Clinical Study Report Pharmacokinetics of LEO 43204 gel in ... · This clinical study report is designed to comply with the standards issued by the International Conference on Harmonisation

Clinical Study Report

Pharmacokinetics of LEO 43204 gel in actinic keratosis administered

under maximum use conditions

An open-label, uncontrolled study to evaluate the systemic exposure and safety of LEO 43204 when applied to full face, balding scalp or an area of approximately 250 cm2

on the arm in subjects with actinic keratosis

A phase I, multi-centre, open-label, uncontrolled 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: LP0084-1077

Date: 05-Feb-2016

Version: Final

eDoc-00581041 - Version 1.0

Trial ID: LP0084-1077 05-Feb-2016 Page 2 of 201

Clinical Study Report Statement

Approval Statement LEO Pharma A/S

The following persons have approved this clinical study report using electronic signatures as

presented on the last page of this document:

MSc

Biostatistics

MD

Medical Department

Approval Statement, Co-ordinating 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:

Edward Lain, MD

International co-ordinating investigator

PPD

PPDPPD

PPD


Guidance Documents

This clinical study report is 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, E6 Good Clinical Practice, E9 Statistical Principles

for Clinical Trials, and M4 Common Technical Document (1, 2, 3, 4, 5).

Registration of the Clinical Trial

The trial was registered at ClinicalTrials.gov on 14-Apr-2015, trial registration number:

NCT02424305. The results are disclosed in accordance with applicable national regulations

and LEO Pharma A/S procedures.

Clinical Trial Period

Date of First Subject First Visit: 04-May-2015

Date of Last Subject Last Visit: 05-Aug-2015

Synopsis

The synopsis of this clinical study report exists as a separately approved document.


Table of Contents

Clinical Study Report Statement ................................................................................................ 2

Guidance Documents ................................................................................................................. 3

Registration of the Clinical Trial ................................................................................................ 3

Clinical Trial Period ................................................................................................................... 3

Synopsis ..................................................................................................................................... 3

Table of Contents ....................................................................................................................... 4

List of Tables (In-Text)............................................................................................................... 7

List of Figures (In-Text) ............................................................................................................. 8

List of Appendices...................................................................................................................... 9

List of Abbreviations and Definition of Terms ........................................................................ 11

1 Ethics ................................................................................................................................... 13

1.1 Institutional Review Board (IRB) ................................................................................... 13

1.2 Ethical Conduct of the Trial ............................................................................................ 13

1.3 Subject Information and Informed Consent .................................................................... 13

2 Investigators and Trial Administrative Structure................................................................. 14

3 Introduction ......................................................................................................................... 15

4 Trial Objectives ................................................................................................................... 17

4.1 Primary Objective............................................................................................................ 17

4.2 Secondary Objective........................................................................................................ 17

5 Investigational Plan ............................................................................................................. 18

5.1 Overall Trial Design ........................................................................................................ 18

5.1.1 Overview of the Trial .................................................................................................. 18

5.1.2 Trial Periods ................................................................................................................ 18

5.2 Discussion of Trial Design, Including the Choice of Control Groups ............................ 18

5.3 Selection of Trial Population........................................................................................... 19

5.3.1 Inclusion Criteria ......................................................................................................... 19

5.3.2 Exclusion Criteria........................................................................................................ 20

5.3.3 Removal of Subjects from Therapy or Assessment..................................................... 21

5.4 Treatments ....................................................................................................................... 22

5.4.1 Treatments Administered............................................................................................. 22

5.4.2 Investigational medicinal products.............................................................................. 22


5.4.3 Method of Assigning Subjects to Treatment Groups................................................... 23

5.4.4 Selection and Timing of Dose for each Subject .......................................................... 24

5.4.5 Blinding ....................................................................................................................... 24

5.4.6 Prior and Concomitant Therapy .................................................................................. 24

5.4.6.1 Prior to the Trial....................................................................................................... 24

5.4.6.2 During the Trial........................................................................................................ 24

5.4.7 Treatment Compliance ................................................................................................ 25

5.5 Assessments..................................................................................................................... 25

5.5.1 Frequency and Timing of Measurements .................................................................... 25

5.5.2 Baseline Characteristics and Demographics Assessed ................................................ 27

5.5.3 Pharmacokinetic Parameters Assessed ........................................................................ 27

5.5.4 Safety Measurements Assessed ................................................................................... 28

5.5.4.1 Adverse Events ........................................................................................................ 28

5.5.4.2 Other Events to be Reported.................................................................................... 28

5.5.4.3 12-lead ECG ............................................................................................................ 29

5.5.4.4 Vital Signs and Physical Examination..................................................................... 30

5.5.4.5 Clinical Laboratory Tests......................................................................................... 30

5.5.5 Appropriateness of Measurements .............................................................................. 31

5.6 Trial Endpoints ................................................................................................................ 31

5.6.1 Primary Endpoints ....................................................................................................... 31

5.6.2 Other Endpoints........................................................................................................... 31

5.7 Data Quality and Assurance ............................................................................................ 32

5.8 Changes to the Conduct of the Trial ................................................................................ 33

6 Statistical Methods .............................................................................................................. 34

6.1 Determination of Sample Size......................................................................................... 34

6.2 Statistical and Analytical Plan......................................................................................... 34

6.2.1 Subject Qualification for Analysis .............................................................................. 34

6.2.2 Subject Disposition...................................................................................................... 34

6.2.3 Baseline Characteristics .............................................................................................. 35

6.2.4 Exposure and Treatment Compliance.......................................................................... 35

6.2.5 Analysis of Primary Response Criteria ....................................................................... 35

6.2.6 Analysis of Safety ....................................................................................................... 35

6.2.6.1 Adverse Events ........................................................................................................ 35

6.2.6.2 Local Skin Responses (LSRs) ................................................................................. 36

6.2.6.3 Laboratory Safety Examinations ............................................................................. 37

6.2.6.4 Vital Signs................................................................................................................ 37

6.2.6.5 ECG ......................................................................................................................... 37


6.2.6.6 Amount of Investigational Medicinal Product Used ............................................... 37

6.2.7 General Principles ....................................................................................................... 37

6.3 Changes to the Statistical Analysis Plan.......................................................................... 38

6.4 Software and Dictionaries ............................................................................................... 38

7 Trial Population ................................................................................................................... 39

7.1 Disposition of Subjects.................................................................................................... 39

7.2 Protocol Deviations ......................................................................................................... 39

7.3 Trial Analysis Sets ........................................................................................................... 40

7.4 Demographics and other Baseline Characteristics .......................................................... 41

7.4.1 Demographics.............................................................................................................. 41

7.4.2 Medical history............................................................................................................ 43

8 Exposure and Treatment Compliance.................................................................................. 46

9 Pharmacokinetic Evaluation ................................................................................................ 48

9.1 Pharmacokinetic Results ................................................................................................. 48

9.2 Pharmacokinetic Conclusions ......................................................................................... 49

10 Safety Evaluation................................................................................................................. 50

10.1 Adverse Events................................................................................................................ 50

10.1.1 Brief Summary of Adverse Events .............................................................................. 50

10.1.2 Display of Adverse Events .......................................................................................... 50

10.1.3 Analysis of Adverse Events......................................................................................... 53

10.2 Deaths, other Serious Adverse Events, and other Significant Adverse Events ............... 60

10.2.1 Deaths and Other Serious Adverse Events .................................................................. 60

10.2.2 Other Significant Adverse Events ............................................................................... 60

10.3 Other Safety Assessment ................................................................................................. 61

10.3.1 Vital Signs and Physical Findings, and other Observations Related to Safety ........... 61

10.3.2 Local Skin Responses Assessment .............................................................................. 62

10.3.2.1 Local Skin Response Assessment............................................................................ 62

10.3.2.2 Composite Local Skin Response Score ................................................................... 63

10.3.2.3 Local Skin Response Components .......................................................................... 68

10.3.2.4 Local Skin Response Scores versus Amount of IMP Used ..................................... 72

10.3.3 ECG Assessments – Change from Baseline ................................................................ 74

10.4 Clinical Laboratory Evaluation ....................................................................................... 74

10.5 Safety Conclusions .......................................................................................................... 75

11 Discussion and Overall Conclusions ................................................................................... 76

11.1 Discussion ....................................................................................................................... 76


11.2 Overall Conclusions ........................................................................................................ 77

12 References ........................................................................................................................... 78

End-of-Text Tables and Figures, Baseline Characteristics, and Investigational Medicinal

Product Data

End-of-Text Tables and Figures, Safety Data

End-of-Text Listings

List of Tables (In-Text)

Table 1 Identity of investigational medicinal products ................................................. 23

Table 2 Schedule of trial procedures............................................................................. 26

Table 3 Subject enrolment and allocation by site: enrolled and included subjects ....... 39

Table 4 Sex, race, ethnicity and skin type: included subjects ....................................... 42

Table 5 AK count at baseline by site: safety analysis set.............................................. 44

Table 6 Duration of AK by site: safety analysis set ...................................................... 45

Table 7 AK treatment history: included subjects .......................................................... 45

Table 8 Skin disease history: safety analysis set ........................................................... 46

Table 9 Total drug usage by treatment group: safety analysis set................................. 47

Table 10 Overall summary of AEs: safety analysis set ................................................... 50

Table 11 Most common AEs by SOC and PT: safety analysis set .................................. 51

Table 12 AEs inside treatment area, excluding administration site reactions by SOC and PT: safety analysis set ...................................................................................... 52

Table 13 Administration Site Reactions by LLT: safety analysis set .............................. 53

Table 14 Intensity of AEs by SOC and PT: safety analysis set....................................... 55

Table 15 Intensity of administration Site Reactions by LLT: safety analysis set............ 56

Table 16 Related AEs by SOC and PT: safety analysis set ............................................. 58

Table 17 Change in vital signs from baseline to Day 15: safety analysis set.................. 62

Table 18 Composite LSR score by visit: safety analysis set ........................................... 65


Table 19 Summary of visit of maximum post baseline composite LSR score: safety analysis set........................................................................................................ 66

Table 20 Summary of visit of return to baseline for composite LSR score: safety analysis set........................................................................................................ 67

Table 21 Maximum post baseline LSR score by LSR component: safety analysis set... 69

List of Figures (In-Text)

Figure 1 Trial analysis sets – overall .............................................................................. 40

Figure 2 Trial analysis sets by treatment group.............................................................. 41

Figure 3 Composite LSR score – mean profiles by treatment group: safety analysis set.......................................................................................................................... 63

Figure 4 Composite LSR score – individual profiles by treatment group: safety analysis set ..................................................................................................................... 64

Figure 5 Maximum post baseline composite LSR score by treatment group: safety analysis set........................................................................................................ 66

Figure 6 LSR component scores by visit and treatment group: safety analysis set........ 71

Figure 7 Maximal composite LSR score versus total drug usage: safety analysis set ... 72

Figure 8 Maximal composite LSR score versus Cmax: PK analysis set ........................ 73

Figure 9 Cmax versus total drug usage: PK analysis set ................................................ 74


List of Appendices

Trial Information

Appendix No. Appendix Title Status

Appendix 1.1 Clinical Study Protocol and Amendments Enclosed

Appendix 1.2 Sample CRF Enclosed

Appendix 1.3 List of IEC or IRBs and Representative Written Information for the Subjects and Sample Consent Form

Enclosed

Appendix 1.4 Trial Administrative Structure, List of Investigators and CV for International Coordinating Investigator

Enclosed

Appendix 1.5 Signatures of Coordinating Investigator Enclosed

Appendix 1.6 Listing of Subjects receiving Investigational MedicinalProduct from Specific Batches

Enclosed

Appendix 1.7 Randomisation Scheme and Codes Enclosed

Appendix 1.8 Audit Certificate NA

Appendix 1.9 Documentation of Statistical Methods Enclosed

Appendix 1.10 Documentation of Inter-Laboratory Standardisation Methods and Quality Assurance Procedures

NA

Appendix 1.11 Publications based on the Trial NA

Appendix 1.12 Important Publications Referenced in the Clinical Study Report

Available upon request

Listings

Appendix No. Appendix Title Status

Appendix 2.1 Discontinued Subjects Enclosed

Appendix 2.2 Protocol Deviations Enclosed

Appendix 2.3 Trial Analysis Sets Enclosed

Appendix 2.4 Demographic Data Enclosed

Appendix 2.5 Compliance and/or Investigational Medicinal Product Concentration Data

Enclosed

Appendix 2.6 Pharmacokinetic Data NA

Appendix 2.7 Safety Data Enclosed

Appendix 2.8 Listing of Laboratory Values by Subject Enclosed


Case Report Forms

Appendix No Appendix Title Status

Appendix 3.1 CRFs for Deaths, other SAEs, and Withdrawals due to AEs

NA

Appendix 3.2 Other CRFs Submitted NA

Additional Related Reports (not part of the appendices)

Report title Status

Cardiovascular Safety Report Enclosed

Pharmacokinetic Report: Pharmacokinetics of LEO 43204 in actinic keratosis administered under maximum use conditions

Enclosed

Determination of LEO 43204 and LEO 136441A in Human Plasma from a clinical study entitled "Pharmacokinetics of LEO 43204 gel in actinic keratosis administered under maximal use conditions"

Enclosed


List of Abbreviations and Definition of Terms

ADR Adverse drug reaction

AE Adverse event

AK Actinic keratosis

AUC Area under the concentration-time curve

AUC0-last Area under the concentration-time curve from time zero up to the time of the last quantifiable concentration

BCC Basal Cell Carcinoma

CRF Case report form

CRP C-reactive protein

CRO Contract research organisation

CMO Contract manufacturing organisation

Cmax Maximum observed concentration

ECG Electrocardiogram

EDC Electronic Data Capture

EU European Union

GCP Good Clinical Practice

ICH International Conference on Harmonisation

ICTM International Clinical Trial Manager

IEC Independent ethics committee

IMP Investigational Medicinal Product

IRB Institutional review board

LLOQ Lower limit of quantification

LLT Lower level term

LSR Local Skin Response

MedDRA Medical Dictionary for Regulatory Activities

MUSE Maximum use systemic exposure

SAE Serious adverse event

SAPU Statistical Analysis Plan Update

SCC Squamous Cell Carcinoma

SOC System Organ Class

SOP Standard Operating Procedure

Tmax Time to maximum observed concentration

T½ Half life

US United States

UVA Ultraviolet Light A


UVB Ultraviolet Light B

WHO World Health Organisation

Definition of Terms

Terms defined by ICH Guidelines are not mentioned here.

