Clinical Study Report Part 1 of Trial LP

Transcription

1 Clinical Study Report Part 1 of Trial LP Safety and efficacy of escalating doses of LEO applied once daily for two consecutive days on full balding scalp in subjects with actinic keratosis Part 1: A phase 1, multicentre, open-label, dose escalation, 2-week trial LEO Pharma A/S Clinical Development and Safety LP Sep-2015 EudraCT : edoc Version 1.0

2 LP Sep-2015 Page 2 of 36 Clinical Study Report Statement Approval Statement, Sponsor The following persons have approved this Clinical Study Report on behalf of LEO Pharma A/S using electronic signatures: PPD PPD Biostatistics PPD PPD Medical Department Approval Statement, Investigator The international co-ordinating investigator approves the Clinical Study Report by manually signing the International Co-ordinating Investigator Clinical Study Report Approval Form, which is a separate document adjoined to this report. The following person has approved this Clinical Study Report: Jonathan Weiss, MD International co-ordinating investigator

3 LP Sep-2015 Page 3 of 36 Compliance with Good Clinical Practice This clinical trial was performed in compliance with GCP, including the archiving of essential documents. This clinical study report, presenting Part 1 of the trial, is together with the LP main clinical study report designed to comply with the standards issued by the International Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical Study Reports and clarified in the ICH E3 Q&A document 07-Jun-2012; E6 Good Clinical Practice; E9 Statistical Principles for Clinical Trials and M4 Common Technical Document) (1, 2, 3, 4, 5). Public Registration of the Clinical Trial The trial was registered at ClinicalTrials.gov on 27-Mar-2014, registration identifier: NCT The results are disclosed in accordance with applicable national regulations and LEO procedures.

4 LP Sep-2015 Page 4 of 36 Table of Contents Clinical Study Report Statement... 2 Compliance with Good Clinical Practice... 3 Table of Contents... 4 List of Tables... 5 List of Figures... 6 List of Appendices... 7 List of Abbreviations Introduction Frequency and Timing of Measurements Trial Objectives and Response Criteria/Endpoints Part Primary Objectives Secondary Objectives Primary Response Criterion Other Evaluations Evaluation of (Serious) Adverse Events Evaluation of Laboratory Data Evaluation of Other Observations Trial Population Part Overview Disposition of Subjects Protocol Deviations Trial Analysis Set Demographics and Other Baseline Characteristics Exposure and Treatment Compliance Part Safety Evaluation Part Adverse Events Brief Summary of Adverse Events Display of Adverse Events Analysis of Adverse Events Deaths, other Serious Adverse Events, and other Significant Adverse Events Deaths... 29

5 LP Sep-2015 Page 5 of Other Serious Adverse Events Other Significant Adverse Events Local Skin Responses Dose-limiting Toxicities Vital Signs, Physical Findings and other Observations Related to Safety Vital Signs and Physical Findings ECG Assessments Clinical Laboratory Evaluation Overall Conclusions of Part References Narratives Part Other Significant Adverse Events End-of-Text Listings End-of-text listings have been moved to Appendix 2.7. List of Tables Table 1 Schedule of trial procedures Table 2 Age overall and by cohort: evaluable subjects analysis set Table 3 Sex, race, ethnicity and skin type overall and by cohort: evaluable subjects analysis set Table 4 Duration of AK overall and by cohort: evaluable subjects analysis set Table 5 AK treatment history overall and by cohort (gel): evaluable subjects analysis set Table 6 Skin disease history overall and by cohort: evaluable subjects analysis set Table 7 AK count at baseline overall and by cohort: evaluable subjects analysis set.. 20 Table 8 Overall summary of adverse events: safety analysis set Table 9 Adverse events by SOC and preferred term: safety analysis set Table 10 with Administration Site Reactions by intensity and cohort: safety analysis set Table 11 DLT by cohort: evaluable subjects analysis set... 32

6 LP Sep-2015 Page 6 of 36 List of Figures Figure 1 Maximum composite LSR score during Week 1 by cohort: safety analysis set Figure 2 Dose Escalation Rules... 31

