexate was 8.9 mg whilst in The Netherlands it was only. mg. Similarly, the modified psoriasis severity score (MPSS) showed most severe disease in Belgium (median 7) and least severe in The Netherlands (median ). Overall, however, the groups were well matched with respect to MPSS: the medians for calcipotriol-treated patients and vehicle-treated patients being and 3, respectively. Any differences between countries have been fully accounted for in the statistical analysis. The primary endpoint was the mean weekly dose of methotrexate taken during phase I and II of the study (Table III). In the calcipotriol group the mean dose was.6 mg per week_ less than in the vehicle group (95% confidence interval from.3 mg/week to 4. mg/week, p<.).
MCO 953 INT Study 5January Page of6 Table III: Major efficacy parameters (intention-to-treat population) Difference between Dose of methotrexate Calcipot riol Vehicle treatment gr oups' (mg/week) (n~s l) (n;46) Difference (95% CI) p-value MEAN DURING PHASE I AND II Lsmean 3. 4 6. Mean 3. 5. 9 -. 6-4. to -.3) P"O.OOl SD 3.7 3.6 Minimum.. Maximum 4.6.9 Number 5 46 END OF' PHASE II Lsmean 6.5 9.9-3.4 ( - 5.5 to -.3) p-. Mean 6. 3 9.6 SD 6.3 5. Minimum.. Maximum. 5. NUmber 5 46 ) Difference between treatment s (calcipot riol minus vehicle) and least squa res means with respect to weekly dose of methotrexate adjust ed for effect of country and baseline methotrexate dose by analysis of covariance. Not only was the mean dose of methotrexate reduced in the calcipotriol group but the dosage at the end of phase II (ie dosage when target response was achieved) was also lower. The mean dose of methotrexate at the end of phase II was 6.5 mgjweek in the calcipotriol group and 9.9 mgjweek in the vehicle group. This difference of 3.4 mg/week (95% CI.3 to 5.5) was highly statistically significant (p=.): As well as reducing the amount of methotrexate required to maintain efficacy, calcipotriol also delayed the time at which methotrexate was restarted. Methotrexate treatment was stopped on entry to the study and the median time until it was restarted (if the MPSS score reached twice baseline) was 3 days for calcipotriol-treated patients but only 35 days for vehicle-treated patients (p<o.ool). The intention of the study is to see if less methotrexate can be used whilst still maintaining efficacy. The design of this study is therefore such that a difference in clinical efficacy should not be seen. The investigators' and patients' overall assessments of efficacy at the end of phase II strongly supported each other:
Page o/6 5January MCO 953INT Study both showed non-statistically significant differences (although both in favour of the cakipotriol-treated patients). (Table IV). Table. IV: Investigators' and patients' overall efficacy assessments (intention-to-treat population). C:alcipotriol Vehicle Tr eatment comparison (n=5) (na46) Number of Number of Odds ratio (95' CI ) p-value patients % patients % END OF PHASE II (incl uding phase I wit hdr awal s) I nvestigators' overall efficacy a s s essment Cleared. o.o Markedly i mpr oved a. 5. 7 o.o l. 96 (.94 to 4. 8) p...68 Moderately improved 9.6 7 5. Sli ghtl y improved 6. 8. 7 Condition unchanged 8. 5.7 5.9 Slightly worse 9.6.7 Moderatel y worse 4 7.8 4 8. 7 Markedly worse 5 9. 8. 7 Total 5. 46. Patients' overall eff icacy assessment Cleared... 9 (. 9 t o 3. 96) pc.8 Markedl y improved.6 4. 3 Moderatel y i mproved 5 9. 8 3 6. 5 Slight l y improved 6. 8 9 9. 6 Condit ion unchanged 3. 5 8 7. 4 Slightly worse 5 9.8 8 7.4 Moderatel y worse 6. 8 5.9 Mar kedly worse 6.8 3. 9 Total 5 l:oo. O 46. ) Odds ratio, adjuste d for effect of country, for the compar ison of calcipotriol relative to vehi cle by logist ic regression using cumulat i ve logi ts. ) Includes end of t r eatment data from pati ents who withdrew dur ing phase I. At the end of Phase II the odds ratio in favour of calcipotriol with eff~cacy assessed by the investigators was.96 (95% CI.94 to 4.8, p=.68); the odds ratio in favour of calcipotriol with efficacy assessed by the patients was.9 (95% CI to.9 to 3.96, p=.8). Similarly, the percentage change in the modified psoriasis severity score from baseline to the end of phase II showed a non-significant difference: the median percentage change in the calcipotriol group was zero whilst in the vehicle group there was a median increase of 4%. The 95% confidence interval for the difference between the treatments was from 53.3% (calcipotriol better) to.4% (calcipotriol worse), p=.8 (Table V).