Assessment

A (cluster of) characteristic(s) measured and/or recorded for a subject.

Concomitant Medication

Any medication used by a subject during the clinical trial apart from the trial medication.

Enrolled Subject

A subject for who informed consent has been obtained and who has been registered in a

clinical trial.

Endpoint

An assessment or a transformation of the assessment(s) described on a subject level, for

which a statistical analysis is performed, i.e. a p-value or a confidence interval is stated, or for

which tabulation serves as important supportive evidence of efficacy/safety.


1 Ethics

1.1 Institutional Review Board (IRB)

The clinical study protocol and any relevant amendments to the clinical study protocol were

approved by/received favourable opinion from the relevant Institutional Review Boards

(IRBs) before the enrolment of subjects.

The appropriate regulatory authorities were notified of/approved the clinical trial, as required.

The details of the IRB consulted are given in Appendix 1.3.

1.2 Ethical Conduct of the Trial

This clinical trial was conducted in accordance with the revision current at the start of the trial

of the World Medical Association’s Declaration of Helsinki – Ethical Principles for Medical

Research Involving Human Subjects.

All subjects received written and verbal information concerning the clinical trial as specified

in Section 1.3.

Subjects were asked to consent that their personal data were recorded, collected, processed

and could be transferred to EU and non-EU countries in accordance with any national

legislation regulating privacy and data protection.

1.3 Subject Information and Informed Consent

All subjects received written and verbal information concerning the clinical trial. This

information emphasised that participation in the clinical trial was voluntary and that the

subject could withdraw from the clinical trial at any time and for any reason. All subjects

were given an opportunity to ask questions and were given sufficient time to consider before

consenting.

The subject’s signed and dated informed consent to participate in the clinical trial was

obtained prior to any trial related activities being carried out in accordance with ICH GCP

Section 4.8 and all applicable laws and regulations.

A representative subject information sheet and informed consent form is provided in

Appendix 1.3.


2 Investigators and Trial Administrative Structure

LEO Pharma A/S was the sponsor of the clinical trial and participating LEO affiliates were

authorised by the sponsor to act on behalf of the sponsor in the countries where the clinical

trial was conducted.

Appendix 1.4 contains detailed information about the trial administrative structure including

authors of the clinical study report as well as a list of trial sites and investigators.


3 Introduction

Actinic Keratosis

Actinic keratosis (AK) is a common skin condition visible as thickened, cornified, scaly

lesions and characterised histologically by atypical epithelial proliferation (6). The lesions

primarily develop on areas that are frequently exposed to the sun (e.g., face, ears, scalp, neck,

forearms, and the back of the hands).

In population studies performed in the EU and US, reported prevalence rates for AK have

been approximately 11-25% of the population, while estimates are higher in Australian studies

(up to 60%) (7, 8, 9). Patients with AK tend to have Fitzpatrick type I or II skin (fair skin)

which burns with sun exposure and does not tan or tans minimally (7).

There is increasing evidence that AK represents squamous cell carcinoma (SCC) in situ in its

earliest stages (6, 10, 11). Histological evidence shows that contiguous AK is present in 97%

of SCC lesions on sun-damaged skin (10). AK is epidemiologically linked to development of

SCC (12), and both conditions share specific gene expression (13). If left untreated, AK may

progress to SCC, resulting in increased morbidity (10).

AK usually occurs on large, actinically damaged areas of the skin (field cancerisation). Field

cancerisation is characterised by the epithelial surface being more susceptible to the

development of AKs or malignancies than normal skin due to DNA mutations generated in

epidermis as a result of excessive sun exposure. This is evidenced by the presence of multiple

subclinical and clinically visible AK lesions as well as multifocal pre-neoplastic changes with

genetic mutations (14). Once field cancerisation has developed, new AKs will continue to

develop. Most treatment therapies are topical, i.e. directed against discrete, visible AKs, and

there is an unmet need for improved therapies for field treatment that will reduce rate of

recurrence of AKs.

Investigational Medicinal Product

LEO 43204 is a novel ingenol derivative being developed for field treatment of AKs on full

face, balding scalp and treatment areas of approximately 250 cm2 (40 in2) on the trunk and

extremities.

LEO 43204 was selected for clinical development based on preclinical data suggesting a

mode of action similar to ingenol mebutate with effects on cell death, protein kinase C, and

stimulation of inflammatory cytokines.

Maximal tolerated doses (MTD) and dose-responses of LEO 43204 have been identified

through dose escalation trials (Part 1 of Trials LP0084-1013, LP0084-1014, and LP0084-


1015) on face/chest, scalp, and trunk/extremities, respectively, using a dosing regimen of once

daily for two consecutive days. Each of these trials consists of a dose escalation part (Part 1)

used for identification of MTD and an efficacy part (Part 2) where the efficacy of doses

selected from Part 1 are evaluated.

In the LP0084-1013, LP0084-1014, and LP0084-1015 trials pre-defined grades of Local Skin

Responses (LSRs) constituted Dose Limiting Toxicity (DLT). The levels of skin reactivity

constituting DLT do not reflect safety concerns but represent what dermatologists consider

limits for peak levels of acceptable visible skin reactions for a given anatomical location.

In Trial LP0084-1013 (face/chest) the MTD was 0.018%, and at this dose LSRs were mild

and application site adverse events (burning, pain) minimal. In Trial LP0084-1014 (scalp) no

subjects met the predefined criteria for DLT and thus no formal MTD was identified using the

pre-defined DLT criteria. Dose escalation was, however, stopped at the 0.075% dose level as

the investigators in this trial felt that the application site adverse events – although

manageable – could pose a problem for some subjects. For this reason Part 2 of

Trial LP0084-1014 was continued with the two doses 0.05% and 0.037%, both doses clearly

better tolerated by the subjects than the 0.075% dose. In Trial LP0084-1015

(trunk/extremities) no DLTs were identified at the highest dose of 0.1% which was well

tolerated by the subjects.

In Trial LP0084-1148 there were early safety and tolerability evaluations performed for each

arm following treatment for 3 days in 18 subjects. As the safety and tolerability were found

acceptable by the Early Data Review Committee, the 3-day regimens were considered

tolerable and were used in the present MUSE trial (LP0084-1077). Enrolment was to be to

treatment groups A and B first, until these were fully recruited as based on the results from the

LP0084-1148 which confirmed that the treatment to be taken forward to phase 3 for the scalp

indication was 0.037% daily for 3 days.


4 Trial Objectives

4.1 Primary Objective

To evaluate systemic exposure under maximum use conditions of LEO 43204 on full face,

balding scalp or on a treatment area of approximately 250 cm2 on the arm.

4.2 Secondary Objective

To evaluate safety under maximum use conditions of LEO 43204 on full face, balding scalp

or on a treatment area of approximately 250 cm2 on the arm.


5 Investigational Plan

5.1 Overall Trial Design

5.1.1 Overview of the Trial

This was an open-label, uncontrolled, non-randomised multi-centre trial to evaluate the

systemic exposure and safety of LEO 43204 when applied to full face, balding scalp or an

area of approximately 250 cm2 on the arm in subjects with actinic keratosis.

The trial included three active treatment groups: (A) once daily application of LEO 43204 gel

0.018% on the full face (minimum 250 cm2), (B) once daily application of LEO 43204 gel

0.1% on the arm on a treatment area of approximately 250 cm2, and (C) once daily application

of LEO 43204 gel 0.037% on approximately 250 cm2 on the balding scalp. For all three

treatment groups treatment application was for three consecutive days.

For all subjects, the treatment was applied at the investigator’s clinic once daily for three

consecutive days. Subjects had a total of approximately 6 visits and were followed for

2 weeks.

The individual parts of the trial consisted of:

Screening: up to 3 weeks

Treatment: 3 days

Post-treatment assessments and sample collections: 1 day

Follow-up: up to 2 weeks post-dose

5.1.2 Trial Periods

The trial consisted of a single period which is briefly described above.

5.2 Discussion of Trial Design, Including the Choice of Control Groups

The trial evaluated the systemic exposure and safety of LEO 43204, when treating larger

areas, under maximal use conditions in subjects in the upper range of the disease severity.

For the purpose of this trial the upper range of disease severity is defined as ≥15 clinically

typical, visible discrete AKs in the treatment areas. The to-be-marketed formulation was used

in this trial.

The entire clinical study protocol and any amendments are presented in Appendix 1.1 and the

unique pages of the case report form (CRF) are presented in Appendix 1.2.


5.3 Selection of Trial Population

5.3.1 Inclusion Criteria

1. Signed and dated Informed Consent has been obtained.

2. Subjects with 15 or more clinically typical, visible and discrete AKs on either:

a. Full face (corresponding to a treatment area of at least 250 cm2 or 40 in2). If

subjects have a beard they must shave no later than the day before first

application of investigational medicinal product.

b. A contiguous area of approximately 250 cm2 (40 in2) on the arm between

wrist and shoulder.

c. Balding scalp (corresponding to a treatment area of approximately 250 cm2).

Subjects with sparse hair on the scalp can be enrolled as long as LSR and AK

assessments are not compromised.

3. Subject at least 18 years of age

4. Female subjects of childbearing potential must be confirmed not pregnant by a

negative urine pregnancy test prior to trial treatment. (Female subjects are considered

of childbearing potential unless they have had a hysterectomy, have undergone tubal

ligation or have been post-menopausal for at least one year prior to first visit.)

5. Female subjects of childbearing potential must be willing to use effective

contraception at trial entry and until completion. Effective contraception is defined as

follows:

a. Abstinence (when this is in line with the preferred and usual lifestyle of the

subject)

b. Vasectomised partner (partner should be the sole partner for the subject)

c. An intrauterine device

d. Double barrier method defined as two distinct methods (either two actual

barrier methods or one actual barrier method and one hormonal method)


e. Hormonal contraceptive (oral hormonal birth control, oestrogenic vaginal

ring, percutaneous contraceptive patches, implants, and injectables) for at

least one menstrual cycle prior to enrolment.

5.3.2 Exclusion Criteria

1. Location of the treatment area (full face, full balding scalp, arm)

within 5 cm (2 in) of an incompletely healed wound

within 5 cm (2 in) of a suspected basal cell carcinoma (BCC) or SCC.

2. Previously assigned treatment in this clinical trial or previously participated in a

clinical trial in the LEO 43204 programme.

3. Treatment with ingenol mebutate gel in the selected treatment area within the last

12 months.

4. Subjects who have received treatment with any non-marketed drug substance (i.e., an

agent which has not yet been made available for clinical use following registration)

within the last 30 days.

5. Lesions in the treatment area that have: atypical clinical appearance (e.g.,

hypertrophic, hyperkeratotic or cutaneous horns) and/or, recalcitrant disease (e.g., did

not respond to cryotherapy on two previous occasions).

6. History or evidence of skin conditions other than the trial indication that would

interfere with the evaluation of the trial medication (e.g., eczema, unstable psoriasis,

xeroderma pigmentosum) at the investigator’s discretion.

7. Use of cosmetic or therapeutic products and procedures which could interfere with the

assessments of the treatment area.

8. Clinical diagnosis/history or evidence of any medical condition that would expose a

subject to an undue risk of a significant adverse event (AE) or interfere with

assessments of safety and efficacy during the course of the trial, as determined by the

investigator's clinical judgement.

9. Subjects infected with HIV.

10. Subjects with any hematological malignancy.

11. Any abnormal laboratory test that is clinically significant and would impact the safety

of the subjects or the interpretation of the study results, as determined by the

investigator. Male subjects with QTcF interval >450 ms and female subjects with

QTcF interval >470 ms (The QTcF intervals are not relevant for subjects with cardiac

pacemaker.) Other abnormal ECG findings that are clinically significant and would


impact the safety of the subjects or the interpretation of the study results, as

determined by the investigator.

12. Known sensitivity or allergy to any of the components in the LEO 43204 gel.

13. Presence of acute sunburn within the treatment area.

14. Current participation in any other interventional clinical trial.

15. Female subjects who are breastfeeding.

16. In the opinion of the investigator, the subject is unlikely to comply with the Clinical

Study Protocol (e.g. alcoholism, drug dependency, or psychotic care).

Prohibited Therapies and/or Medications within 2 weeks prior to Visit 2/Day 1

17. Cosmetic or therapeutic procedures (e.g., use of liquid nitrogen, surgical excision,

curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing):

within 2 cm (1 in) of the treatment area.

18. Use of topical keratolytic therapeutic products (e.g., alpha- and beta- hydroxy acids,

including glycolic acid, lactic acid and other fruit acids, salicylic acid, topical

retinoids, urea or light chemical peels): within 2 cm (1 in) of the treatment area.

19. Use of topical medicated creams, ointments, lotions, gels, foams or sprays including

topical steroids: within 2 cm (1 in) of the treatment area; artificial tanners: within 5 cm

of the treatment area. (Non-medicated/non-irritant lotions/creams/sunscreens are

acceptable).

Prohibited Therapies and/or Medications: within 4 weeks prior to Visit 2/Day 1

20. Treatment with systemic chemotherapeutic antineoplastic therapy.

21. Treatment with systemic medications that suppress the immune system (e.g.,

cyclosporine, prednisone).

Note: inhaled, nasal, intra-articular, ophthalmic and intra-auricular corticosteroids are

permitted

22. Treatment/therapy with ultraviolet light A (UVA) or ultraviolet light B (UVB)

23. Treatment with imiquimod within 2 cm of the treatment area.

5.3.3 Removal of Subjects from Therapy or Assessment

Subjects may have withdrawn for any of the following reasons:


1. Unacceptable treatment efficacy: the investigator was free to withdraw the subject at

any time for medical reasons.

2. Unacceptable adverse events/LSRs: any adverse events/LSRs that the investigator or

the subject considered unacceptable.

3. Exclusion criteria: any exclusion criteria which emerged/became apparent during the

subject’s participation in the clinical trial.

4. Voluntary withdrawal: subjects were free to withdraw from the clinical trial at any time

and for any reason. If applicable, the subject´s legal representative can withdraw the

subject from the trial.

5. Other reasons: other reasons than stated above which required the subject to (be) with-

draw(n) should be specified.