7 LP Sep-2015 Page 7 of 36 List of Appendices Listings Appendix No Appendix Title Status 1.6 Listing of Subjects receiving Investigational Product from Specific Batches (Part 1) Enclosed 2.1 Discontinued Subjects (Part 1) Enclosed 2.2 Protocol Deviations (Part 1) Enclosed 2.3 Trial Analysis Sets (Part 1) Enclosed 2.4 Demographic Data (Part 1) Enclosed 2.5 Compliance and/or Investigational Product Concentration Data (Part 1) Enclosed 2.6 Efficacy Data (Part 1) Enclosed 2.7 Safety Data (Part 1) Enclosed 2.8 Listing of Laboratory Values by Subject (Part 1) Enclosed Additional Related Reports (not part of appendices) Report title LP main clinical study report ECG Safety Report Status Enclosed Enclosed

8 LP Sep-2015 Page 8 of 36 List of Abbreviations AE AK DLT ICH IP LSR MedDRA MTD PT SAE SOC Adverse event Actinic keratosis Dose limiting toxicity International Conference on Harmonisation Investigational product Local skin response Medical Dictionary for Regulatory Activities Maximum tolerated dose Preferred term Serious adverse event System Organ Class

9 LP Sep-2015 Page 9 of 36 1 Introduction Trial LP was a seamless phase 1/2 clinical trial constituting 2 parts: a phase 1 open label, dose escalation part and a phase 2 randomised double-blind, vehicle-controlled part. The trial is reported in two interdependent clinical study reports each presenting one part of the trial. This report describes the results of Part 1 of the trial, identifying the maximum tolerated dose (MTD) with a focus on safety and tolerability of LEO gel and undertaken in a dose escalation manner. All tables and figures in Part 1 are presented in-text in this CSR Part 1 document. The LP main clinical study report contains the introduction, information on ethics, objectives, trial administrative structure, investigational plan, and statistical methods for the whole of the trial. Also, the results from Part 2 of the trial (dose selection) are reported here and finally, the trial in full is evaluated in the discussion. The clinical study report synopsis exists as a separately approved document and includes both Part 1 and Part 2 results. The schedule of all trial procedures for all trial visits for Part 1 is presented in Table 1.

10 LP Sep-2015 Page 10 of Frequency and Timing of Measurements Table 1 Schedule of trial procedures Part 1 Visit Visit (window) Informed consent Within 35 days prior to Day 1 In-/exclusion criteria X X 2 Medical/surgical history 3 X X 2 Concurrent diagnosis X X 2 Skin diseases X X 2 AK treatment history X X 2 Fitzpatrick skin type Demographics Height and weight X X X X Unscheduled 1 / Early Term Day 1 Day 2 Day 3 Day 8 Week 2 N/A None None None ±1 day ±2 days Concomitant med. X X X X X X X Treatments and procedures X X X X X X Physical exam X X X X Vital signs X X X X X X X Laboratory X X 4 X 6 X ECG X X 4 X 6 X Urine pregnancy test 5 X X X X Identify treatment area X X 2 Dose assignment AK assessment X X Apply trial medication X X X LSR X X X X X X Adverse events X X X X X X Photos X X X X X X 1. For unscheduled visits, only assessments that were required as judged by the investigator were conducted 2. Re-check 3. Medical/surgical history within 12 months prior to Visit 1 4. Not required if screening visit performed within the last 21 days 5. Only subjects of childbearing potential 6. If there were clinically significant changes from baseline at Visit 4 the test was to be repeated at Visit 5

11 LP Sep-2015 Page 11 of 36 2 Trial Objectives and Response Criteria/Endpoints Part Primary Objectives To identify the maximum tolerated dose (MTD) of LEO after once daily treatment for 2 consecutive days 2.2 Secondary Objectives To evaluate safety of LEO in escalating doses after once daily treatment for 2 consecutive days 2.3 Primary Response Criterion Dose limiting toxicity (DLT) up to and including Day Other Evaluations Evaluation of (Serious) Adverse Events Incidence of AEs and SAEs Incidence of AEs and LSRs leading to discontinuation of the trial medication Incidence and severity of LSRs Changes in vital signs, ECGs, and blood laboratory parameters that are out of normal range and clinically relevant Reason for withdrawal Evaluation of Laboratory Data Abnormal haematology and biochemistry laboratory values Evaluation of Other Observations Change from baseline to Day 3 in ECG assessments.

