Clinical Trial Report Synopsis

Transcription

1 This document has been do\vnloaded from \v ww.leo-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 all studies related to a product_ As a document of scientific nature it is notto be seen as a recommendation or adv1c-e regarding the use of any products and you must always consult the speci.fic prescribing information approved for the product prior to any prescription or use. Clinical Trial Report Synopsis LEO aerosol foam compared to calcipotriol plus betamethasone dipropionate gel in subjects with psoriasis vulgaris A phase 3 trial comparing LEO aerosol foam with calcipotriol plus betamethasone dipropionate gel, aerosol foam vehicle, and gel vehicle in subjects with psoriasis vulgaris. An intemational, multi-centre, prospective, randomised, active- and vehicle- controlled, investigator blinded, 4-atm, parallel group 12-week trial LEO in psoriasis - the effect of prolonged use of calcipotriol and betamethasone dipropionate combination therapy, a randomised, active- and vehicle-controlled 12-week trial; The PSO-ABLE trial LEO Pharma A/S Clinical Development and Safety Trial ID: Report Date: LP Sep

2 LP Sep-2015 Page 2 of 6 1 Clinical Trial Report Synopsis Approval/Acknowledgements 1.1 Approval Statement, LEO Pharma A/S On behalf of LEO Pharma A/S, only the head of Medical Department and the head of Biostatistics are authorised to approve the Clinical Study Protocol and Consolidated Clinical Study Protocol(s) comprising any subsequent amendment(s). The following persons have approved this Clinical Study Synopsis using electronic signatures as presented on the last page of this document. The following persons have approved this clinical trial report synopsis on behalf of LEO Pharma A/S using electronic signatures: Biostatistics Medical Department 1.2 Approval Statement, International Coordinating Investigator The international coordinating investigator approves the clinical trial report synopsis by manually signing the International Coordinating Investigator Clinical Trial Report Approval Form, which is a separate document adjoined to the clinical trial report. The following person has approved this clinical trial report synopsis: Professor, France International Co-ordinating Investigator 1.3 Acknowledge Statement Investigator(s) Each participating investigator must agree to the approved Clinical Study Protocol and Consolidated Clinical Study Protocol(s) comprising any subsequent amendment(s) by signing the Clinical Study Synopsis Acknowledgement Form

3 LP Sep-2015 Page 3 of 6 Synopsis Name of sponsor: LEO Pharma A/S Trial Registration Number LP EudraCT Number Title of Trial LEO aerosol foam compared to calcipotriol plus betamethasone dipropionate gel in subjects with psoriasis vulgaris, France, was International Co- Investigators This was a multi-centre trial. There were 41 Principal Investigators. Professor ordinating Investigator. Trial Centres This trial was conducted at 11 centres in FR, 15 centres in the UK, and 15 sites in US. Publications None at the time of the final clinical trial report. Trial Period Date of first enrolment (informed consent signed and CRF started): 30-Jun-2014 Date of last subject completed: 04-Mar-2015 Development Phase Phase 3 Objectives The primary objective was to compare the efficacy of treatment with LEO at Week 4 to that of calcipotriol plus betamethasone dipropionate (BDP) gel at Week 8 in subjects with psoriasis vulgaris. The secondary objective was to compare the safety and efficacy of treatment with LEO to that of calcipotriol BPD gel for up to 12 weeks in subjects with psoriasis vulgaris. Methodology This was an international, multi-centre, prospective, randomised, active- and vehicle- controlled, investigator blinded, 4-arm, parallel group, 12-week trial in subjects with psoriasis vulgaris. Subjects were randomised to one of the following treatments: LEO aerosol foam Calcipotriol BDP gel Foam vehicle Gel vehicle The investigational product (IP) was applied to psoriasis vulgaris affected areas on the trunk, arms and legs once daily for up to 12 weeks. Eight trial visits were performed during the treatment phase: Day 0 (baseline), Week 1 (± 2 days), Week 2 (± 3 days), Week 4 (± 5 days), Week 6 (± 3 days), Week 8 (± 5 days), Week 10 (± 3 days), and Week 12 (± 3 days). A safety follow-up visit was scheduled, if required. Number of Subjects Planned and Analysed According to the protocol, 460 subjects were planned to be randomised in a 4:4:1:1 ratio, i.e., 184 in the active groups and 46 in the vehicle groups. 463 subjects were randomised in the trial as follows: 185 subjects to LEO 90100, 188 to calcipotriol BDP gel, 47 to foam vehicle, and 43 to gel vehicle.