Subjects who were discovered, after enrolment not to have fulfilled all in-/exclusion criteria at

time of enrolment, were to have been withdrawn from treatment unless the investigator, based

on clinical and ethical evaluation, found withdrawal inappropriate. Such deviation(s) from the

(Consolidated) Clinical Study Protocol should have been reported to LEO Pharma A/S (and

IEC/IRB, as appropriate) and are recorded in the Clinical Study Report.

Reason(s) for withdrawal were recorded in the CRF.

It was estimated that the number of subjects included in the trial was adequate to ensure

16 completers in each of the three 3-day treatment groups.

Enrolment was to continue until the required number of completers was achieved.

5.4 Treatments

5.4.1 Treatments Administered

The investigational medicinal product (IMP) was administered by trained trial staff using

gloves at Visit 2, Visit 3 and Visit 4 according to the explicit guidance in Section 10.2.1 in the

clinical study protocol (Appendix 1.1). In addition, a special tool was supplied to trial staff to

ensure that as much IMP was emptied from the tube for application.

During each application a thin and wet layer of IMP was to be applied evenly on the treatment

area.

5.4.2 Investigational medicinal products

Details of the investigational medicinal products are given in Table 1.


Table 1 Identity of investigational medicinal products

Name of finished IMP: LEO 43204 0.018%, 0.037%, and 0.1% gel

Formulation: Gel

Active ingredient name/strength: LEO 43204/0.018% (Face), 0.037% (Scalp), and 0.1% (Arm)

Excipients:

Manufacturer’s name: LEO Pharma A/S

55 Industriparken

2750 Ballerup

Denmark

Or

LEO Laboratories Ltd

285 Cashel Road

Dublin 12

Ireland

Lot numbers/expiry dates 132717101/AUG2015 (Face 0.018%)

P14007/FEB2016 (Scalp 0.037%)

P14013/FEB2016 (Arm 0.1%)

5.4.3 Method of Assigning Subjects to Treatment Groups

Subjects who complied with all the inclusion and exclusion criteria were enrolled to receive

treatment with either LEO 43204 0.018% on the face (Treatment group A), LEO 43204 0.1%

on the arm (Treatment group B) or LEO 43204 0.037% on the balding scalp (Treatment group

C).

It was the responsibility of the International Clinical Trial Manager (ICTM) by use of the

electronic data capture (EDC) to have oversight that an adequate number of subjects were

enrolled in each treatment group. Sites were regularly updated by the ICTM on the total

number of subjects recruited in the study and were informed when recruitment in each group

was to be stopped. Subjects eligible for more than one treatment group were assigned to a

treatment group in the following order:

Treatment group A (face)

CCI


Treatment group B (arm)

Treatment group C (scalp)

5.4.4 Selection and Timing of Dose for each Subject

The selected doses have been tested in phase 1/2 trials to confirm safety and tolerability of the

regimen for each anatomical region (LP0084-13, LP0084-14, and LP0084-15).

The IMP should have been applied at approximately the same time at all treatment days with a

time window of +/- 1 hour allowed. There were no specific requirements for timing of dose

with relation to dietary intake.

5.4.5 Blinding

Not applicable as this is an open-label trial.

5.4.6 Prior and Concomitant Therapy

5.4.6.1 Prior to the Trial

Prohibited treatments and procedures prior to trial entry are detailed in the Exclusion Criteria

(Section 5.3.2).

5.4.6.2 During the Trial

Use of non-marketed/other investigational medicinal products during the trial was not

permitted.

All medications currently being taken at the time of Visit 1 were to be recorded in the CRF,

along with the reasons for administration of the medication or treatment as well as location,

described as in the treatment area, outside the treatment area or not applicable.

Any medication taken, treatments given or procedures performed during the trial were to be

recorded along with the indication.

Subjects could have been advised to use icepacks and cooling fans to attenuate any burning

sensation and pain. Icepacks and cooling fans were not considered a medical intervention but

should be recorded as a concomitant treatment. Topical applied analgesics could have been

used only in case icepacks and cooling fans did not give relief.

Subjects should not have undergone any elective medical procedure without prior consultation

with the investigator. Elective procedures (e.g., minor day-surgery, dental surgery, etc.) that


might require hospitalisation or anaesthesia should have been deferred during the first 15 days

after first application (Visit 2), whenever clinically appropriate or possible.

5.4.7 Treatment Compliance

Responsibilities for IMP Storage and Dispensing

The investigator was fully responsible for the IMPs at the trial site but could delegate, e.g., to

a hospital pharmacy as locally applicable. The person responsible for dispensing the IMPs

was responsible for maintaining adequate control of the IMPs and for documenting all

transactions with them. IMPs were to be stored in a safe and secure place, and proper

dispensing arrangements must have been made.

Sponsor-Investigator IMP Accountability

All IMPs supplied by the Contract Manufacturing Organisation (CMO) on behalf of LEO

Pharma A/S were to be returned to the CMO. Prior to their return, they were to be fully

accounted for by the monitor with the help of the person responsible for dispensing the IMPs.

Accountability was documented by using drug accountability forms.

IMPs may have been returned from the trial site either to the CMO directly or via the LEO

Pharma A/S affiliate/CRO responsible for the running of the clinical trial.

Investigator-Subject IMP Accountability

An inventory was kept of the IMPs assigned to each subject enrolled in the trial. This

inventory was available for inspection during monitoring visits and was checked by the

monitor to ensure correct dispensing of investigational medicinal product.

End of IMP Accountability

The IMPs returned to the CMO were reconciled. The used tubes were weighed individually.

5.5 Assessments

5.5.1 Frequency and Timing of Measurements

The schedule of all trial procedures for all trial visits is presented in Table 2.


Table 2 Schedule of trial procedures

Visit Number 1 2 3 4 5 6 Unscheduled

/ Early Term1)

Visit Screening Day 1 Day 2 Day 3 Day 4 Day 15 NA

Window Day -21 to Day -1

±2 Days

Informed Consent X

Inclusion/exclusion criteria

X X2)

Demographic data X

Body weight and

height

X

Fitzpatrick skin

type

X

Skin disease

history

X

AK treatment

history

X

Medical/surgical

history3)

X

Physical

examination

X X

Vital signs X X X

Urine pregnancy

test4)

X X X X

Clinical laboratory

evaluations

X X9) X5) X

ECG X X9) X5) X

Treatment

assignment

X

Identify treatment

area

X

AK lesion count X

Investigational

medicinal product

application6)

X X X

Compliance X X X

Concomitant

medication/

procedures

X X X X X X X

Adverse event X X X X X X


Visit Number 1 2 3 4 5 6 Unscheduled

/ Early Term1)

Visit Screening Day 1 Day 2 Day 3 Day 4 Day 15 NA

Window Day -21 to Day -1

±2 Days

LSR X X X X X X

24 hour Urine

sampling for

Metabolite

profiling7)

X

Blood sampling for

PK and metabolite

profiling8)

+ 2 h

+ 8 h

+ 24 h

(predose)

0h

(predose)

+ 2 h

+ 4 h

+ 8 h

+ 12 h

+ 24 h

1. For unscheduled visits, only assessments that are required as judged by the investigator were to be conducted

2. Recheck

3. Medical/surgical history within 12 months

4. Only subjects of childbearing potential

5. To be performed only if there are clinically significant changes from Baseline (Visit 1) at Visit 4

6. Investigational medicinal product should be applied at approximately the same time all three days. A time window of ±1 hour is

allowed

7. Urine collection will be collected for 24 hours in two 12 hour containers labelled as container #1 and #2. First container will be, started

at the PI site on Day 3 (Visit 4) and the second container will be taken home, to be returned at Day 4 (Visit 5).The start and stop time

for each container will be recorded in the CRF.

8. A time window of ±10 min relative to the given time points is allowed. A window of ±30 min is allowed for the 8 hour and 12 hour

sample and a window of ±1 hour is allowed for the 24hour sample.

9. To be performed after the 12 hour PK sample

5.5.2 Baseline Characteristics and Demographics Assessed

Demographics include age, sex, race, ethnicity, and skin type. Other baseline characteristics

include height, weight, BMI, vital signs, concurrent diagnoses, and concomitant medication.

Baseline AK characteristics include treatment location and baseline lesion count for the

treatment area, duration of disease, previous treatment of AKs (anywhere) and previous

treatment of AKs in the treatment area.

5.5.3 Pharmacokinetic Parameters Assessed

Blood samples (2 × 4 mL at each time point) were drawn for the pharmacokinetic analysis of

LEO 43204 and its major metabolite (LEO136441A). The time points are presented in Table

2. In addition, urine samples were collected over a 24 hour period on Day 4 (these results will

be reported separately).


The following pharmacokinetic (PK) parameters were calculated, if possible, for each assayed

compound based on the obtained blood concentrations: AUC0-tlast, AUC0-∞, Cmax, Tmax, and T½.

The lower limit of quantification (LLOQ) was 5 pg/mL.

5.5.4 Safety Measurements Assessed

5.5.4.1 Adverse Events

The definition of adverse events and serious adverse event as well as the means of obtaining

and reporting events and the rating of these, are described in the clinical trial protocol

(Section 9 and Appendix 3 and 4) in Appendix 1.1.

5.5.4.2 Other Events to be Reported

Adverse Events of Special Interest

Due to the sun-damage, the target population is prone to SCC development. Sun-damaged

skin also is prone to development of keratoacanthoma (KA) as a response to local irritation

and/or inflammation. To ensure that all information relevant for surveillance was collected,

SCCs and KAs in the selected treatment area were considered adverse events of special

interest.

For SCCs and KAs in the selected treatment area, the relevant information was to be collected

in the CRF. In addition, the histology report should be faxed or emailed to Global

Pharmacovigilance using the following fax number or email address.

SCCs and KAs in the selected treatment area that meet the criteria for being serious should

have been reported as SAEs.

The pathology slides that have been used for the initial diagnosis of SCC or KA were to be

sent for central pathology review. Central pathology reports were to be distributed to the

investigator. If there were any discrepancies between the local pathology report and the

central pathology report, there should not be any changes in the CRF. Only if the original

slides could not be sent was it acceptable to use new slides made from the tissue block.

Local Skin Responses

Assessment of local skin responses in the treatment area using the LSR Grading Scale were

performed at Visit 2 and at all subsequent visits as indicated in Table 2.

Local skin responses are defined as erythema, flaking/scaling, crusting, swelling, vesiculation/

pustulation and erosion/ulceration. The presence/absence and grade of each LSR were


recorded using the LSR Grading Scale shown in the Clinical Trial Protocol Appendix 5. This

grading scale was also provided as a hard copy to the site. Any local skin responses identified

within the treatment area that did not match the criteria in the LSR Grading Scale should have

been reported as AEs.

Pregnancy and lactation

A pregnancy with conception during the clinical trial with an IMP must have been reported to

LEO Pharma A/S within 24 hours of first knowledge using the Pregnancy Follow-up Form.

All such pregnancies must be followed up until delivery or termination and final outcome

should be reported.

Overdose, Medication Errors, Misuse and Intended Abuse

AEs originating from overdose, medication errors, misuse and intended abuse were to be

documented on the adverse event form of the CRF book. In addition the term

overdose/medication error/misuse/intended abuse must have been documented on a separate

line.

Aggravation of condition

Any clinically significant aggravation/exacerbation/worsening of the medical condition(s),

compared to baseline, should have been reported as an AE.

5.5.4.3 12-lead ECG

A standard 12-lead ECG was recorded after 5 minutes of rest in the supine position. Each

recording was marked with the Subject number, date and time of the recording.

The following ECG parameters were recorded: heart rate, PR interval, QRS duration, QT

interval, QTc interval. The ECG was performed at the Visits specified in Schedule/Chart of

Trial Procedures (Section 3.1). Subjects with QTcF interval >450 ms for men and 470 ms for

women or other relevant pathological changes in the ECG in opinion of the investigator

should be excluded. These intervals apply at screening. Clinically significant ECG findings

from the screening visit should be recorded as medical history. Clinically significant ECG

findings from subsequent visits should be recorded as an AE.

The ECG data were interpreted by a central CRO and the results were made available to the

investigator.


5.5.4.4 Vital Signs and Physical Examination

Vital signs (resting blood pressure and heart rate) and oral or ear temperature were obtained.

Abbreviated physical examination including general appearance, regional lymph nodes, and

dermatological examination of the skin in general was conducted at Visit 1.

5.5.4.5 Clinical Laboratory Tests

Blood samples were collected for central laboratory analyses (haematology and biochemistry)

and pharmacokinetic analysis at visits specified in the Schedule/Chart of Trial Procedures

(Table 2).

Haematology

Leucocytes, erythrocytes, haemoglobin, haematocrit, thrombocytes, mean corpuscular

volume, automated differentiation: lymphocytes, monocytes, eosinophils, basophils,

neutrophils.

Biochemistry

Total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), aspartate

aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine

aminotransferase (ALT)/serum glutamic pyruvate transaminase (SGPT), lactate

dehydrogenase, creatinine, urea, uric acid, total protein, albumin, globulin, glucose,

bicarbonate, inorganic phosphate, sodium, potassium, calcium, chloride, magnesium.

The sampling, storage and shipment procedures were to be carried out according to the central

laboratory manual.

Minimum volume of blood, corresponding to approximately 10.5 mL, was taken for

haematology and biochemistry panels. 2 × 4 mL blood was to be drawn for pharmacokinetic

analysis at each sampling time point.

For female subjects of childbearing potential a urine pregnancy test was to be performed and

tested locally.

The investigator was to evaluate all results outside the reference range (‘clinically significant’

or ‘not clinically significant’) and sign and date the results form. The signed and dated version

was filed with the investigator’s trial documentation. If a result was considered clinically

significant and it fulfilled the criteria for a clinical laboratory AE, it should have been reported

in accordance with Section 10.7.5 of the clinical trial protocol. Clinically significant

laboratory findings from the screening visit were to be recorded as ongoing medical history,


and it was at the investigator’s discretion if the subject should have been enrolled into the

trial.

5.5.5 Appropriateness of Measurements

Drug Concentration Measurements

A validated bioanalytical assay was used for quantification of LEO 43204 and the metabolite

LEO136441A in human plasma (Section 6.2.5).

Safety Assessments

Safety was assessed using standard clinical methods of subject evaluations, such as AE

monitoring, vital signs measurements, ECG, physical examination, and laboratory tests.

Measurements of LSR incidence and grade, developed and used during the ingenol mebutate

gel development programme, were used as in all previous trials with LEO 43204.

