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1 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 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. LEO G21 16-JUN-2009 Page 1 of 7 SYNOPSIS Title of study/protocol Code Number: Efficacy and Safety of Calcipotriol plus Betamethasone Gel Compared with Tacalcitol Ointment and the Gel Vehicle Alone in Patients with Psoriasis Vulgaris LEO G21 Centre details: Multicentre study conducted at 18 centres in Canada Publication references: To be decided Study period details: First subject first visit: 09 April 2008 Last subject last visit: 25 February 2009 Phase of development: III Objectives/hypothesis, if applicable: The primary objective was to compare the efficacy of once daily treatment for up to 8 weeks of with tacalcitol 4 mcg/g ointment and the gel vehicle alone in subjects with psoriasis vulgaris on the body. Secondary objectives were to compare the safety of versus tacalcitol ointment and the gel vehicle alone, to investigate the occurrence and the time to relapse and occurrence of rebound after end of treatment in subjects with controlled disease and to obtain quality of life data on subjects treated with, tacalcitol ointment and the gel vehicle alone. Study methodology: Multi-centre, prospective, randomised, Investigator-blind, active and vehicle controlled, 3- arm, parallel group 8 week study followed by an observation phase of up to 8 weeks in subjects with psoriasis vulgaris on the body. Subjects were randomised in a 2:2:1 ratio to v1.0

2 LEO G21 16-JUN-2009 Page 2 of 7 receive once daily treatment for up to 8 weeks with either 1) or 2) Tacalcitol ointment OR 3) Gel vehicle. Prior to randomisation (Visit 1), a washout period (up to 4 weeks = 28 days) was completed if the subject was treated, or had recently been treated, with anti-psoriatic treatments or other relevant medication, as defined in the exclusion criteria. During the Treatment Phase, Visits were performed at baseline (Day 0) and at week 1, 2, 4, 6 and 8. If a subject cleared according to the Investigator s global assessment of disease severity before week 8, the subject continued in the study and used study medication, as required, until the end of week 8. The initial study period was followed by a treatment-free observation period of 8 weeks for subjects who were graded to have controlled disease ( clear or almost clear ) by the Investigator s global assessment of disease severity at week 8. This was to investigate the occurrence and the time to relapse and occurrence of rebound. Visits took place at week 10, 12 and 16. An extra visit was scheduled for those subjects who experienced a worsening of body psoriasis and needed to reinitiate treatment between the two scheduled visits. Subjects who relapsed in the observation period, as verified by the Investigator, completed the trial at that visit and were given treatment according to the Investigators discretion. A follow-up visit took place 14 (± 2) days after the subject s last on-treatment visit if a treatment related adverse event (possible, probable or not assessable relationship to study medication) was ongoing. Efficacy assessments including the investigator s and the patient s global assessment of disease severity and the investigator s assessment of extent and clinical signs (redness, thickness and scaliness) were performed at all visits. Safety assessments were performed at all post randomisation visits. Number of subjects enrolled: A total of 450 subjects were planned: 180 subjects in the treatment group, 180 subjects in the tacalcitol ointment treatment group and 90 subjects in the gel vehicle treatment group. A total of 458 subjects were randomised: 183 subjects to, 184 subjects to tacalcitol ointment and 91 subjects in the gel vehicle. Diagnosis and main criteria for subject selection: Hospital out-patients or patients attending the private practice of a dermatologist, aged 18

3 LEO G21 16-JUN-2009 Page 3 of 7 years or above, with a diagnosis of psoriasis vulgaris on the trunk and/or limbs amenable to treatment with a maximum of 100 g of or 70 g of tacalcitol ointment per week, a disease severity of at least moderate according to the investigator s global assessment of disease severity and a minimum Psoriasis Area and Severity Index (PASI) for extent of 2 in at least one body region. Informed consent given. Investigational product: : Calcipotriol 50 mcg/g (as hydrate) plus betamethasone 0.5 mg/g (as dipropionate) gel applied topically once daily on affected areas on the trunk and/or limbs. Lot number: Reference product CURATODERM ointment: tacalcitol 4 mcg/g (as monohydrate) ointment. Lot number: LEO Gel vehicle. Lot number: Duration of treatment: The treatment period lasted for up to 8 weeks followed by a treatment free, observation period, of up to 8 weeks Criteria for evaluation Efficacy : Primary response criterion: Subjects with controlled disease ( clear or almost clear disease) according to Investigator s global assessment of disease severity at week 8 Secondary response criteria: Subjects with controlled disease according to the Investigator s global assessment of disease severity at week 4 The percentage change in PASI from baseline to week 4 and 8 Subjects with relapse during the study and time to relapse Subjects with rebound during the study Quality of Life: Change in quality of life from baseline to week 4 and 8 using SF-36 (v2) and Skindex-16