12 LP Sep-2015 Page 12 of 36 3 Trial Population Part Overview This report describes the results from Part 1 of the trial. Part 2 results are described in LP main clinical study report. 3.2 Disposition of Subjects A total of 65 subjects from 7 centres in the US were enrolled into Part 1 of the trial; 7 were screening failures, 1 was excluded as recruitment goals for all cohorts were met, and thus 57 subjects were included and received trial medication. Ten subjects were included in the cohort, 11 subjects in the cohort, and 12 subjects each in the 0.037, 0.05, and cohorts. All 57 subjects completed all visits. The first subject was enrolled on 14-May-2014 and the last subject s last visit was on 12-Aug The individual visit dates are listed in Appendix 2.4 (Part 1), Listing 4-4 (Part 1). A listing of discontinued subjects is in Appendix 2.1 (Part 1). 3.3 Protocol Deviations A listing of the protocol deviations during the trial conduct is in Appendix 2.2 (Part 1), Listing 2-1. All comments made in the comment field in the electronic case report form are in Appendix 2.2 (Part 1), Listing 2-2. Subject no. PPD and subject no. PPD did not receive the second dose of investigational product due to AEs. Both subjects applied prohibited medication on the treatment area; subject no. PPD applied polysporin and subject no. PPD applied xylocaine (see narratives in Section 8.1). Other protocol deviations were considered minor and are not discussed further in the text. 3.4 Trial Analysis Set The evaluable subjects analysis set was defined as all subjects who received at least one application of trial medication and had LSRs recorded at all visits up to and including Day 8 or had experienced a DLT at one or more visits up to and including Day 8.The safety analysis set was defined as all subjects who received at least one application of trial medication and had safety information available post treatment.

13 LP Sep-2015 Page 13 of 36 Of the 65 enrolled subjects, 57 subjects were included in the trial, of which all were included in the evaluable subjects analysis set and in the safety analysis set. Listings of the trial analysis sets are in Appendix 2.3 (Part 1). 3.5 Demographics and Other Baseline Characteristics All subjects were men, all white, self-assessed non-hispanic or Latino, and the majority had Fitzpatrick skin type II or III (Table 3). The median age at baseline was 69.0 years (range 45-86) for all cohorts in total (Table 2). The median duration of AK was 6.0 years (range 0-44) (Table 4) and most subjects (93) had previously been treated for AK, the most common treatment being cryo/liquid nitrogen (Table 5). Approximately 70 had a history of skin diseases, the most common being basal cell carcinoma, squamous cell carcinoma of skin and seborrhoeic keratosis (Table 6). The median number of AKs at baseline was 8.0 (Table 7). There were some differences in demographics and baseline characteristics between cohorts, as would be expected with groups of such small sizes, but these are not expected to influence the interpretation of the results with regard to MTD. Listings of demographic and baseline data are in Appendix 2.4 (Part 1). Table 2 Age overall and by cohort: evaluable subjects analysis set Age(Years) Total (n=57) (n=10) (n=11) Median Minimum Maximum MAY15:10:25:30 LP t01 age.doc

14 LP Sep-2015 Page 14 of 36 Table 3 Sex, race, ethnicity and skin type overall and by cohort: evaluable subjects analysis set Total (n=57) (n=10) (n=11) of subject s of subject s of subject s of subject s of subject s of subject s Sex Male Total Race White Total Ethnicity Not Hispanic or Latino Total Skin Type Type I Type II Type III Type IV Total MAY15:10:25:35 LP t02 sex race ect.doc

15 LP Sep-2015 Page 15 of 36 Table 4 Duration of AK overall and by cohort: evaluable subjects analysis set AK duration (years) Total (n=57) (n=10) (n=11) Median Minimum Maximum MAY15:10:25:40 LP t03 ak dur.doc

16 LP Sep-2015 Page 16 of 36 Table 5 AK treatment history overall and by cohort: evaluable subjects analysis set AK Treatment History Total (n=57) (n=10) (n=11) Cryo/Liquid nitrogen Photodynamic therapy Fluorouracil Surgical excision/curettage Imiquimod Ingenol mebutate Laser resurfacing Diclofenac Medium or greater depth chemical peel Retinoids Total number of treatments Total number of treated subjects MAY15:12:04:34 LP t04_aktrthist.doc

17 LP Sep-2015 Page 17 of 36 Table 6 Skin disease history overall and by cohort: evaluable subjects analysis set Total (n=57) (n=10) (n=11) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma Squamous cell carcinoma of skin Seborrhoeic keratosis Melanocytic naevus Acrochordon Malignant melanoma Skin papilloma Basosquamous carcinoma Neurofibroma Skin cancer SOC total Skin and subcutaneous tissue disorders Campbell de morgan spots Actinic elastosis Solar lentigo Dermal cyst Dry skin MAY15:13:49:43 LP t05 skdishist.doc Continued...