5.6 Trial Endpoints

5.6.1 Primary Endpoints

The following pharmacokinetic (PK) parameters were calculated, when possible, for the

LEO 43204 based on the obtained plasma concentrations: AUC0-tlast, AUC0-∞, Cmax, Tmax, and

T½.

5.6.2 Other Endpoints

Standard safety data and local skin responses were reported.

Evaluation of (Serious) Adverse Events and LSRs

Incidence of AEs and SAEs

Incidence and severity of LSRs following treatment

Incidence of AEs and LSRs leading to discontinuation of trial medication


Evaluation of Laboratory Data

Abnormal haematology and biochemistry laboratory values

Vital Signs and Physical Findings

Change in vital signs

5.7 Data Quality and Assurance

Quality Assurance System

LEO Pharma A/S has implemented a system of quality assurance, including all the elements

described in this report. Within this system company Standard Operating Procedures (SOPs)

are implemented to ensure that clinical trials are conducted in compliance with regulatory

requirements and Good Clinical Practice (GCP). Quality control is applied to each stage of

data handling to ensure that data are accurate, reliable and processed correctly.

Trial sites, facilities, laboratories and all data (including sources) and documentation were

available for GCP audit by LEO Pharma A/S or inspection by competent authorities.

Trial Monitoring

LEO Pharma A/S, as sponsor of this clinical trial, is responsible to the authorities for assuring

the proper conduct of the trial with regard to protocol adherence and validity of the data

recorded on the CRFs. The company, therefore, assigned persons to monitor this clinical trial.

It was their duty to serve as the principal link between (sub)investigators and LEO Pharma

A/S and advise the investigators on the collection and maintenance of complete, legible, well

organised, and easily retrievable data for the clinical trial. In addition, they were to explain to

the investigators any aspect of the (conduct of the) trial, including interpretation of the

protocol, and purpose of collection of the specified data and reporting responsibilities.

Case Report Forms

An electronic data capture (EDC) system was used in this trial. Data were captured onto

source data documents and were entered into the EDC system by staff at the clinical sites.

Following data entry, the data was to be 100% monitored. Any discrepancies were to be

resolved. Queries for discrepant data could have been generated automatically by the system

upon entry or generated manually by the monitor or the study data manager. All queries,

whether generated by the system or by a user, were in an electronic format. This systematic

validation was to ensure that a clean and consistent database was provided prior to the

statistical analysis being performed. Following all data validation steps, the Investigator

electronically signed each eCRF prior to database lock.


Data Handling

Subject data were to be entered into the electronic CRF by authorised site staff in a timely

manner. Data were to be entered by site staff and systematic data validation was performed

through the discrepancy management system within the data collection software. Queries for

discrepant data were generated either automatically by the system upon entry or generated

manually by the monitor or the trial data manager. All queries, whether generated by the

system or by a user, would be in an electronic format. This systematic validation was made to

ensure that a clean and consistent database was provided prior to the statistical analysis being

performed.

5.8 Changes to the Conduct of the Trial

It was planned to have 20 subjects included in each of the 3 treatment groups, in order to

achieve at least 16 completers in each group, giving an overall total of 60 subjects

(Section 6.1). However, recruitment was stopped in error after a total of 58 subjects based on

an expectation that the 16 completers was already achieved in each group according to

protocol (for further details see Sections 7.2 and 7.3).


6 Statistical Methods

6.1 Determination of Sample Size

A total of 60 subjects eligible for treatment were planned to be included in the trial in order to

have 16 completers in each of the three treatment groups (LEO 43204 gel, 0.018% on the

face, LEO 43204 gel, 0.1% on the arm or LEO 43204 gel, 0.037% on the balding scalp). A

completer was defined as a subject receiving all applications with IMP and who had at least 5

blood samples taken after last application.

No formal power calculation has been performed. The sample size of 16 subjects providing

PK data for each treatment regimen in a maximal use setting was considered adequate based

on previous regulatory guidance for similar clinical development programmes.

6.2 Statistical and Analytical Plan

The statistical analysis was planned in the clinical study protocol, Appendix 1.1, and further

detailed in the statistical analysis plan update (SAPU), Appendix 1.9.

6.2.1 Subject Qualification for Analysis

All subjects enrolled in the trial are accounted for in this trial report.

Subjects found eligible for treatment constitute the included subjects, which form the basis for

baseline presentations.

PK evaluation was based on the PK analysis set, which was defined as all included subjects

receiving all applications with investigational medicinal product, who had at least 5 blood

samples taken after last application.

Safety evaluation was based on the safety analysis set which was defined as enrolled subjects,

excluding subjects who either received no treatment with IMP and/or for whom no post-

baseline safety evaluations are available.

The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial

analysis sets are documented in this Clinical Trial Report as well as in the SAPU.

6.2.2 Subject Disposition

The reasons for leaving the trial are presented for all enrolled subjects, by last visit attended

and by treatment group.


6.2.3 Baseline Characteristics

Descriptive statistics of demographics and other baseline characteristics are presented for all

subjects in the safety analysis set and by treatment group. The descriptive statistics are also

presented for all subjects in the PK analysis. Presentations of age, sex, ethnicity, race, and

baseline AK lesion count by treatment will also be given by trial site.

Demographics include age, sex, race, ethnicity, and skin type. Other baseline characteristics

include height, weight, BMI, vital signs, concurrent diagnoses, and concomitant medication.

Baseline AK characteristics include treatment location, baseline lesion count for the treatment

area, duration of disease, previous treatment of AKs (anywhere) and previous treatment of

AKs in the treatment area.

6.2.4 Exposure and Treatment Compliance

The number of applications of trial medication (0, 1, 2, 3) was tabulated by treatment group

for all enrolled subjects who received investigational medicinal product.

6.2.5 Analysis of Primary Response Criteria

The analysis of the PK parameters was done for all available blood samples but the

conclusions drawn are based on the PK analysis set.

A validated bioanalytical assay was used for human plasma for quantification of LEO 43204

and the major metabolite LEO136441A (Additional Related Reports). Individual plasma

concentrations are tabulated by subject and time point, and summarised descriptively by time

point in graphical formats, as appropriate.

The plasma concentration versus time data were analysed by Covance Laboratories Limited

by calculating relevant PK parameters (AUC0-tlast, AUC0-∞, Cmax, Tmax, and T½), as the data

permitted. The PK parameters are listed by subject and descriptive statistics are tabulated by

treatment group.

6.2.6 Analysis of Safety

The analysis of safety was based on the safety analysis set.

6.2.6.1 Adverse Events

Adverse events were coded during the course of the trial in accordance with the MedDRA

dictionary. The adverse events are presented by Preferred Terms and Primary System Organ

Class.


All adverse events recorded during the course of the trial are included in the subject data

listings. An event was considered emergent with the trial treatment if it started after the first

application or if started before this and worsened in intensity after. The tabulations described

in the following only include the events that were emergent with trial treatment.

The number of subjects experiencing each type of adverse events (according to MedDRA

Preferred Terms within Primary System Organ Class) is tabulated by treatment group

regardless of the number of times each adverse event was reported by each subject.

The intensity for each type of adverse event (according to the Preferred Term) is tabulated by

treatment group. Where there were several recordings of intensity for a given type of adverse

event (according to the Preferred Term), intensity was taken as the most severe recording for

that adverse event.

The causal relationship to trial medication for each type of adverse events (according to the

coding system) is tabulated by treatment group. Where there are several recordings of causal

relationship to trial medication for a given type of adverse event, causal relationship were

taken as the worst recording from the last report of that adverse event, as that was when the

Investigator was in possession of most information and so best able to judge causal

relationship.

Adverse drug reactions (ADRs) are defined as adverse events for which the Investigator has

not described the causal relationship to trial medication as ‘not related’. The number of

subjects experiencing each type of ADR (according to the Preferred Term) is tabulated

regardless of the number of times each ADR was reported by each subject.

Serious adverse events were evaluated separately, and a narrative for each is given.

Withdrawals from trial or from IP due to AEs are listed.

6.2.6.2 Local Skin Responses (LSRs)

The incidences and grade of LSRs are summarised by treatment group overall at each visit

(Visit 2 to 6). Local skin response grades are summarised by frequency counts and descriptive

statistics by treatment group for each of the six individual LSRs: erythema, flaking/scaling,

crusting, swelling, vesiculation/pustulation, and erosion/ulceration. Change from baseline

(Visit 2) to each visit (Visit 3 to 6) for each of the six individual LSRs are summarised by

descriptive statistics by treatment group. LSRs leading to withdrawal from trial and/or

withdrawal of IP are tabulated.


A composite LSR (sum) score was obtained by summing the six individual LSR scores (range

0-24) at each visit (Visit 2 to 6). The composite score and change from baseline was

summarised by treatment group at each visit using descriptive statistics. The maximum

composite LSR score across visits and the visits of occurrence of the maximum composite

LSR score is tabulated by treatment group. After the maximum is attained, the first visit

where the composite LSR score is less than or equal to the composite score at baseline will be

tabulated by treatment group.

6.2.6.3 Laboratory Safety Examinations

A listing of abnormal haematology and biochemistry laboratory values are presented.

Laboratory parameters are summarised by visit for each treatment group. The change in

laboratory parameters from baseline (Visit 1) to the day after last treatment day (Visit 4) are

summarised for each treatment group using observed cases.

6.2.6.4 Vital Signs

The change in vital signs (resting blood pressure, heart rate, and ear or oral temperature) from

baseline (Visit 1) to Visit 6 are summarised for each treatment group.

6.2.6.5 ECG

A listing of abnormal ECG parameters is presented. Changes in ECG parameters from

Baseline (Screening Visit) to Visit 4 are summarised using observed cases. The results are

reported separately (Additional Related Reports).

6.2.6.6 Amount of Investigational Medicinal Product Used

Further to the number of applications of trial medication the number of tubes used per

application are summarised by treatment group for all included subjects.

All used tubes were weighed individually without labels after their return. Subtracting these

weights from an average weight of a full tube the amount of investigational drug used per

subject was derived. A summary of the total amount used per subject per treatment group is

presented. The individual amounts used per subject per application are listed.

6.2.7 General Principles

An observed cases approach was used for tabulations of data by visit (i.e. involving only

those subjects who attended each specific visit).


Categorical data is summarised using the number and percentage of subjects in each treatment

group. Continuous data is summarised using the mean, median, standard deviation (SD),

minimum and maximum values.

Any changes from the statistical analysis planned in this clinical trial protocol are described

and justified in a protocol amendment /the statistical analysis plan update and/or in the

clinical trial report dependent on the type of deviation.

6.3 Changes to the Statistical Analysis Plan

No changes were made to the statistical analyses planned in the clinical trial protocol. A few

additional data displays were completed as detailed in the SAPU.

6.4 Software and Dictionaries

SAS version 9.3 was used to create listings, tables, and figures.

MedDRA version 15.1 was used for coding of AEs and medical history.

WHO-DD version 2012Q3 was used for coding concomitant medication.


7 Trial Population

7.1 Disposition of Subjects

Out of the 71 subjects enrolled, 58 subjects were included in the trial at 2 sites in the US. The

distribution of subject enrolment and allocation by trial site is in Table 3. Ten subjects failed

screening and 3 subjects withdrew from the trial prior to Day 1 (Appendix 2.1). The

distribution of the subjects per treatment group was as follows: 19 subjects for scalp group,

18 subjects for face group and 21 subjects for the arm group. Subject visit attendance by

treatment group is in EoT Figure 1-1.

Table 3 Subject enrolment and allocation by site: enrolled and included subjects

Total number

of subjectsenrolled(n=71)

Total number

of subjectsassigned treatment(n=58)

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Site ID

31 24 9 11 440 34 9 10 15

Total 71 58 18 21 19

16NOV15:11:23:24 LP0084 1077 t01 enrol.doc

Cross-reference: EoT Table 1–1

7.2 Protocol Deviations

Protocol Deviations and Comments in the CRF

In Appendix 2.2 are the protocol deviations (Listing 2-1) and the comments made in the

comments field of the eCRF (Listing 2-2). There were 3 major protocol deviations: 2 subjects

received dexamethasone (prohibited treatment) during the course of the trial; 1 subject did not

have a follow-up assessment of a grade 3 LSR.

Procedure Compliance Deviations

Eight subjects did not apply both tubes of investigational drug at all 3 visits. These were

regarded as non-completers in the PK analysis and hence excluded from the PK analysis set.

As a consequence, the PK analysis set for each of the treatment groups consists of 20 subjects

for the arm group and 15 subjects for both the face and scalp groups.

Subject stopped treatment after Day 1 due to an unacceptable LSR reaction. The subject

continued in the trial but did not apply the investigational drug on Days 2 and 3 and

consequently did not have any PK samples drawn after Day 1. Subject did not apply any

PPDPPD

PPD

PPD


71

58Included

10 screening failures

3 Voluntary withdrawal

58Safety analysis set

50PK analysis set

Enrolled

8 not fully compliant

investigational drug on Day 3 and Subject did not apply any investigational drug on

Day 2 or 3. Five subjects (Subjects , , , , and ) did not apply the full

2 tubes on one or more of the 3 treatment days.

The remaining minor deviations concerned visits outside of the visit window for multiple

subjects and the site not completing the safety labs at Visit 4 for four subjects ( ),

reconciliation of IP or temperatures on site ) and inclusion of temperature

monitoring device for PK sample ( ).

7.3 Trial Analysis Sets

All 58 subjects were included in the safety analysis set of which 50 subjects were included in

the PK analysis set (Figure 1). See SAPU for details. For the trial analysis sets by treatment

group see Figure 2.

Figure 1 Trial analysis sets – overall

Cross-reference: EoT Figure 1–2

PPD

PPDPPD PPD PPD PPD

PPD

PPD

PPD


21Included


20PK analysis set

1 not fully

compliant

ARM

18

18

15

3 not fully

compliant

FACE

19

19

15

4 not fully

compliant

SCALP

Figure 2 Trial analysis sets by treatment group

Cross-reference: EoT Figure 1–3

7.4 Demographics and other Baseline Characteristics

7.4.1 Demographics

The sex, race, ethnicity and skin type data can be found in Table 4 and Appendix 2.4,

Listing 4-1.