4 LP Sep-2015 Page 4 of 6 Diagnosis and Main Criteria for Inclusion 1. Age 18 years or above 2. Psoriasis vulgaris on the trunk and/or limbs (excluding face, scalp, genitals or skin folds) involving 2-30% of the body surface area 3. A Physician's Global Assessment of disease severity (PGA) of at least mild on trunk and limbs 4. A modified Psoriasis Area and Severity Index (m-pasi) score of at least 2. Investigational Product, Dose and Mode of Administration, Batch Number LEO aerosol foam, containing calcipotriol 50 mcg/g and betamethasone 0.5 mg/g (as dipropionate) applied once daily; batch number: P14035 Duration of Treatment Wash-out up to 4 weeks, treatment up to 12 weeks, follow-up 2 weeks after last visit, if required. Reference Therapy, Dose and Mode of Administration, Batch Number Calcipotriol BDP gel, containing calcipotriol 50 mcg/g and betamethasone 0.5 mg/g (as dipropionate) applied once daily; batch number: Foam vehicle without any active ingredients, applied once daily; batch number: P14036 Gel vehicle without any active ingredients applied once daily; batch number: Criteria for Evaluation Primary endpoint: Subjects with treatment success according to the PGA at Week 4 for LEO and at Week 8 for calcipotriol BDP gel. PGA assessments were made on a 5-point scale (clear, almost clear, mild, moderate, severe). Subjects with at least moderate disease at baseline had to achieve clear or almost clear to be considered as a treatment success; subjects with mild disease at baseline had to achieve clear to be considered as a treatment success. Secondary endpoints: PASI 75 at Week 4 for LEO and at Week 8 for calcipotriol BDP gel Time to treatment success according to the PGA (LEO vs. calcipotriol BDP gel) Change in itch as assessed by the Visual Analogue Scale (VAS) from baseline to Week 4 (LEO vs. foam vehicle) Change in itch (VAS) from baseline to Week 4 (LEO 90100) vs. baseline to Week 8 (calcipotriol BDP gel) Safety evaluation: Evaluation of Adverse Events Any reported adverse events Any reported adverse drug reactions Evaluation of Laboratory Data Change in albumin-corrected serum calcium from base to Weeks 4, 8 and 12 Change in urine calcium:creatinine ratio from baseline to Weeks 4, 8 and 12 Evaluation of Other Observations Reasons for withdrawal from the trial Change in vital signs (blood pressure, heart rate) from baseline to Weeks 4, 8 and 12 Local safety and tolerability at baseline and Weeks 4, 8 and 12 Weight of trial medication used Compliance with treatment instructions

5 LP Sep-2015 Page 5 of 6 Statistical methods Primary endpoint The 2 active treatment groups were compared by calculating the Cochran-Mantel-Haenszel (CMH) odds ratio and its 95% confidence interval adjusting for pooled centre and baseline PGA (mild vs. at least moderate). Multiple imputation was used to handle missing PGA values. Two sensitivity analyses (observed cases analysis, last observation carried forward analysis) and 2 supportive analyses (per protocol analysis, multiple imputation analysis of larger centres) were carried out. Secondary endpoints PASI 75 The 2 active treatment groups were compared by calculating the CMH odds ratio and its 95% confidence interval adjusting for pooled centre and baseline PGA (mild vs. at least moderate). Multiple imputation was used to handle missing data. Time to treatment success The time to treatment success was summarised using Kaplan-Meier estimates and the 2 active treatments were compared using the Log-Rank test. Change in itch The change in itch as assessed by VAS was compared using analysis of covariance including pooled centre, baseline PGA, treatment and baseline itch VAS score in the model. Multiple imputation was used to handle missing data. Summary Trial Population 463 subjects were treated with at least one application of investigational product (185 subjects in the LEO group; 188 in the calcipotriol BDP gel group; 47 in the foam vehicle group; 43 in the gel vehicle group). 416 subjects completed the trial. 47 subjects withdrew from the trial. Withdrawal rates were higher in the vehicle groups (19.1% in the foam vehicle group; 32.6% in the gel vehicle group) than in the 2 active treatment arms (5.4% in the LEO group; 7.4% in the calcipotriol BDP gel group). 57 subjects were excluded from the per protocol analysis. The trial population comprised 295 (63.7%) men and 168 (36.3%) women. The majority of the subjects (95.2%) were white and 87.3% reported their ethnicity as Not Hispanic or Latino. The mean duration of psoriasis was 19.2 years (range 1-62 years); the mean BSA was 7.3% (range 2-30%), and the mean m-pasi score was 7.0 (range 2-28). Most subjects (63.7%) had moderate disease severity according to the PGA while 26.3% were mild and 9.9% were severe. Efficacy Results Primary Endpoint The proportion of subjects achieving treatment success using multiple imputation for missing data was higher in the LEO group at Week 4 (38.3%) than in the calcipotriol BDP gel group at Week 8 (22.5%). LEO was significantly more effective than calcipotriol BDP gel (OR, 2.55; 95% CI, ; p < 0.001). The sensitivity analyses and supportive analyses were all in agreement with the primary analysis. Secondary Endpoints The proportion of subjects achieving PASI 75 using multiple imputation for missing data was higher in the LEO group at Week 4 (52.1%) than in the calcipotriol BDP gel group at Week 8 (34.6%). Statistical analysis adjusted for pooled centre and baseline PGA showed that LEO was significantly more effective than calcipotriol BDP gel (p = 0.001). Treatment success occurred more rapidly in subjects treated with LEO than in subjects treated with calcipotriol BDP gel (p < 0.001). The median time to first treatment success was 6 weeks for the LEO group but could not be estimated for the calcipotriol BDP group since less than 50% of the subjects achieved treatment success. The adjusted mean change in itch severity from baseline to Week 4 was larger in the LEO group (-30.5) than in the foam vehicle group (-15.9) (using multiple imputation for missing data and adjusted for pooled centre, baseline PGA and baseline itch). The difference (-14.60) was statistically significant (p < 0.001). The adjusted mean change in itch severity was only slightly larger in the LEO group (-30.5 [baseline to Week 4]) than in the calcipotriol BDP gel group (-28.5 [baseline to Week 8]) (using multiple imputation for missing data and adjusted for pooled centre, baseline PGA and baseline itch). The difference (-1.93) was not statistically significant (p = 0.33).