18 LP Sep-2015 Page 18 of 36 Table 6 Skin disease history overall and by cohort: evaluable subjects analysis set, continued Total (n=57) (n=10) (n=11) Skin and subcutaneous tissue disorders Photodermatosis Rosacea Dermatitis Eczema Eczema nummular Hyperkeratosis Keloid scar Lichenoid keratosis Neurodermatitis Pruritus Psoriasis Sebaceous hyperplasia Seborrhoea Seborrhoeic dermatitis Telangiectasia SOC total Infections and infestations Folliculitis Herpes simplex Onychomycosis MAY15:13:49:43 LP t05 skdishist.doc Continued...

19 LP Sep-2015 Page 19 of 36 Table 6 Skin disease history overall and by cohort: evaluable subjects analysis set, continued Total (n=57) (n=10) (n=11) Infections and infestations Herpes zoster Tinea pedis SOC total General disorders and administration site conditions Polyp Xerosis SOC total Congenital, familial and genetic disorders Dermoid cyst SOC total Immune system disorders Drug hypersensitivity SOC total Total number MAY15:13:49:43 LP t05 skdishist.doc 1) Classification according to MedDRA version ) Different diagnoses within the same preferred term and involving the same subject have been counted as one. A subject could appear in multiple classes.

20 LP Sep-2015 Page 20 of 36 Table 7 AK count at baseline overall and by cohort: evaluable subjects analysis set AK lesion count Total (n=57) (n=10) (n=11) Median Minimum Maximum MAY15:10:25:46 LP t06 akcount.doc

21 LP Sep-2015 Page 21 of 36 4 Exposure and Treatment Compliance Part 1 Treatment compliance was high. All 57 subjects received the first application of trial medication and 55 subjects received the second application. The 2 subjects not receiving the second application were both in the cohort. A listing is provided in Appendix 2.5 (Part 1), Listing 5-1.

22 LP Sep-2015 Page 22 of 36 5 Safety Evaluation Part 1 Note that the primary response criterion for Part 1 was DLT up to and including Day 8, and this information is presented in Section Adverse Events Brief Summary of Adverse Events All cohorts had subjects with AEs (Table 8). The total number of AEs and the number of AEs related to treatment tended to increase with increasing dose of LEO There was a shift in the intensity of AEs within the MedDRA high level group term administration site reactions with increasing intensity in the higher dose cohorts (Table 10). There were relatively few AEs of severe intensity, no deaths, and no other SAEs. A total of 2 subjects discontinued treatment due to AEs (see Section 5.2) Display of Adverse Events All AEs are presented by MedDRA primary SOC and preferred term (PT) in Table 9. Listings of AEs are available in Appendix 2.7 (Part 1), Listings 7-1, 7-2, 7-3.

23 LP Sep-2015 Page 23 of 36 Table 8 Overall summary of adverse events: safety analysis set (n=10) (n=11) Adverse event category AE 1,2 n 3 () AE 1,2 n 3 () AE 1,2 n 3 () AE 1,2 n 3 () AE 1,2 n 3 () All adverse events 10 7 ( 70.0) 11 7 ( 63.6) (100.0) ( 83.3) (100.0) Severe adverse events 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 1 1 ( 8.3) 5 3 ( 25.0) Related adverse events 7 5 ( 50.0) 8 6 ( 54.5) (100.0) ( 83.3) (100.0) AEs leading to 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) withdrawal from trial SAEs 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) AEs leading to death 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 19MAY15:10:58:29 LP t01 sum ae.doc 1) AE= of adverse events. 2) Different adverse events within the same preferred term and system organ class and involving the same subject have been counted as one. 3) n=.

24 LP Sep-2015 Page 24 of Analysis of Adverse Events The most commonly reported AEs among all cohorts were within the primary SOC general disorders and administration site conditions, the most common PTs being application site pain and application site pruritus (Table 9). The number with AEs within the MedDRA high level group term administration site reactions increased with increasing dose of LEO (40, 54.5, 100, 83.3, and 100, respectively). Most of the administration site reactions were of mild or moderate intensity and the severe AEs were reported in the 2 highest dose cohorts involving 1 subject in the 0.05 group and 3 subjects in the group (Table 8 and Table 10). Adverse events within the eye disorders SOC were reported for 4 subjects (2 with periorbital oedema in the cohort and 1 in the cohort, and 1 with lacrimation increased in the cohort) (Table 9). A total of 6 subjects reported headache or tension headache and 4 subjects, all in the cohort, reported insomnia (Table 9).