The distribution of subjects were 18 subjects in the face group, 21 subjects in the arm group

and 19 subjects in the scalp group (Table 4). The majority of subjects included in the trial,

across the 3 groups, were non-Hispanic Caucasians. The mean age in years was 64.4 years

(scalp), 65.6 years (face) and 65.0 years (arm). The majority of subjects were men (range of

55.6 to 100%). The age, height, weight, and BMI information is in EoT Table 1-2 and

Appendix 2.4, Listing 4-1.

All subjects were classified as Fitzpatrick Skin Type II-IV with the majority of subjects in all

3 groups classified as Type II (range 78.9 to 83.3%).

Overall, the subjects recruited for this trial were younger and included more treatment naïve

individuals than the typical population that suffers from actinic keratosis. Further, due to the

staggered method of recruitment for this trial there was a non-uniform distribution; there are

more subjects in the arm group (Section 3) and the dispositions between sites as well as for

the scalp treatment group : 4 subjects; : 15 subjects) was not uniform.

PPD PPD


Table 4 Sex, race, ethnicity and skin type: included subjects

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

N1 % N1 % N1 %

USA0321

Sex Male 4 44.4 7 63.6 4 100.0 Female 5 55.6 4 36.4 0 0.0 Total 9 100.0 11 100.0 4 100.0

Race White 8 88.9 11 100.0 4 100.0 Asian 1 11.1 0 0.0 0 0.0 Total 9 100.0 11 100.0 4 100.0

Ethnicity Not Hispanic or Latino 8 88.9 8 72.7 2 50.0 Hispanic or Latino 1 11.1 3 27.3 2 50.0 Total 9 100.0 11 100.0 4 100.0

Skin classification Type II 7 77.8 7 63.6 3 75.0 Type III 2 22.2 3 27.3 1 25.0 Type IV 0 0.0 1 9.1 0 0.0 Total 9 100.0 11 100.0 4 100.0

USA0364


Race White 9 100.0 10 100.0 15 100.0 Total 9 100.0 10 100.0 15 100.0

Ethnicity Not Hispanic or Latino 9 100.0 10 100.0 15 100.0 Total 9 100.0 10 100.0 15 100.0

Skin classification Type II 8 88.9 10 100.0 12 80.0 Type III 1 11.1 0 0.0 3 20.0 Total 9 100.0 10 100.0 15 100.0

17NOV15:14:43:01 LP0084 1077 t03 sex race eth skin.doc Continued...


Table 4 Sex, race, ethnicity and skin type: included subjects (continued)

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

N1 % N1 % N1 %

Total





17NOV15:14:43:01 LP0084 1077 t03 sex race eth skin.doc

1) N=Number of subjectsCross-reference: EoT Table 1–3

7.4.2 Medical history

There were 6 subjects in the face treatment group and 10 subject in the arm treatment group

and 13 subjects in the scalp treatment group with a history of skin disease (EoT Table 1-6).

The number of AKs at baseline by treatment group is in Table 5 ranging from 15 to 49 with an

average count around 20. The mean duration of AK was 3.2 years in the face treatment group,

7.9 years in the arm treatment group, and 9.0 years in the scalp treatment group (Table 6,

Appendix 2.4 Listing 4-2). The most common previous treatment for AK was cryotherapy for

all treatment groups (Table 7, Appendix 2.4 Listing 4-3). The non-melanoma skin cancers

reported were basal cell carcinoma and squamous cell carcinoma of skin (Table 8).

Ongoing medical diagnoses are summarised in EoT Table 1-9, Appendix 2.4 Listing 4-6 and

concomitant medications are summarised in EoT Table 1-10, Appendix 2.4 Listing 4-7. Of the

concomitant medications used at baseline there were no subjects that used dermatological

agents inside of the treatment area (Appendix 2.4 Listing 4-7).


Table 5 AK count at baseline by site: safety analysis set

Total AK count by site

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Mean 17.4 17.5 16.0 SD 1.9 3.6 1.4 Median 18.0 16.0 15.5 Minimum 15 15 15 Maximum 20 28 18 Number 9 11 4


TotalMean 19.8 18.9 20.7 SD 5.1 4.4 8.1 Median 19.0 17.0 18.0 Minimum 15 15 15 Maximum 38 28 49 Number 18 21 19

17NOV15:14:58:01 LP0084 1077 t11 AKcount.doc


PPD

PPD


Table 6 Duration of AK by site: safety analysis set

Duration of AK (years)

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)




17NOV15:14:54:11 LP0084 1077 t04 ak dur.doc


Table 7 AK treatment history: included subjects

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

AK treatments N1 % N1 % N1 %

Cryo/Liquid nitrogen 2 11.1 5 23.8 8 42.1 Dermabrasion 1 5.6 0 0.0 0 0.0 5-Fluorouracil 0 0.0 1 4.8 0 0.0 Imiquimod 0 0.0 1 4.8 0 0.0 Photodynamic therapy 0 0.0 0 0.0 1 5.3 Total number of previous treatments

3 7 9

Total number of previously treated subjects

2 11.1 6 28.6 8 42.1

16NOV15:11:24:10 LP0084 1077 t07 AKhist inside.doc


PPD

PPD


Table 8 Skin disease history: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

System Organ Class (SOC)Preferred Term2 N1 % N1 % N1 %

Neoplasms benign, malignant and unspecified(incl cysts and polyps)Seborrhoeic keratosis 6 33.3 3 14.3 11 57.9Basal cell carcinoma 0 0.0 4 19.0 2 10.5Haemangioma 1 5.6 0 0.0 2 10.5Melanocytic naevus 0 0.0 0 0.0 2 10.5Squamous cell carcinoma of skin 0 0.0 1 4.8 1 5.3SOC total 6 33.3 7 33.3 11 57.9

Skin and subcutaneous tissue disordersAcne 1 5.6 0 0.0 1 5.3Eczema 0 0.0 1 4.8 1 5.3Seborrhoeic dermatitis 0 0.0 1 4.8 1 5.3Dermatitis 0 0.0 1 4.8 0 0.0Rosacea 0 0.0 0 0.0 1 5.3Sebaceous hyperplasia 0 0.0 0 0.0 1 5.3Skin irritation 0 0.0 1 4.8 0 0.0Skin lesion 0 0.0 1 4.8 0 0.0SOC total 1 5.6 5 23.8 5 26.3

Infections and infestationsBody tinea 0 0.0 0 0.0 1 5.3Onychomycosis 0 0.0 0 0.0 1 5.3Tinea pedis 0 0.0 0 0.0 1 5.3SOC total 0 0.0 0 0.0 2 10.5

General disorders and administration siteconditionsCyst 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 0 0.0

Total number of diagnoses3 8 14 26

Total number of subjects 6 33.3 10 47.6 13 68.4

16NOV15:11:24:00 LP0084 1077 t06 dishist.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) Different diagnoses 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.


8 Exposure and Treatment Compliance

In Table 9 is the total amount of drug used by treatment group and the total drug usage by site

is in EoT Table 1-17. The details of the drug usage are in Appendix 2.5 Listing 5-1 and

accountability of IMP is presented in Appendix 2.5 Listing 5-2.


Across the groups subjects received roughly the same mean amount of IMP applied over the

treatment period of 3 applications: 3.56 g for the face treatment group, 3.69 g for the arm

treatment group, and 3.58 g for the scalp treatment group (Table 9). The mean amount of IMP

in a full tube was up to 0.69 g, corresponding to a possible 3-day maximal use amount of

approximately 4.14 g over the 3 treatment days. The minimum values of 1.35 g and 1.38 g

represent subjects who did not apply all 6 tubes; for details of the subjects who did not receive

full doses see Procedural Compliance Deviations in Section 7.2.

Table 9 Total drug usage by treatment group: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Total amount used (g) Mean 3.56 3.69 3.58 SD 0.64 0.20 0.83 Median 3.78 3.72 4.11 Minimum 1.35 3.34 1.38 Maximum 4.05 3.97 4.13 Number 18 19 17

05JAN16:09:40:16 LP0084 1077 t16 drug usage.doc



9 Pharmacokinetic Evaluation

9.1 Pharmacokinetic Results

A validated bioanalytical assay was used for human plasma for quantification of LEO 43204

and its major metabolite LEO136441A (Section 6.2.5). There were 8 subjects excluded from

the PK analysis (Section 7.2 and Figure 2).

Pharmacokinetic data from the face, scalp and arm treatment groups demonstrate that

systemic exposure of LEO 43204 and its major metabolite (LEO136441A) was within the

sub-nanomolar range (<1.0 nM). Overall exposure (AUC) was low with the highest value

found in the arm group (1.56 h*ng/ml). Time to reach maximal plasma concentrations (Tmax)

was variable and Tmax occured between 2 to 24 hour post-dose and was on the average about

10 hour for all individuals in all treatment groups.

- 12 of 15 subjects in the face group had quantifiable LEO 43204 levels and the highest

observed value was 0.044 ng/ml (0.088 nM). The highest observed AUC was 0.733

h*ng/ml and was observed in the same individual.

- 10 of 15 subjects in the scalp group had quantifiable LEO 43204 levels and the highest

observed value was 0.024 ng/ml (0.047 nM). The highest observed AUC was

0.455 h*ng/ml and was observed in the same individual.

- 10 of 20 subjects in the arm group had quantifiable LEO 43204 levels and the highest



- 9 of 15 subjects in the face group had quantifiable LEO136441A levels and the highest



- 8 of 15 subjects in the scalp group had quantifiable LEO136441A levels and the highest



- 6 of 20 subjects in the arm group had quantifiable LEO136441A levels and the highest



The full PK report, including all subjects, is in Additional Related Reports. However, none of

the subjects excluded from the PK analysis set had higher Cmax or AUC than the subjects

included in the PK analysis set. Plots of Cmax values for subjects included in PK analysis set

versus LSR scores are in Section 10.3.2.4.


9.2 Pharmacokinetic Conclusions

Sub-nanomolar levels of LEO 43204 were detected in 12 of the 15 subjects in the face

group, 10 of the 15 subjects in the scalp group and in 10 of the 20 subjects in the arm

group.

There were quantifiable, sub-nanomolar levels of the metabolite LEO136441A in 9 of

the 15 subjects in the face group, 8 of the 15 subjects in the scalp group and in 6 of the

20 subjects in the arm group.

AUC was generally low with the highest exposure (found in the arm group),

1.56 h*ng/ml. Tmax was variable (2-24h) and on the average about 10 hour in all

treatment groups.


10 Safety Evaluation

10.1 Adverse Events

10.1.1 Brief Summary of Adverse Events

In Table 10 an overview of the adverse events by group is presented. There were no SAEs or

deaths in the trial.

All (100%) subjects in the scalp group, 94.4% of the subjects in the face group, and 81.0% in

the arm group reported at least one AE. There were no AEs leading to withdrawal. Further,

there were 2 AEs in the face group and 1 AE in the arm group rated as severe.

Table 10 Overall summary of AEs: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Adverse event category AE1,2 N3 (%) AE1,2 N3 (%) AE1,2 N3 (%)

All adverse events 29 17 ( 94.4) 35 17 ( 81.0) 36 19 (100.0) Severe adverse events 2 1 ( 5.6) 1 1 ( 4.8) 0 0 ( 0.0) Related adverse events 28 16 ( 88.9) 34 17 ( 81.0) 36 19 (100.0) AEs leading to withdrawal from trial

0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0)

SAEs 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)

16NOV15:12:45:33 LP0084 1077 t01 summary.doc

1) AE=Number 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=Number of subjects.

Cross-reference: EoT Table 3-1

10.1.2 Display of Adverse Events

The adverse events are summarised by SOC in EoT Table 3-2 and by SOC and preferred term

in EoT Table 3-3. The most common AEs are summarised by SOC and preferred term in

Table 11 and the AEs inside the treatment area, excluding administration site reactions, are in

Table 12. The AE listings are in Appendix 2.7.


Table 11 Most common AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

System Organ Class (SOC)Preferred Term2,3 N1 % N1 % N1 %

General disorders and administrationsite conditionsApplication site pain 16 88.9 12 57.1 19 100.0Application site pruritus 9 50.0 11 52.4 8 42.1Application site erythema 0 0.0 3 14.3 2 10.5Chills 0 0.0 0 0.0 2 10.5Pain 0 0.0 2 9.5 0 0.0

Eye disordersEye pain 1 5.6 0 0.0 1 5.3

16NOV15:12:46:03 LP0084 1077 t04 ae soc pt most common.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) Most common adverse events are experienced by at least 2 subjects


Reported events of application site erythema are normally captured in the LSR score

(Section 6.2.6.2 ); however, these events were captured and followed-up as AEs, as these were

due to subjects experiencing a grade 3 LSR score at their last visit (Day 15) and according to

the protocol these events should be followed-up as AEs.


Table 12 AEs inside treatment area, excluding administration site reactions by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)


Infections and infestationsApplication site cellulitis 0 0.0 1 4.8 0 0.0Purulent discharge 0 0.0 1 4.8 0 0.0SOC total 0 0.0 2 9.5 0 0.0


Total number of adverse events3 0 3 0


16NOV15:12:46:29 LP0084 1077 t07 inside soc pt.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) 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.



10.1.3 Analysis of Adverse Events

Adverse Events by Frequency

In the scalp treatment group 19 subjects (100%) reported 36 AEs; this was similar to the

percentage of subjects reporting from the face treatment group with 17 subjects (94.4%)

reporting 29 AEs, and slightly higher for the arm treatment group with 17 subjects (81.0%)

reporting 35 AEs (Table 10).

The most commonly reported AEs among all treatment groups were within the primary SOC

‘General disorders and administration site conditions’ (Table 11).

The most commonly reported AEs in all treatment groups were application site pain (Table

11). Overall, the percentage of subjects with administration site pain was highest in the scalp

treatment group (100%), followed by the face treatment group (88.9%), and the arm treatment

group (57.1%).

All AEs within the higher level group ‘Administration site reactions’, is presented by lowest

level term (LLT) in Table 13. The most commonly reported events in each group were

application site burning in the face group (83.3%), application site itching in the arm group

(52.4%), and application site pain in the scalp group (89.5%).