4 LEO G21 16-JUN-2009 Page 4 of 7 Safety: Any reported adverse events or any reported adverse drug reactions. Reasons for withdrawal from the study Statistical methodology: The primary response criterion was analysed based on the full analysis set and per protocol analysis set. Two hypotheses were tested in sequential order: 1) was superior to gel vehicle and 2) was superior to tacalcitol ointment, for the proportion of subjects with controlled disease at week 8 according to the Investigator s global assessment of disease severity. The second hypothesis was only tested if the first test was significant (p<0.05). Testing was conducted at the 5% level of significance using the Cochran-Mantel-Haenszel (CMH) test adjusting for centre. For the secondary response criteria, the proportion of subjects with controlled disease at week 4 according to the Investigator s global assessment of disease severity was compared between the treatment groups using the CMH test. Analysis of variance (ANOVA) was used to compare the treatment groups for the percentage change in PASI at week 4 and 8 and quality of life measurements at week 4 and 8. Paired t-tests were used to analyse change in quality of life within treatment groups. Safety analysis was based on the safety analysis set. The proportions of subjects who experienced adverse events and adverse drug reactions were compared between the treatment groups using chi-square tests. Summary Conclusions Efficacy results: A total of 458 subjects (mean age 51.6 years [range 18 to 82], 62.2% male, 93.9% white and 68.3% moderate, 29.5% severe and 2.2% very severe disease) were randomised and 398 completed the 8 week double blind treatment phase. The proportion of subjects who achieved controlled disease at week 8 (LOCF) in the group was 39.9% compared with 5.5% in the gel vehicle group and 17.9% in the tacalcitol group. was statistically significantly more effective than the gel vehicle (OR 13.9; 95% CI 4.99 to 38.7; p<0.001) and the sequential test versus tacalcitol

5 LEO G21 16-JUN-2009 Page 5 of 7 also showed that was more effective (OR 3.42; 95% CI 2.05 to 5.70; p<0.001). There were no treatment by centre interactions (p>0.10). The analysis of the per protocol analysis set supported the results for the full analysis set. The results for the secondary response criteria in the treatment phase of the study were as follows: DAIVOBET GEL (N=183) TACALCITOL (N=184) GEL VEHICLE (N=91) CONTROLLED DISEASE (IGA)N (%) WEEK 4 (LOCF) 34 (18.6) 12 (6.5)* 1 (1.1)* MEAN % CHANGE IN PASI FROM BASELINE WEEK * 13.3* WEEK * 17.9* * COMPARISON STATISTICALLY SIGNIFI ANT IN FAVOUR OF DAIVOBET GEL Among the subjects that entered the observation phase at the end of the 8-week treatment phase the occurrence of relapse and rebound was as follows: DAIVOBET GEL (N=67) TACALCITOL (N=31) GEL VEHICLE (N=5) RELAPSE N(%) 28 (41.8) 7 (22.6) 3 (60.0) MEDIAN TIME TO 63 DAYS 61 DAYS 61 DAYS RELAPSE REBOUND N(%) 0 (0.0) 0 (0.0) 0 (0.0) Quality of Life: In the SF-36 (v2) general health questionnaire the scores for the Physical Component Summary and Mental Component Summary were similar among the groups. When comparing response within the group, there were no significant changes from baseline in the Physical Component Summary but the change from baseline in the Mental Component Summary score was statistically significant at Weeks 4 and 8 (p=0.002 and p=0.012 respectively). For the skin disease specific questionnaire (Skindex- 16) the changes from baseline within each treatment group were statistically significant for total score in all treatment groups at Weeks 4 and 8 (p<0.001 for both timepoints). There were statistically significant differences in favour of at Weeks

6 LEO G21 16-JUN-2009 Page 6 of 7 4 and 8 compared with tacalcitol (p= and p=0.007 respectively) and also compared with the gel vehicle (p<0.001 at both timepoints). Safety results: In the treatment phase of the study, the proportion of patients with at least one adverse event was similar and not statistically significant between the group (72 subjects, 39.6%) versus the tacalcitol group (83 subjects, 45.1%, p= 0.28) and versus the gel vehicle group (35 subjects, 38.5%, p=0.86). The proportion of subjects with at least one adverse drug reaction was significantly lower in the group than in the other two groups; 16 (8.8%) versus 29 (15.8%), p=0.042 for tacalcitol and 16 (8.8%) versus 16 (17.6%), p=0.033 for the gel vehicle. A similar pattern was observed for lesional/perilesional adverse events on the body. Pruritus and skin irritation were the most frequently reported adverse drug reactions and lesional/perilesional adverse events in the group; both reported by 6 (3.3) subjects. Pruritus was also the most common adverse drug reaction and lesional/perilesional adverse event in the other two groups and was reported with a higher frequency than in the group. In the tacalcitol group pruritus was reported as an adverse drug reaction by 11 (6.0%) subjects and as a lesional/perilesional adverse event by 12 (6.5%) subjects. In the gel vehicle group the same number 6 (6.6%) subjects reported pruritus as an adverse drug reaction and a lesional/perilesional adverse event. The other most common adverse drug reaction in the tacalcitol group was skin irritation reported by 4 (2.2%) subjects and in the gel vehicle group it was burning sensation reported by 4 (4.4%) subjects. Withdrawals due to adverse events in the treatment phase were lower in the group 3 (1.6%) subjects compared with 4 (2.2%) in the tacalcitol group and 4 (4.4%) in the gel vehicle group. In the observation phase no patients withdrew due to adverse events and the incidences of adverse events in the and the gel vehicle groups were not statistically significantly different (p=0.91) but there was a trend towards a higher incidence in the tacalcitol group (p=0.055). There were no deaths or treatment related serious adverse events.

7 LEO G21 16-JUN-2009 Page 7 of 7 Conclusion: was statistically significantly more effective than the gel vehicle and tacalcitol ointment in the treatment of psoriasis vulgaris on the body. The incidence of adverse drug reactions and lesional/perilesional adverse events was also significantly lower resulting in a more favourable benefit/risk ratio for compared with the gel vehicle and tacalcitol ointment. Report date: 16 June 2009