6 LP Sep-2015 Page 6 of 6 Safety Results Eight SAEs in 8 subjects were reported among the randomised subjects in the trial: 4 subjects (2.2%) in the LEO group; 3 subjects (1.6%) in the calcipotriol BDP gel group, and 1 subject (2.3%) in the gel vehicle group. One of the SAEs (exacerbation of psoriasis after 68 days of treatment with LEO 90100) was assessed to be possibly related to the study treatment by the investigator. The incidence of AEs was similar between the 4 treatment groups. Most AEs were mild or moderate, with only 12 subjects experiencing severe AEs (6 subjects [3.2%] in the LEO group, 5 [2.7%] in the calcipotriol BDP gel group, and 1 [2.1%] in the foam vehicle group). Pruritus had a slightly higher incidence in the LEO group (2.7%) and in the foam vehicle group (2.1%) than in the calcipotriol BDP gel group (1.1%) and the gel vehicle group (0.0%). Adverse drug reactions (i.e., AEs for which a causal relationship to the study drug could not be ruled out) occurred with slightly higher rates in the LEO and foam vehicle groups ( %) than in the calcipotriol BDP gel and gel vehicle groups ( %). The most frequent lesional/perilesional AEs (reported by at least 2 subjects) were grouped under 3 preferred terms: pruritus, psoriasis, and application site pruritus. For each of these preferred terms, the proportion of subjects in the active treatment arms was not higher than in the foam vehicle group. None of these preferred terms were reported in the gel vehicle group. The proportion of subjects with AEs leading to withdrawal from the trial or permanent discontinuation of trial medication was similar in the 2 active treatment arms ( %) and lower than in the foam vehicle group (4.3%). No subjects withdrew from the trial in the gel vehicle group. Local reactions were few and occurred with similar frequency in the 4 treatment groups. The most frequently reported local reactions were erythema, dryness, and burning/pain. The majority of local reactions were mild or moderate and there was no indication that any of these local reactions were more severe in the LEO group than in the comparator groups No significant changes in albumin-corrected serum calcium levels and spot urinary calcium:creatinine ratios were observed in any of the 4 groups. Overall Conclusions The trial showed that the efficacy of LEO at Week 4 was superior to that of calcipotriol BDP gel at Week 8 in subjects with mild to severe psoriasis vulgaris. In both active treatment groups prolonged treatment up to 12 Weeks led to continued improvement in disease severity. LEO was safe and well tolerated in the treatment of psoriasis vulgaris on trunk and limbs for up to 12 weeks. The clinical trial was conducted in compliance with the clinical trial protocol, ICH Good Clinical Practice and the Declaration of Helsinki as adopted by the 18th World Medical Association General Assembly in 1964 (and subsequent amendments).

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