Table 13 Administration Site Reactions by LLT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Lowest Level Term1 N2 % N2 % N2 %

Application site burning 15 83.3 10 47.6 8 42.1Application site itching 9 50.0 11 52.4 8 42.1Application site pain 7 38.9 2 9.5 17 89.5Application site stinging 7 38.9 5 23.8 3 15.8Application site erythema 0 0.0 3 14.3 2 10.5Application site tenderness 1 5.6 0 0.0 3 15.8Application site allergy 1 5.6 0 0.0 0 0.0 Total number of adverse events3 40 31 41 Total number of subjects 16 88.9 17 81.0 19 100.0

16NOV15:12:46:24 LP0084 1077 t06 app soc llt.doc

1) Classification according to MedDRA version 15.1.2) N=Number of subjects.3) Different adverse events within the same LLT and system organ class and involving the same subject have been counted as one. A single subject could appear in multiple classes.



Adverse Events by Intensity

All AEs were assessed for intensity (mild, moderate, or severe) and presented by SOC and

preferred term for all AEs (Table 14) and for ‘administration site reactions’ by LLT (Table

15).

Overall, most AEs in all 3 treatment groups were assessed as either moderate or mild. The

scalp treatment group had highest number of moderate AEs (27), followed by the arm

treatment group (19), and the face treatment group (15). There was 1 severe AE in the arm

treatment group (application site pain), and 2 severe AEs, both in the same subject, in the face

treatment group (application site pruritus and application site pain) (Appendix 2.7,

Listing 7-2).

Within the administration site reaction category, application site pain was the most commonly

reported LLT of moderate intensity in the scalp treatment group, where as for the face and

arm treatment groups it was application site burning. There was 1 event each of application

site pain, application site burning, and application site itch that was severe.


Table 14 Intensity of AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

System Organ Class(SOC)Preferred Term1,2 Mild Mod3 Sev3 Mild Mod3 Sev3 Mild Mod3 Sev3

General disorders and administration site conditionsApplication site pain 5 10 1 4 7 1 2 17 0Application site pruritus 5 3 1 6 5 0 2 6 0Application site erythema 0 0 0 1 2 0 0 2 0Chills 0 0 0 0 0 0 2 0 0Pain 0 0 0 2 0 0 0 0 0Application sitehypersensitivity

1 0 0 0 0 0 0 0 0

Cyst 0 0 0 0 1 0 0 0 0Pyrexia 0 0 0 1 0 0 0 0 0

Eye disordersEye pain 0 1 0 0 0 0 1 0 0Dry eye 0 1 0 0 0 0 0 0 0Eye irritation 0 0 0 0 0 0 0 1 0Eyelid oedema 0 0 0 0 0 0 0 1 0

Infections and infestationsApplication site cellulitis 0 0 0 0 1 0 0 0 0Purulent discharge 0 0 0 0 1 0 0 0 0

Blood and lymphatic system disordersLymphadenopathy 0 0 0 0 0 0 1 0 0

InvestigationsElectrocardiogram QRS complexprolonged

1 0 0 0 0 0 0 0 0

Musculoskeletal and connective tissue disordersPain in extremity 0 0 0 1 0 0 0 0 0

Nervous system disordersLethargy 0 0 0 0 1 0 0 0 0

05JAN16:10:05:07 LP0084 1077 t08 ae int.doc Continued...


Table 14 Intensity of AEs by SOC and PT: safety analysis set (continued)

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)


Respiratory, thoracic and mediastinal disordersOropharyngeal pain 0 0 0 0 0 0 1 0 0

Skin and subcutaneous tissue disordersUrticaria 0 0 0 0 1 0 0 0 0

Total number of adverse events 12 15 2 15 19 1 9 27 0

05JAN16:10:05:07 LP0084 1077 t08_ae_int.doc

1) Classification according to MedDRA version 15.1.2) Subjects with more than one AE within the same lowest level term is counted only once in the most severe intensity group.3) Mod = Moderate. Sev = Severe.


Table 15 Intensity of administration Site Reactions by LLT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Lowest Level Term1,2 Mild Mod3 Sev3 Mild Mod3 Sev3 Mild Mod3 Sev3

Application site burning 6 8 1 4 6 0 4 4 0Application site itching 5 3 1 6 5 0 2 6 0Application site pain 1 6 0 0 1 1 3 14 0Application site stinging 2 5 0 1 4 0 1 2 0Application site erythema 0 0 0 1 2 0 0 2 0Application site tenderness 0 1 0 0 0 0 2 1 0Application site allergy 1 0 0 0 0 0 0 0 0Total number of adverse events 15 23 2 12 18 1 12 29 0

05JAN16:11:34:15 LP0084 1077 t09_app_int.doc

1) Classification according to MedDRA version 15.1.2) Subjects with more than one AE within the same lowest level term is counted only once in the most severe intensity group.3) Mod = Moderate. Sev = Severe.



Adverse Events Related to Investigational medicinal product

The investigators assessed most AEs for all 3 treatment groups to be related to the IMP

(adverse drug reactions):

19 subjects (100%) in the scalp treatment group experienced 36 AEs considered

related to the investigational medicinal product

16 subjects (88.9%) in the face treatment group experienced 28 AEs considered

related related to the investigational medicinal product

17 subjects (81.0%) in the arm treatment group experienced 34 AEs considered related

related to the investigational medicinal product

For further details see Table 10 and Table 16.

The most commonly reported related AEs in all treatment groups were application site pain,

and application site pruritus (Table 16, EoT Table 3-10). All AEs considered related to the

IMP were reported as recovered (Appendix 2.7, Listing 7-1).


Table 16 Related AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)


General disorders and administrationsite conditionsApplication site pain 16 88.9 12 57.1 19 100.0Application site pruritus 9 50.0 11 52.4 8 42.1Application site erythema 0 0.0 3 14.3 2 10.5Chills 0 0.0 0 0.0 2 10.5Pain 0 0.0 2 9.5 0 0.0Application site hypersensitivity 1 5.6 0 0.0 0 0.0Cyst 0 0.0 1 4.8 0 0.0Pyrexia 0 0.0 1 4.8 0 0.0SOC total 16 88.9 17 81.0 19 100.0

Eye disordersEye pain 1 5.6 0 0.0 1 5.3Dry eye 1 5.6 0 0.0 0 0.0Eye irritation 0 0.0 0 0.0 1 5.3Eyelid oedema 0 0.0 0 0.0 1 5.3SOC total 2 11.1 0 0.0 3 15.8


Blood and lymphatic system disordersLymphadenopathy 0 0.0 0 0.0 1 5.3SOC total 0 0.0 0 0.0 1 5.3

Musculoskeletal and connectivetissue disordersPain in extremity 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 0 0.0

Nervous system disordersLethargy 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 0 0.0

16NOV15:12:46:14 LP0084 1077 t05 ae rel soc pt.doc Continued...


Table 16 Related AEs by SOC and PT: safety analysis set (continued)

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)


Respiratory, thoracic andmediastinal disordersOropharyngeal pain 0 0.0 0 0.0 1 5.3SOC total 0 0.0 0 0.0 1 5.3

Total number of related adverseevents3

28 34 36


16NOV15:12:46:14 LP0084 1077 t05 ae rel soc pt.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) 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.



10.2 Deaths, other Serious Adverse Events, and other Significant Adverse

Events

10.2.1 Deaths and Other Serious Adverse Events

There were no deaths or SAEs in this trial.

10.2.2 Other Significant Adverse Events

There were 2 subjects whose cases are considered necessary for further elaboration. There

was one subject in the face group (Subject ) who experienced grade 4 erosion/ulceration

and one subject in the arm group (Subject ) who experienced application site cellulitis

(moderate). Both cases are further described below.

Subject ; Erosion/Ulceration (grade 4)

This case concerns a treated with LEO 43204 gel 0.018% on the face.

The first study medication was applied on the face on and the subject

adhered to the 3-day treatment regimen. The subject had a baseline composite LSR of

2. At the third day of treatment the subject had a composite LSR of 17, with grade 4

erosion/ulceration and grade 4 vesiculation, and to relieve the symptoms the subject

was prescribed mild analgesics. The following day the condition had improved

markedly with vesiculation scoring 1 and ulceration scoring 2, and a composite LSR

of 14. On Day 15 there were no signs of ulcerations or vesiculations, with both of

these skin responses scoring 0, and the composite LSR was 3.

Subject ; Application Site Cellulitis; (moderate)

This case concerns a treated with LEO 43204 gel 0.1%, on the arm.

The subject had previously been diagnosed with ,

and . At baseline the subject’s daily prescriptions

consisted of as a . The first study medication was applied

on the arm on and the subject adhered to the 3-day treatment regimen. On

the subject experienced severe pain and a light degree of swelling in the

treatment area (total LSR-score of 3), and he was initially treated with white petroleum

jelly and ice packs. However, the condition deteriorated the following two days to a

total LSR of 13, and on the suspicion of cellulitis the subject started treatments

intramuscular dexamethasone and ceftriaxone. The subject received the last injections

on and the event was reported as recovered on follow-up ( ).

The investigator classified the event as moderate in severity and probably related to

the IMP.

>70 year-old

>50 year-old

Day 1Day 2

Day 8 Day 25

Day 1

PPD

PPD

PPD

PPD

PPD PPD PPD

PPD

PPD PPD

PPD PPD

PPD


10.3 Other Safety Assessment

10.3.1 Vital Signs and Physical Findings, and other Observations Related to

Safety

Descriptive statistics for systolic blood pressure, diastolic blood pressure, heart rate, and body

temperature by visit are presented for the safety analysis set in EoT Table 3-19 and are listed

in Appendix 2.8, Listing 8-5. The changes in vital signs from baseline to Day 15 are in Table

17. Physical examinations were performed at screening and at early termination when

applicable. A listing per subject for abnormal findings is in Appendix 2.8, Listing 8-1.

Overall, the vital signs systolic and diastolic blood pressure, heart rate, and temperature were

similar at Baseline as compared with Day 15 (Visit 6) (Table 17). No clinically significant

changes from baseline were recorded in the vital signs or physical examination findings

during the trial.


Table 17 Change in vital signs from baseline to Day 15: safety analysis set

Vital sign

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Systolic Blood Pressure (mmHg)Mean 0.9 3.0 -4.1 SD 10.1 16.1 16.5 Median 1.5 1.0 -6.0 Minimum -21.0 -21.0 -38.0 Maximum 22.0 37.0 40.0 Number 18 21 19

Diastolic Blood Pressure (mmHg)Mean 0.2 -0.6 -1.5 SD 7.2 10.8 6.6 Median 1.0 -2.0 -2.0 Minimum -16.0 -17.0 -13.0 Maximum 12.0 22.0 11.0 Number 18 21 19

Heart Rate (beats/min)Mean -0.5 3.5 0.8 SD 10.0 7.5 6.7 Median 1.0 4.0 1.0 Minimum -27.0 -10.0 -13.0 Maximum 15.0 16.0 12.0 Number 18 21 19

Temperature (°C)Mean -0.1 -0.1 0.1 SD 0.3 0.5 0.3 Median -0.1 0.0 0.1 Minimum -0.6 -1.2 -0.5 Maximum 0.6 0.6 0.7 Number 18 21 19

16NOV15:12:48:27 LP0084 1077 t20 vs chg.doc


10.3.2 Local Skin Responses Assessment

10.3.2.1 Local Skin Response Assessment

The treatment areas were assessed at 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 grades, was

calculated for each treatment area at each visit (Appendix 2.7, Listing 7-3).

Presentations of the frequencies of LSR components by visit were produced for the safety

analysis set, see EoT Table 3-12.


10.3.2.2 Composite Local Skin Response Score

Composite LSR score versus time by treatment group is shown in Figure 3 and Table 18. The

change from baseline (Visit 1) in composite LSR score is presented in EoT Table 3-16. The

maximum post baseline composite LSR score by treatment group is in Figure 5 and

summarised in EoT Table 3-15. The summary of the maximal intensity for composite LSR

score is in Table 19 and the corresponding summary of the return to baseline is in Table 20.

For all 3 treatment groups the mean composite LSR scores rose gradually from baseline to

Day 2 with steady, yet greater, increases from Day 2 to Day 3. There were gradual increases

from Day 3 to the peak scores at Day 4 for all 3 treatment groups: 9.9 for scalp, 9.6 for face,

and 9.5 for arm. The decline towards mild levels, approaching baseline values, in mean

composite LSR score at Day 15 post-dose was largest for the face (1.9) and scalp (2.6) groups

as compared to the arm group (4.7) (Table 18). Composite LSR scores for individual profiles

by visit are presented in Figure 4.

Figure 3 Composite LSR score – mean profiles by treatment group: safety analysis set

Cross-reference: EoT Figure 3-2


Figure 4 Composite LSR score – individual profiles by treatment group: safety analysis set



Table 18 Composite LSR score by visit: safety analysis set

Composite LSR scoreVisit

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Visit 2/Day 1Mean 1.0 0.9 1.3 SD 1.1 1.0 1.0 Median 0.5 0.0 1.0 Minimum 0 0 0 Maximum 3 2 3 Number 18 21 19





16NOV15:12:47:36 LP0084 1077 t14 LSR visit.doc



Figure 5 Maximum post baseline composite LSR score by treatment group: safety analysis set


Table 19 Summary of visit of maximum post baseline composite LSR score: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Max LSR visit2 N1 % N1 % N1 %

Visit 3/Day 2 2 11.1 0 0.0 0 0.0 Visit 4/Day 3 8 44.4 8 38.1 5 26.3 Visit 5/Day 4 13 72.2 16 76.2 15 78.9 Visit 6/Day 15 0 0.0 1 4.8 0 0.0 Unscheduled 0 0.0 2 9.5 0 0.0

16NOV15:12:48:02 LP0084 1077 t17 visit maxlsr.doc

1) N=Number of subjects.2) Subjects with maximum score at more than one visit will appear at all visits in question.



Table 20 Summary of visit of return to baseline for composite LSR score: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Visit of return to baseline LSR

Number of subjects %



Visit 6/Day 15 8 44.4 3 14.3 7 36.8 Unscheduled 6.02 1 5.6 0 0.0 0 0.0 LSR not returned to baseline level

9 50.0 18 85.7 12 63.2

Total 18 100.0 21 100.0 19 100.0

16NOV15:12:48:13 LP0084 1077 t18 visit return base.doc



10.3.2.3 Local Skin Response Components

Maximum LSR scores post-baseline are shown by component in Table 21. The LSR

component scores by visit and treatment group are in Figure 6 and the related frequencies are

in EoT Table 3-12.

The LSR components that did not return to baseline values on Day 15 were typically

erythema in all 3 groups and flaking/scaling (in the arm group) and to a lesser extent crusting

(Figure 6).


