Clinical Trial Report Synopsis. Efficacy of twice daily applications of LEO ointment 30 mg/g for 12 weeks to subjects with alopecia areata

Transcription

1 Clinical Trial Report Synopsis Efficacy of twice daily applications of LEO ointment 30 mg/g for 12 weeks to subjects with alopecia areata Design of trial: A phase 2a, multi-centre, prospective, randomised, double-blind, 2-arm, parallel-group, vehicle-controlled clinical trial The clinical trial, including the archival of essential documents, was conducted in compliance with the clinical trial protocol, GCP, and the applicable regulatory requirement(s). LEO Pharma A/S Trial ID: EXP-1222 Date: 25-Sep-2017 Version: 1.0 edoc Version 1.0

2 EXP Sep-2017 Page 2 of 5 Clinical Trial Report Synopsis Statement Approval Statement, LEO Pharma A/S The following persons have approved this clinical trial report synopsis using electronic signatures as presented on the last page of this document:, M.Sc., Global Clinical Operations, M.D., Medical Science and Safety Approval Statement, Coordinating Investigator The 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: Emma Guttman, M.D. International Coordinating Investigator

3 EXP Sep-2017 Page 3 of 5 Trial Registration Number NCT Title of Trial Efficacy of twice daily applications of LEO ointment 30 mg/g for 12 weeks to subjects with alopecia areata Investigators This was a 2-centre trial. Emma Guttman, M.D., The Mount Sinai Hospital, New York, USA was appointed as signatory investigator. Amy Paller, M.D. was appointed the investigator at Northwestern University, Chicago Trial Centres This trial was conducted at 2 centres in USA. Publications None at the time of the final clinical trial report. Clinical Trial Period Date of First Subject First Visit: 02-Feb-2016 Date of Last Subject Last Visit: 06-Dec-2016 Development Phase Phase 2a Objectives Primary objective: To compare the efficacy of twice daily topical application of LEO ointment versus vehicle for 12 weeks in the treatment of hair loss in subjects with alopecia areata (AA). Secondary objectives: To evaluate: Safety of twice daily topical LEO ointment for 12 weeks. Hair regrowth time course by Severity of Alopecia Areata Tool (SALT) score (absolute, absolute change, percentage change) during treatment. Hair regrowth by global assessment during treatment using standardised photographs and independent expert review. Hair length, growth rate, relative thickness, hair type and colour during treatment. Subject Global Assessment (SGA) of hair regrowth during treatment. Alopecia Areata Quality of Life questionnaire (AA-QLI) at baseline and end of treatment. Treatment Satisfaction Questionnaire for Medication (TSQM II) at end of treatment. Systemic pharmacokinetics of LEO ointment at steady state (4 weeks of treatment). Methodology This was a 2-centre, single-country, randomised, double-blind, vehicle-controlled trial. The trial was divided into 3 phases: Screening: Check of subject s eligibility for the trial including documentation of demographic data. Treatment: At baseline (Day 1), subject s eligibility and informed consent were rechecked and baseline assessments were performed. The subjects had Biopsy 1 and Biopsy 2 taken from the scalp (Biopsy 2 not applicable for subjects with alopecia areata totalis (AT) and alopecia areata universalis (AU)). Day 3, a phone visit was held to inquire about application site reactions and adverse events (AEs), and to address any questions regarding use of the IMP. At Week 2, the biopsy wounds were checked and the sutures removed. Safety, including application site reactions, was assessed and recorded. At Weeks 4, 8 and 12 (end of treatment), efficacy and safety assessments, including application site reactions, were recorded. At end of treatment, subjects had Biopsy 3 taken from the scalp. Follow-up: At end of trial (2-week follow-up), the biopsy wound from Week 12 (end of treatment) was checked and the sutures were removed. AEs and concomitant medication were assessed and recorded. The subjects completed the end of trial form. Number of Subjects Planned and Analysed A total of 35 subjects were planned for randomisation in a 2:1 ratio to LEO ointment and vehicle, respectively. In the trial, 31 subjects were randomised and allocated to treatment as follows: 20 subjects to LEO ointment group and 11 subjects to vehicle group. Diagnosis and Main Criteria for Inclusion Diagnosis: alopecia areata Main criteria for inclusion: Man or woman between 18 and 65 years of age.