25 LP Sep-2015 Page 25 of 36 Table 9 Adverse events by SOC and preferred term: safety analysis set System Organ Class (SOC) Preferred Term (n=10) of (n=11) of of 0.05 of of General disorders and administration site conditions Application site pain Application site pruritus Application site discomfort Application site paraesthesia Fatigue SOC total Nervous system disorders Headache Tension headache SOC total Eye disorders Periorbital oedema Lacrimation increased SOC total Psychiatric disorders Insomnia SOC total MAY15:11:24:55 LP t02 ae soc pt.doc Continued...

26 LP Sep-2015 Page 26 of 36 Table 9 Adverse events by SOC and preferred term: safety analysis set, continued System Organ Class (SOC) Preferred Term (n=10) of (n=11) of of 0.05 of of Gastrointestinal disorders Nausea Vomiting SOC total Blood and lymphatic system disorders Lymphadenopathy SOC total Ear and labyrinth disorders Ear pain SOC total Infections and infestations Gastroenteritis Hordeolum SOC total Injury, poisoning and procedural complications Laceration SOC total MAY15:11:24:55 LP t02 ae soc pt.doc Continued...

27 LP Sep-2015 Page 27 of 36 Table 9 Adverse events by SOC and preferred term: safety analysis set, continued System Organ Class (SOC) Preferred Term (n=10) of (n=11) of of 0.05 of of Respiratory, thoracic and mediastinal disorders Oropharyngeal pain SOC total Total number of adverse events 2 Total number MAY15:11:24:55 LP t02_ae_soc_pt.doc 1) Classification according to MedDRA version ) Different adverse events within the same preferred term and system organ class and involving the same subject have been counted as one. A single subject could appear in multiple classes.

28 LP Sep-2015 Page 28 of 36 Table 10 with Administration Site Reactions by intensity and cohort: safety analysis set (n=10) (n=11) Intensity of of of of of Mild Moderate Severe Total MAY15:11:27:50 LP t04 subj asr.doc

29 LP Sep-2015 Page 29 of Deaths, other Serious Adverse Events, and other Significant Adverse Events Deaths No deaths were reported Other Serious Adverse Events No SAEs were reported Other Significant Adverse Events Two subjects (Subject no. PPD and Subject no. PPD ) discontinued treatment with IP due to AEs after the first application but remained in the trial. Subject no. PPD had application site pain, application site pruritus, and insomnia, and subject no. PPD had application site pain and insomnia (Appendix 2.7 (Part 1), Listings 5-1 and 7-1). Narratives are provided in Section Local Skin Responses The treatment area was assessed at baseline (Day 1) and at each subsequent trial visit for the presence/absence and grade (0 to 4) of the following individual LSRs: erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. A composite LSR score (0 to 24), reflecting the sum of the individual LSR components, was calculated at each visit. The median maximum composite LSR score increased with increasing dose from to (Figure 1). No further increase was observed in the other dose cohorts (0.05 and 0.075). Individual LSR measurements are in Appendix 2.7, listing 7-4.

30 LP Sep-2015 Page 30 of 36 Figure 1 Maximum composite LSR score during Week 1 by cohort: safety analysis set Dose-limiting Toxicities The objective of Part 1 was to identify the MTD of LEO gel, after once daily treatment for 2 consecutive days. The MTD was defined as the highest dose level with less than 4 out of 12 subjects experiencing a DLT. The dose escalation rules are presented in Figure 2, an overview of DLTs in Table 11 and individual DLT measurements are in Appendix 2.7 (Part 1), Listing 7-4. No subjects met the predefined criteria for DLT (Table 11). However, as described in Section 5.1 there was a dose dependent increase in the number and severity of AEs. In cohort 5 (0.075), 3 out of 12 subjects experienced severe application site burning or pain (Appendix 2.7 [Part 1], Listing 7-3). Two of these subjects discontinued treatment (see narratives Section 8.1). Based on the general tolerability profile observed in this cohort, the dose escalation committee decided to stop dose escalation and appoint as the MTD.