Table 21 Maximum post baseline LSR score by LSR component: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

LSR componentMaximum score N1 % N1 % N1 %

ErythemaSlightly pink <50% 3 16.7 0 0.0 0 0.0 Pink or light red >50% 2 11.1 5 23.8 4 21.1 Red, restricted to treatment area 13 72.2 10 47.6 12 63.2 Red extending outside treatment area

0 0.0 6 28.6 3 15.8

Total 18 100.0 21 100.0 19 100.0

Flaking/ScalingNot present 3 16.7 1 4.8 5 26.3 Isolated scale, specific to lesions

5 27.8 11 52.4 11 57.9

Scale <50% 5 27.8 7 33.3 1 5.3 Scale >50% 5 27.8 2 9.5 2 10.5 Total 18 100.0 21 100.0 19 100.0

CrustingNot present 4 22.2 2 9.5 4 21.1 Isolated crusting 9 50.0 11 52.4 5 26.3 Crusting <50% 3 16.7 5 23.8 8 42.1 Crusting >50% 2 11.1 2 9.5 2 10.5 Crusting extending outside treatment area

0 0.0 1 4.8 0 0.0

Total 18 100.0 21 100.0 19 100.0

SwellingNot present 1 5.6 0 0.0 1 5.3 Slight, lesion specific oedema 4 22.2 6 28.6 1 5.3 Palpable oedema extending beyond individual lesions

3 16.7 8 38.1 6 31.6

Confluent and/or visible oedema 5 27.8 6 28.6 9 47.4 Marked swelling extending outside treatment area

5 27.8 1 4.8 2 10.5

Total 18 100.0 21 100.0 19 100.0

Vesiculation/PustulationNot present 3 16.7 3 14.3 0 0.0 Vesicles only 2 11.1 1 4.8 3 15.8 Transudate or pustules, with or without vesicles <50%

2 11.1 6 28.6 2 10.5

Transudate or pustules, with or without vesicles >50%

8 44.4 9 42.9 12 63.2

Transudate or pustules, with or without ...2

3 16.7 2 9.5 2 10.5

Total 18 100.0 21 100.0 19 100.0

16NOV15:12:47:27 LP0084 1077 t13 maxlsr comp.doc Continued...


Table 21 Maximum post baseline LSR score by LSR component: safety analysis set (continued)

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Erosion/UlcerationNot present 3 16.7 3 14.3 3 15.8 Lesion specific erosion 7 38.9 10 47.6 7 36.8 Erosion extending beyond individual lesions

6 33.3 8 38.1 6 31.6

Erosion >50% 1 5.6 0 0.0 3 15.8 Black eschar or ulceration 1 5.6 0 0.0 0 0.0 Total 18 100.0 21 100.0 19 100.0

16NOV15:12:47:27 LP0084 1077 t13 maxlsr comp.doc



Figure 6 LSR component scores by visit and treatment group: safety analysis set



During the trial period, and with the exception of erosion/ulceration, all individual LSR

categories were present in all 3 treatment groups with erythema and flaking/scaling being the

most common components. Approximately half of the subjects had some level of erythema

and/or flaking/scaling already at Day 1. For all components the symptoms worsened the day

after starting treatment with a peak at Day 4 with the exception for flaking/scaling and

crusting in the arm group where the frequencies were greatest at Day 15. The components

swelling, vesiculation/pustulation, and erosion/ulceration were generally not present on Day 1

for any of the subjects in the 3 treatment groups (EoT Table 3-12 and Figure 6).

10.3.2.4 Local Skin Response Scores versus Amount of IMP Used

The maximal composite LSR score versus total drug usage for all 3 treatment groups is

presented in Figure 7 and the corresponding figure showing the change in LSR composite

score is in EoT Figure 3-5. No correlation between maximal composite LSR score and total

drug usage can be established; however, the variation in total use amongst the subjects

applying all 6 tubes was very small.

Figure 7 Maximal composite LSR score versus total drug usage: safety analysis set



The maximal composite score versus Cmax is in Figure 8 and Cmax versus total drug used is in

Figure 9. A correlation between systemic exposure (Cmax) of LEO 43204 and maximal

composite LSRs (Figure 8) could not be established. Further, there is no apparent relation

between systemic exposure (Cmax) and amount of drug used (Figure 9).

The maximal composite LSR score for subjects with at least one PK value above LLOQ is in

EoT Figure 3-9. The corresponding change in composite LSR score versus PK values is in

EoT Figure 3-10.

Figure 8 Maximal composite LSR score versus Cmax: PK analysis set



Figure 9 Cmax versus total drug usage: PK analysis set


10.3.3 ECG Assessments – Change from Baseline

The ECG assessment was analysed by a central CRO and the results evaluation and

conclusion is presented in a separate ECG Safety Report (Additional Related Reports).

There were no post-dose emergent ECG abnormalities that were clinically significant and

there was no trend for an increase in the frequency of abnormal ECG values with increasing

treatment duration. In conclusion, the results did not indicate an effect of LEO 43204 on

QTcF or on the other ECG intervals of interest.

10.4 Clinical Laboratory Evaluation

Laboratory Assessments

Laboratory assessments were performed at Screening (Visit 1), Day 3 (Visit 4), Day 15

(Visit 6), and upon early termination. A listing of individual biochemistry and haematology

laboratory values is presented in Appendix 2.8, Listing 8-1 and abnormal laboratory values

are in Appendix 2.8, Listing 8-2.


Laboratory Values over Time

For the haematology parameters, the summary table is in EOT Table 3-21, the change from

baseline is in EoT Table 3-22 and the corresponding shift table is in EoT Table 3-23.

For the biochemistry parameters, the summary table is in EOT Table 3-24, the change from

baseline is in EoT Table 3-25 and the corresponding shift table is in EoT Table 3-26.

Overall, the haematology- and biochemistry laboratory parameters were similar at Baseline

and Day 4 for all treatment groups.

Individual Clinically Significant Abnormalities

No clinically relevant abnormalities were recorded in the haematology- or biochemistry

laboratory parameters during the trial (Appendix 2.8, Listing 8-4).

10.5 Safety Conclusions

There were no deaths or SAEs in the trial.

The percentage of subjects reporting AEs was 100% in the scalp treatment group, 94.4%

in the face treatment group, and 81.0% in the arm treatment group.

Most AEs in all 3 treatment groups were assessed as related to investigational medicinal

product by the investigator.

The most common AE considered related to investigational medicinal product (adverse

drug reactions) in all treatment groups was application site pain.

All AEs considered related to the investigational medicinal product were recorded as

recovered.

In all treatment groups application site pain was the most commonly reported event (by

preferred term). Most of these events were of moderate intensity.

In the face treatment group application site burning was the most commonly reported

event (by lowest level term). Most of these events were of moderate intensity.

In the arm treatment group application site burning and application site itching were the

most commonly reported events (by lowest level term). Most of these events were of

moderate intensity.

In the scalp treatment group application site pain was the most commonly reported event

(by lowest level term). Most of these events were of moderate intensity.

There was 1 severe event of application site pain in the arm treatment group.


There was 1 severe event each of application site pruritus and application site pain in the

same subject in the face treatment group.

For all 3 treatment groups the mean composite LSR scores rose gradually from baseline to

Day 2. The mean composite LSR score was highest at Day 4 (Visit 5) for all 3 treatment

groups and approached values close to baseline at Day 15 (Visit 6). The mean composite

LSR score decline in the arm treatment group was slower than that for the face or scalp

treatment groups.

ECG monitoring showed no association between LEO 43204 treatment and evidence of

any cardiac effects.

Overall, the haematology- and biochemistry laboratory parameters changes from Baseline

were not clinically relevant for any of the treatment groups.

11 Discussion and Overall Conclusions

11.1 Discussion

This phase 1, multi-centre, open-label, uncontrolled, non-randomised trial evaluated the

systemic exposure and safety of LEO 43204 gel when applied to full face, balding scalp or an

area of approximately 250 cm2 on the arm in subjects with actinic keratosis under maximum

use conditions.

A total of 58 subjects received trial medication of which 50 were included in the PK analysis

set.

Due to the staggered design of the trial recruitment, there was a non-uniform distribution of

subjects between sites and for the scalp treatment group; however, the numbers in the two

other treatment groups were evenly distributed between the two sites. There was little

difference between the corresponding treatment groups of each site and any influence on the

trial results is miniscule.

The trial staff was instructed to ensure that the tubes were emptied with the aid of a special

tool, so that the maximum amount of gel was applied to ensure maximum use conditions. It is

anticipated that during normal clinical conditions, the tubes can not be emptied to the same

extent. There was little variation observed in the amount of drug squeezed out of the tubes

and generally these amounts were close to the theoretical maximum that could be obtained

from the tubes.


A validated bioanalytical assay with an LLOQ of 0.005 ng/ml was used to analyse plasma

samples for LEO 43204 and its major metabolite; the very low detection limit of this assay

accounts for the numbers of subjects with detectable amounts of parent and metabolite. There

were 12 out of 15 subjects in the face treatment group, 10 out of 15 subjects in the scalp

treatment group and 10 out of 20 subjects in the arm treatment group with detectable levels of

LEO 43204; the highest level observed was 0.166 ng/mL (0.33 nM) found in the arm

treatment group following application of the highest strength (0.1%). There were detectable

levels of the major metabolite quantified in all of the 3 treatment groups; the highest level of

all subjects across the groups was 0.113 ng/mL (0.22 nM) found in the scalp treatment group

following application of the 0.037% strength. Eight additional subjects not included in the PK

analysis set (due to not taking all six required tubes) showed no increased plasma levels or

AUC compared to subjects included in the PK analysis set.

There was no evidence of the Cmax values obtained being related to the total amount of drug

used.

Overall, in the larger treatment areas examined in this trial, the data indicate that there is very

low systemic absorption of LEO 43204 in the maximum use setting (sub-nanomolar levels).

Although the planned number of 16 completers was not achieved in all three treatment groups

with only 15 completers in the face and scalp groups, this trial is considered to fulfil the

overall criteria for MUSE conditions.

The most commonly reported AE in all 3 treatment groups was application site pain.

For all 3 treatment groups, mean composite LSR scores rose gradually from baseline to Day 2

with steady increases from Day 2 to Day 3 and reaching peak scores at Day 4. The mean

composite LSR scores declined to mild levels and approached baseline values at Day 15. One

factor to be noted is that the high amount of gel applied in this maximum use setting likely

contributed to the higher composite LSR scores.

11.2 Overall Conclusions

A total of 32 subjects out of 50 had quantifiable levels of LEO 43204: 12 subjects in the face

treatment group, 10 subjects in the scalp treatment group, and 10 subjects in the arm treatment

group. The results of this trial demonstrate that following once daily administration for

3 consecutive days under MUSE conditions there was very low (sub-nanomolar) systemic

exposure when LEO 43204 gel was applied to the full face, balding scalp or on a treatment

area of approximately 250 cm2 on the arm. In this maximal use setting treatment LEO 43204

gel, 0.018%, 0.037%, and 0.1%, was safe and well tolerated.


12 References

1. ICH E3. Structure and Content of Clinical Study Reports. November 1995.

2. ICH E3 (R1). ICH E3 Guideline: Structure and Content of Clinical Study Reports

Questions and Answers. July 2012.

3. ICH E6 (R1). Guideline for Good Clinical Practice. June 1996.

4. ICH E9. Statistical Principles for Clinical Trials. February 1998.

5. M4E(R1). The Common Technical Document for the Registration of Pharmaceuticals

for Human Use Efficacy. September 2002.

6. Einspahr JG, Stratton SP, Bowden GT, et al. Chemoprevention of human skin cancer.

Crit Rev Omcol Hematol. 2002;41:269-85.

7. Alam M. Actinic keratosis: prevalence, pathogenesis, presentation, and prevention.

Adv Stud Med. 2006;6(8A):S785-90.

8. Ibrahim SF, Brown MD. Actinic keratosis: a comprehensive review. J Clin Aesthetic

Dermatol. 2009;2(7):43-8.

9. Frost CA, Green AC. Epidemiology of solar keratosis. Br J Dermatol. 1994;131:455-

64.

10. Fu W, Cockerell CJ. The actinic (solar) keratosis: A 21st century perspective. Arch

Dermatol. 2003;139(1):66-70.

11. Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol.

2002;146(Suppl 61):20-3.

12. Cohen JL. Actinic keratosis treatment as a key component of preventive strategies for

nonmelanoma skin cancer. J Clin Aesthetic Dermatol. 2010;3(6):39-44.

13. Padilla RS, Sebastian S, Jiang Z, Nindl I, Larson R. Gene expression patterns of

normal human skin, actinic keratosis, and squamous cell carcinoma: a spectrum of

disease progression, Arch Dermatol. 2010;146(3):288-293.

14. Vatve M, Ortonne JP, Birch-Machin MA, Gupta G. Management of field change in

actinic keratosis. Br J Dermatol. 2007;157(Suppl 2):21-4.


1 Tables and Figures, Baseline Characteristics and Investigational Product

Data

List of Tables

Table 1–1: Subject enrolment and allocation by site: enrolled and included subjects ............. 80

Table 1–2: Age, height, weight and BMI by site: safety analysis set....................................... 81

Table 1–3: Sex, race, ethnicity and skin type by site: safety analysis set ................................ 84

Table 1–4: Duration of AK by site: safety analysis set ............................................................ 86

Table 1–5: AK treatment history: safety analysis set ............................................................... 87

Table 1–6: Skin disease history: safety analysis set ................................................................. 88

Table 1–7: AK treatment history, inside treatment area: safety analysis set ............................ 89

Table 1–8: Skin disease history, inside treatment area: safety analysis set .............................. 90

Table 1–9: Concurrent diagnoses: safety analysis set .............................................................. 91

Table 1–10: Concomitant medication at baseline: safety analysis set...................................... 96

Table 1–11: AK count at baseline by site: safety analysis set ................................................ 106

Table 1–12: Vital signs at baseline: safety analysis set .......................................................... 107

Table 1–13: Age, height, weight and BMI by site: PK analysis set ....................................... 108

Table 1–14: Sex, race, ethnicity and skin type by site: PK analysis set ................................. 111

Table 1–15: Compliance by visit: safety analysis set............................................................. 113

Table 1–16: Total drug usage: safety analysis set .................................................................. 114

Table 1–17: Total drug usage by site: safety analysis set....................................................... 115

List of Figures

Figure 1-1: Visit attendance by treatment group .................................................................... 116

Figure 1-2: Trial analysis sets overall .................................................................................... 117

Figure 1-3: Trial analysis sets by treatment group ................................................................. 118


Table 1–1: Subject enrolment and allocation by site: enrolled and included subjects

Total number

of subjectsenrolled(n=71)

Total number

of subjectsassigned treatment(n=58)

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Site ID

31 24 9 11 440 34 9 10 15

Total 71 58 18 21 19

16NOV15:11:23:24 LP0084 1077 t01_enrol.doc

PPDPPD


Table 1–2: Age, height, weight and BMI by site: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Age (years) Mean 60.0 60.0 48.3 SD 11.4 10.5 9.8 Median 59.0 57.0 49.5 Minimum 42 45 37 Maximum 78 75 57 Number 9 11 4

Height (cm) Mean 161.4 169.5 175.9 SD 12.1 6.9 6.4 Median 160.0 170.2 176.5 Minimum 142 157 168 Maximum 175 178 183 Number 9 11 4

Weight (kg) Mean 75.4 83.0 105.6 SD 15.8 18.6 21.3 Median 76.7 82.6 109.1 Minimum 55 58 79 Maximum 104 111 125 Number 9 11 4

BMI (kg/m/m) Mean 29.5 28.7 33.9 SD 8.9 5.3 5.6 Median 27.3 29.2 33.5 Minimum 20 22 28 Maximum 52 38 41 Number 9 11 4

17NOV15:13:48:12 LP0084 1077 t02_age_height_weight_bmi.doc Continued...