4 EXP Sep-2017 Page 4 of 5 Unequivocal clinical diagnosis of moderate to severe scalp AA (patch type, AT, or AU), affecting a minimum of 30% of the scalp area at screening and randomisation. Minimum 6-month duration of hair loss at screening. No upper time limit. No evidence of significant ongoing hair loss or regrowth at screening or randomisation. Must accept to not cut hair in the treated scalp areas during the trial. Test Product, Dose and Mode of Administration, Batch Number LEO ointment, topical administration twice daily. Batch number: P15020 Duration of Treatment Wash-out up to 4 weeks, treatment for 12 weeks, follow-up 2 weeks after end of treatment to check the biopsy wound from Week 12 and remove the sutures. Reference Product, Dose and Mode of Administration, Batch Number vehicle, topical administration twice daily. Batch number: P15005 Criteria for Evaluation Primary endpoint: Change in SALT score from baseline (Day 1) to end of treatment (Week 12). Secondary endpoints: Safety profile by reported AE s from screening to end of trial (Week 14). Evaluation of the following at baseline (Day 1), Week 4, Week 8, and end of treatment (Week 12): Absolute SALT score, SALT score change from baseline, SALT score percentage change from baseline, occurrence of at least 50% reduction in SALT score, hair length, hair growth rate, relative hair thickness, hair type, hair colour, global assessment of hair regrowth based on standardized photographs, SGA of hair regrowth. Evaluation of the following at baseline (Day 1) and end of treatment (Week 12): Derivation of endpoints from AA-QLI questionnaire as specified in the SAPU. Derivation of endpoints from TSQM II as specified in the SAPU. Statistical Methods Descriptive statistics were used to present the demographics and other baseline characteristics. The primary endpoint was analysed for the full analysis set (FAS) and the per protocol (PP) set. The analysis for the FAS was regarded as primary. Differences in SALT scores between baseline (Day 1) and end of treatment (Week 12) were compared in an analysis of covariance (ANCOVA) model with treatment and stratification factor as fixed effects and baseline SALT score as covariate, followed by a two-sided t-test. A supportive analysis applying the non-parametric Wilcoxon rank sum test was performed. Descriptive statistics was presented for all secondary endpoints including AA-QLI and TSQM II sum scores. A mixed effect model repeated measures (MMRM) was used as a sensitivity analysis to detect any overall differences in the treatment effect, as evaluated by SALT score, between LEO ointment and vehicle. The differences in SALT score from baseline to Weeks 4, 8, and 12 were estimated without imputing the missing values for subjects who prematurely discontinued the study. A one-tailed Fisher exact test was used to compare the percentage of subjects who achieved 50% improvement in SALT score after 12 weeks of treatment with either LEO ointment or vehicle. Safety was evaluated by tabulation of treatment-emergent AEs using descriptive statistics. Summary of Results Trial Population Disposition of Subjects 31 subjects were treated (20 subjects with LEO ointment and 11 subjects with vehicle) with at least one application of IMP and 23 subjects completed the trial. 8 subjects withdrew from the trial (3 subjects from the LEO ointment group and 5 subjects from the vehicle group. The most common reason for withdrawal was voluntary withdrawal (7 subjects). 1 subject was lost to follow-up. Protocol Deviations No protocol deviations were classified as major in the ecrf or the clinical trial monitoring system. Review of the protocol deviations after the trial was completed, however, identified some deviations that could potentially be considered major. The most frequent category of protocol deviations was violation of exclusion criteria. Treatment Compliance The majority of subjects in both the LEO ointment and the vehicle group missed 0-10% of applications (75.0% and

5 EXP Sep-2017 Page 5 of %) during the total treatment period. No subjects from the LEO ointment group missed >20% applications in comparison to 18.2% of subjects from the vehicle group. Efficacy Results The mean change in SALT score at baseline to Week 12 showed no change in hair growth and a p-value of 0.97 and 0.56 for the FAS and sensitivity analysis set respectively. Also, the supportive sensitivity analysis did not show significant differences in the treatment groups. There were neither clinically relevant nor statistically significant differences in SALT score from baseline to end of treatment between subjects treated with LEO ointment and subjects treated with vehicle. Overall, there was no difference observed in the treatment groups in terms of absolute SALT scores, SALT score change from baseline, percentage change in SALT score from baseline, occurrence of at least 50% improvement in SALT score, hair length and regrowth, thickness, hair type and colour. Investigator's global assessment of overall hair regrowth demonstrated no change in hair regrowth for more than half of the subjects in both treatment groups and a very low cosmetic acceptability. 4 subjects (23.5%) from the LEO ointment group rated to have cosmetically acceptable hair regrowth versus none in the vehicle group. The AA-QLI showed no statistically significant differences between the subjects treated with LEO ointment and the subjects treated with vehicle for the 3 domains (subjective symptoms, relationship and objective signs) at Week 12. The subject's assessment of treatment satisfaction using TSQM II revealed the highest mean score for 'side-effects' and lowest mean score for 'effectiveness'. No noteworthy differences were observed between the two treatment groups. Safety Results LEO ointment showed an acceptable safety profile and was well tolerated in subjects with AA for up to 12 weeks of treatment. 7 subjects reported AEs, most of them being mild in intensity and possibly/probably related to IMP administration. 2 subjects reported AEs (worsening of alopecia) of moderate intensity, possibly related to the IMP. This led to discontinuation of IMP in 1 subject. This subject was from the vehicle group. No deaths, other serious adverse events or withdrawals due to AEs were reported during the trial. There were no clinically significant abnormal findings for vital signs, physical findings or laboratory values found during the course of the trial. Conclusion There was no statistically significant difference between LEO ointment and its vehicle from baseline until 12 weeks of treatment in terms of efficacy. LEO ointment demonstrated an acceptable safety profile and was well tolerated for treatment on scalp for up to 12 weeks. The observed systemic exposure of LEO in AA subjects was low.

6 Signature Page for edoc v1.0 Reason for signing: Approved Reason for signing: Approved Management / Lead Approver Verdict(s) Name: Capacity: Biostatistics Date of signature: 25-Sep :29:06 GMT+0000 Management / Lead Approver Verdict(s) Name: Capacity: Medical Date of signature: 26-Sep :33:25 GMT+0000 Signature Page for edoc v1.0