MCO 953 INT Study 5 January Page 3 of6 Table V: Percentage change in modified psoriasis severity score from visit Fl to the end of phase II: intention-to-treat population Percentage change in Calcipotriol vehicle Difference between modified psoriasis (n=sll (n=46) treatment groups' severity scor e Difference (95% CI) p-value % CHANGE TO END OF PHASE II (including phase I wi thdrawa l s ) Median 4-6.7 {-53.3 to.4) p=o. 8 Min -77-67 Max 95 445 Number 5 46 ) Median difference between treatments. The Wilcoxon rank sum test was used to compare the treatment groups. ) Incl udes end of treatment data from patients who wi t hdrew during phase I. Adverse events were experienced by 4 (76.9%) calcipotriol-.treated patients and 36 (78.3%) vehicle-treated patients. (Table VI). Table VI: Number of patients with adverse events by system organ class: safety population System Organ Classification' Calcipotriol {n=5) Vehicl e (n=46) Number of patients % Number of patients % Benign & malignant neoplasms {including cysts and polyps) Cardiac disorders Disorders of metabolism & nutrition Disorders of the ear & labyrinth Disorders of the eye Disorders of the reproductive system and breast Gastrointestinal disorders General disorders Hepato-biliary disorders Infections & infestations Injury & poisoning Investigations Musculoskeletal, connective tissue & bone disorder Neurological disorders Psychiatric disorders Renal & urinary disorders Respiratory, thoracic & mediast inal disorders Skin & subcutaneous t issue disorders vascular disorders 5 4 6 7 3 4 3 7 5..9. 3.8.5 3.8 9.6 7. 7 3.8. 5 3. 8.9 3.5 5. 8.9 7.7 5. 8 5.9 9.6 5 3 7 4 6 3.. 4.3 4.3...9 6.5. 5. 4. 3. 8.7 4.3.. 3. 47.8 6.5 Tot a l riumber of patients 4 76.9 36 78.3 ) Classification according to the Medical Dictionary for Regul atory Activities {MedORA).
Page 4 of 6 5January MCO 953 INT Study The most common events were skin and subcutaneous tissue disorders (7 calcipotriol-treated patients (5%), vehicle-treated patients (48% ), and these were predominantly pruritis ( calcipotriol patients, 9 vehicle patients); burning sensation (8 calcipotriol, 3 vehicle); and erythematous rash (4 calcipotriol, 6 vehicle). Adve~se reactions (defined as any event considered as.. 'possibly' or 'probably' related to study ointment) were predominantly of mild or moderate intensity. Patients randornised to receive calcipotriol experienced 3 adverse reactions (4 mild, moderate and 7 severe). Patients randomised to receive vehicle experienced 4 adverse reactions (7 mild,.7 moderate and severe) (Table VII). Table VII: Intensity of adverse drng reactions: safety population Preferred term' Calcipotriol Vehicle (n=5) (n 46) Mild Moderate Severe Mild Moderate Severe Burning sensati on 4 skin Cys t NOS Dermat itis NOS Pry s kin Extrasystoles NOS Eye irritat ion Folliculiti s Impetigo NOS Paraesthesi a Pruritus 6 3 l 4 Psoriasis aggravated Rash erythematous l l Skin irritation l 3 Skin soreness l l Smarting Total number of 4 i i i adverse reactions l ) classification according to the Medical Dictionary for Drug Regulatory Affairs (MEDdra). ) An adverse drug react ion is an adverse event that has been classified as either possibly or probably related to treatment. } Only one serious adverse event was reported in a patient randomised to calcipotriol (CRF number. The event was hospitalisation for fatigue, hypertension, slurred speech and cyanosis of the lips, nose and fingers; the
MCO 953 INT Study 5[anuary Page 5 of6 subsequent diagnosis was Pickwickian syndrome. It was considered as unlikely to be related to study medication. Mean decreases in ASAT of 8% (calcipotriol) and % (vehicle) and in ALAT of % (calcipotriol) and % (vehicle) were observed across the course of the study. A mean increase in bilirubin of 3% (calcipotriol) and 7% (vehicle) was also observed. No other clinically important changes were seen for any haematology or blood chemistry parameters. Conclusions The combined use of calcipotriol with methotrexate to treat patients with psoriasis vulgaris results in a methotrexate sparing effect whilst still maintaining efficacy. Calcipotriol treatment increases the time to relapse of psoriasis following discontinuation of methotrexate. The combination of calcipotriol and methotrexate is safe and well tolerated.