31 LP Sep-2015 Page 31 of 36 Doses to be used in Part 2 Due to the increased number and intensity of application site reactions seen in cohort 5 (0.075) it was decided to move forward with the two doses 0.05 and in Part 2, both doses clearly better tolerated by the subjects than the dose. Figure 2 Dose Escalation Rules

32 LP Sep-2015 Page 32 of 36 Table 11 DLT by cohort: evaluable subjects analysis set (n=10) (n=11) Did subject experience DLT? of of of of of No Total MAY15:11:25:05 LP t03_dlt.doc

33 LP Sep-2015 Page 33 of Vital Signs, Physical Findings and other Observations Related to Safety Vital Signs and Physical Findings Vital sign monitoring showed no findings of concern. Listings are in Appendix 2.8 (Part 1), Listing ECG Assessments The ECG assessments were analysed by a central contract research organisation and the results evaluation and conclusion is presented in a separate ECG Safety Report. The ECG analysis assessed the change in ECG recordings from baseline to Day 3 for all dose cohorts. A small increase in QTcF was noted on Day 3 in one of the dose cohorts (0.05) but there was no obvious relationship to the dose administered regarding this effect. 5.5 Clinical Laboratory Evaluation There were sporadic elevations in clinical laboratory variables, but none of the abnormal laboratory values were considered clinically significant and none were reported as AEs. Haematology and biochemistry parameters are available in Appendix 2.8 (Part 1), Listings 8-1 and 8-2.

34 LP Sep-2015 Page 34 of 36 6 Overall Conclusions of Part 1 No formal MTD was identified as no subjects met the predefined criteria for DLT. Based on the general tolerability profile observed in the cohort, dose escalation was stopped at this dose level and was appointed as the MTD of LEO gel on scalp. Due to the intensity of application site AEs experienced by some subjects in the dose cohort, the doses 0.05 and were taken forward into Part 2 of the trial. All dose cohorts had subjects with AEs, most AEs were related to treatment and relatively few AEs were of severe intensity. The number and intensity of administration site reactions (MedDRA high level group term) increased with increasing dose and all severe administration site reactions were observed in the 0.05 and cohorts. There were no deaths and no SAEs. Two subjects discontinued treatment due to AEs. Vital signs and laboratory monitoring showed no evidence of safety concern. ECG monitoring showed no association between LEO gel treatment and evidence of cardiac effects.

35 LP Sep-2015 Page 35 of 36 7 References 1. ICH E3. Structure and Content of Clinical Study Reports. November ICH E3 (R1). ICH E3 Guideline: Structure and Content of Clinical Study Reports Questions and Answers. July ICH E6 (R1). Guideline for Good Clinical Practice. June ICH E9. Statistical Principles for Clinical Trials. February M4E(R1). The Common Technical Document for the Registration of Pharmaceuticals for Human Use Efficacy. September 2002

36 LP Sep-2015 Page 36 of 36 8 Narratives Part Other Significant Adverse Events Discontinuation from Treatment due to Adverse Event Subject PPD ; application site pain, application site pruritus, insomnia (all severe) >70 year-old This case concerns a. The subject was treated with LEO gel, 0.075, once. The treatment was administered on scalp. Day 1 Day 1 On the subject discontinued treatment due to application site pain, application site pruritus and insomnia. On Day 5 the subject started treatment with polysporin on the treatment area. The treatment with polysporin ended on Day 11. The stop dates of the events were Day 22 for application site pain and insomnia, and Day 11 for application site pruritus. The outcome of all events was recovered/resolved. Causality as per investigator: probable for all events. Subject PPD ; application site pain (severe), insomnia (moderate) >80 year-old This case concerns a. The subject was treated with LEO gel, 0.075, once. The treatment was administered on scalp. Day 1 Day 1 On the subject discontinued treatment due to application site pain and insomnia. On Day 2 the subject started treatment with topical xylocaine, applied on the treatment area due to the application site pain. The treatment with xylocaine ended on Day 5. The stop dates of the events were and, respectively. DAy 5 Day 3 The outcome of the events was recovered/resolved. Causality as per investigator: probable for both events.

37 LP Clinical Study Report Part 1 EudraCT no Sep-2015 ELECTRONIC SIGNATURES Electronic signature made within edoc LEO by LEO Pharma A/S employees or employees of any LEO Pharma A/S affiliate located anywhere in the world, are to be considered to be legally binding equivalent of traditional handwritten signatures. PPD PPD Signed by Meaning of Signature Server Date (dd-mmm-yyyy HH:mm GMT Z) PPD Medical 25-Sep :06 GMT+02 Approval PPD Biostatistics Approval 25-Sep :18 GMT+02