PPD


Table 1- 2: Age, height, weight and BMI by site: safety analysis set, continued

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)






PPD


Table 1- 2: Age, height, weight and BMI by site: safety analysis set, continued

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Total





17NOV15:13:48:12 LP0084 1077 t02_age_height_weight_bmi.doc


Table 1–3: Sex, race, ethnicity and skin type by site: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

N1 % N1 % N1 %






Race White 9 100.0 10 100.0 15 100.0 Total 9 100.0 10 100.0 15 100.0




PPD

PPD


Table 1-3: Sex, race, ethnicity and skin type by site: safety analysis set, continued

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

N1 % N1 % N1 %

Total






1) N=Number of subjects


Table 1–4: Duration of AK by site: safety analysis set

Duration of AK (years)

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)




17NOV15:14:54:11 LP0084 1077 t04 ak dur.doc

PPD

PPD


Table 1–5: AK treatment history: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Cryo/Liquid nitrogen 9 50.0 10 47.6 15 78.9 Surgical excision/curettage 4 22.2 6 28.6 7 36.8 Dermabrasion 1 5.6 1 4.8 0 0.0 Medium or greater depth chemical peel

2 11.1 0 0.0 0 0.0

Laser resurfacing 0 0.0 1 4.8 0 0.0 5-Fluorouracil 0 0.0 3 14.3 3 15.8 Imiquimod 0 0.0 3 14.3 0 0.0 Photodynamic therapy 0 0.0 1 4.8 3 15.8 Ingenol mebutate 2 11.1 3 14.3 4 21.1 Total number of previous treatments

18 28 32


9 50.0 10 47.6 15 78.9

16NOV15:11:23:55 LP0084 1077 t05 AKhist.doc

1) N=Number of subjects.


Table 1–6: Skin disease history: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Neoplasms benign, malignant and unspecified(incl cysts and polyps)Seborrhoeic keratosis 6 33.3 3 14.3 11 57.9Basal cell carcinoma 0 0.0 4 19.0 2 10.5Haemangioma 1 5.6 0 0.0 2 10.5Melanocytic naevus 0 0.0 0 0.0 2 10.5Squamous cell carcinoma of skin 0 0.0 1 4.8 1 5.3SOC total 6 33.3 7 33.3 11 57.9

Skin and subcutaneous tissue disordersAcne 1 5.6 0 0.0 1 5.3Eczema 0 0.0 1 4.8 1 5.3Seborrhoeic dermatitis 0 0.0 1 4.8 1 5.3Dermatitis 0 0.0 1 4.8 0 0.0Rosacea 0 0.0 0 0.0 1 5.3Sebaceous hyperplasia 0 0.0 0 0.0 1 5.3Skin irritation 0 0.0 1 4.8 0 0.0Skin lesion 0 0.0 1 4.8 0 0.0SOC total 1 5.6 5 23.8 5 26.3

Infections and infestationsBody tinea 0 0.0 0 0.0 1 5.3Onychomycosis 0 0.0 0 0.0 1 5.3Tinea pedis 0 0.0 0 0.0 1 5.3SOC total 0 0.0 0 0.0 2 10.5




16NOV15:11:24:00 LP0084 1077 t06 dishist.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) Different diagnoses 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.


Table 1–7: AK treatment history, inside treatment area: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Cryo/Liquid nitrogen 2 11.1 5 23.8 8 42.1 Dermabrasion 1 5.6 0 0.0 0 0.0 5-Fluorouracil 0 0.0 1 4.8 0 0.0 Imiquimod 0 0.0 1 4.8 0 0.0 Photodynamic therapy 0 0.0 0 0.0 1 5.3 Total number of previous treatments

3 7 9


2 11.1 6 28.6 8 42.1

16NOV15:11:24:10 LP0084 1077 t07 AKhist inside.doc

1) N=Number of subjects.


Table 1–8: Skin disease history, inside treatment area: safety analysis set

Not applicable.


Table 1–9: Concurrent diagnoses: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Metabolism and nutrition disordersHyperlipidaemia 2 11.1 3 14.3 7 36.8Diabetes mellitus 3 16.7 3 14.3 3 15.8Dyslipidaemia 4 22.2 3 14.3 0 0.0Hypercholesterolaemia 3 16.7 0 0.0 4 21.1Type 2 diabetes mellitus 2 11.1 3 14.3 1 5.3Gout 0 0.0 0 0.0 1 5.3Hypovitaminosis 0 0.0 1 4.8 0 0.0SOC total 11 61.1 9 42.9 12 63.2

Vascular disordersHypertension 8 44.4 7 33.3 12 63.2Aortic aneurysm 1 5.6 0 0.0 0 0.0Arteriosclerosis 0 0.0 1 4.8 0 0.0Peripheral arterial occlusive

disease 1 5.6 0 0.0 0 0.0

SOC total 8 44.4 7 33.3 12 63.2 Immune system disordersSeasonal allergy 5 27.8 7 33.3 5 26.3Drug hypersensitivity 1 5.6 1 4.8 1 5.3Hypersensitivity 1 5.6 0 0.0 1 5.3Allergy to animal 0 0.0 0 0.0 1 5.3House dust allergy 0 0.0 0 0.0 1 5.3SOC total 7 38.9 8 38.1 6 31.6

Cardiac disordersCardiac disorder 5 27.8 5 23.8 8 42.1Atrial fibrillation 0 0.0 1 4.8 0 0.0Cardiovascular disorder 1 5.6 0 0.0 0 0.0Coronary artery disease 0 0.0 1 4.8 0 0.0Mitral valve prolapse 1 5.6 0 0.0 0 0.0SOC total 6 33.3 6 28.6 8 42.1

Gastrointestinal disordersGastrooesophageal reflux disease 1 5.6 6 28.6 8 42.1Abdominal distension 1 5.6 0 0.0 0 0.0

16NOV15:11:24:17 LP0084 1077 t09_condiag.doc Continued...


Table 1-9: Concurrent diagnoses: safety analysis set, continued

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Gastrointestinal disordersColonic polyp 0 0.0 1 4.8 0 0.0Constipation 0 0.0 0 0.0 1 5.3Gastric ulcer 1 5.6 0 0.0 0 0.0Haemorrhoids 0 0.0 1 4.8 0 0.0Hiatus hernia 0 0.0 1 4.8 0 0.0Irritable bowel syndrome 1 5.6 0 0.0 0 0.0SOC total 3 16.7 7 33.3 8 42.1

Surgical and medical proceduresMedical diet 7 38.9 6 28.6 3 15.8Cardiovascular event prophylaxis 0 0.0 1 4.8 0 0.0Thrombosis prophylaxis 0 0.0 1 4.8 0 0.0Vitamin supplementation 0 0.0 1 4.8 0 0.0SOC total 7 38.9 7 33.3 3 15.8

Musculoskeletal and connective tissuedisordersBack pain 0 0.0 2 9.5 3 15.8Osteoarthritis 1 5.6 2 9.5 0 0.0Arthralgia 0 0.0 0 0.0 2 10.5Arthritis 0 0.0 1 4.8 1 5.3Muscle spasms 0 0.0 1 4.8 1 5.3Rheumatoid arthritis 1 5.6 0 0.0 1 5.3Lumbar spinal stenosis 1 5.6 0 0.0 0 0.0Musculoskeletal stiffness 0 0.0 0 0.0 1 5.3Neck pain 0 0.0 0 0.0 1 5.3Osteopenia 1 5.6 0 0.0 0 0.0Plantar fascial fibromatosis 0 0.0 1 4.8 0 0.0SOC total 3 16.7 5 23.8 7 36.8

Psychiatric disordersAnxiety 3 16.7 3 14.3 3 15.8Insomnia 0 0.0 3 14.3 3 15.8Depression 2 11.1 1 4.8 2 10.5Affective disorder 1 5.6 0 0.0 0 0.0Attention deficit/hyperactivity

disorder 1 5.6 0 0.0 0 0.0

16NOV15:11:24:17 LP0084 1077 t09 condiag.doc Continued...



Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Psychiatric disordersBipolar disorder 1 5.6 0 0.0 0 0.0SOC total 5 27.8 5 23.8 5 26.3

Nervous system disordersDiabetic neuropathy 3 16.7 1 4.8 0 0.0Migraine 1 5.6 0 0.0 1 5.3Restless legs syndrome 1 5.6 1 4.8 0 0.0Headache 0 0.0 0 0.0 1 5.3Neuralgia 0 0.0 0 0.0 1 5.3Neuropathy peripheral 0 0.0 0 0.0 1 5.3Sciatica 0 0.0 0 0.0 1 5.3SOC total 5 27.8 2 9.5 4 21.1

Endocrine disordersHypothyroidism 4 22.2 1 4.8 2 10.5Hypogonadism 0 0.0 0 0.0 1 5.3Thyroid disorder 0 0.0 0 0.0 1 5.3SOC total 4 22.2 1 4.8 4 21.1

InvestigationsBlood testosterone decreased 0 0.0 0 0.0 2 10.5Blood triglycerides increased 1 5.6 1 4.8 0 0.0Gamma-Glutamyltransferase increased 1 5.6 1 4.8 0 0.0Vitamin d decreased 0 0.0 2 9.5 0 0.0SOC total 2 11.1 4 19.0 2 10.5

Respiratory, thoracic and mediastinaldisordersSleep apnoea syndrome 0 0.0 1 4.8 4 21.1Asthma 0 0.0 0 0.0 2 10.5Chronic obstructive pulmonary

disease 1 5.6 0 0.0 0 0.0

SOC total 1 5.6 1 4.8 5 26.3 Reproductive system and breast disordersBenign prostatic hyperplasia 1 5.6 2 9.5 1 5.3Erectile dysfunction 1 5.6 0 0.0 0 0.0SOC total 2 11.1 2 9.5 1 5.3




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Renal and urinary disordersNephrolithiasis 0 0.0 2 9.5 0 0.0Renal failure chronic 1 5.6 0 0.0 0 0.0Urinary incontinence 0 0.0 0 0.0 1 5.3SOC total 1 5.6 2 9.5 1 5.3

Skin and subcutaneous tissue disordersEczema 0 0.0 0 0.0 1 5.3Night sweats 1 5.6 0 0.0 0 0.0Psoriasis 1 5.6 0 0.0 0 0.0Rosacea 0 0.0 0 0.0 1 5.3SOC total 2 11.1 0 0.0 2 10.5

Social circumstancesPostmenopause 3 16.7 1 4.8 0 0.0SOC total 3 16.7 1 4.8 0 0.0

General disorders and administration siteconditionsPain 0 0.0 0 0.0 2 10.5SOC total 0 0.0 0 0.0 2 10.5

Infections and infestationsOtitis media 0 0.0 0 0.0 1 5.3Urinary tract infection 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 1 5.3

Blood and lymphatic system disordersLymphadenopathy mediastinal 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 0 0.0

Ear and labyrinth disordersTinnitus 0 0.0 0 0.0 1 5.3SOC total 0 0.0 0 0.0 1 5.3

Eye disordersGlaucoma 1 5.6 0 0.0 0 0.0SOC total 1 5.6 0 0.0 0 0.0

Hepatobiliary disordersHepatomegaly 0 0.0 1 4.8 0 0.0




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Hepatobiliary disordersSOC total 0 0.0 1 4.8 0 0.0



16NOV15:11:24:17 LP0084 1077 t09 condiag.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) Different diagnoses within the same preferred term and system



Table 1–10: Concomitant medication at baseline: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

ATC classification index level 4WHO Dictionary Derived Term1 N2 % N2 % N2 %

HMG COA REDUCTASE INHIBITORSSimvastatin 2 11.1 0 0.0 5 26.3Atorvastatin 0 0.0 1 4.8 3 15.8Lovastatin 1 5.6 1 4.8 1 5.3Rosuvastatin calcium 1 5.6 2 9.5 0 0.0Atorvastatin calcium 0 0.0 1 4.8 0 0.0Pravastatin 1 5.6 0 0.0 0 0.0Pravastatin sodium 0 0.0 0 0.0 1 5.3Rosuvastatin 0 0.0 1 4.8 0 0.0ATC4 total 5 27.8 6 28.6 10 52.6

PLATELET AGGREGATION INHIBITORS EXCL. HEPARINAcetylsalicylic acid 4 22.2 2 9.5 4 21.1Platelet aggregation inhibitors

excl. heparin 2 11.1 4 19.0 4 21.1

Clopidogrel bisulfate 1 5.6 1 4.8 0 0.0Clopidogrel 0 0.0 0 0.0 1 5.3ATC4 total 6 33.3 6 28.6 9 47.4

PROTON PUMP INHIBITORSOmeprazole 1 5.6 2 9.5 5 26.3Esomeprazole magnesium 0 0.0 2 9.5 2 10.5Lansoprazole 0 0.0 1 4.8 0 0.0ATC4 total 1 5.6 5 23.8 7 36.8

BETA BLOCKING AGENTS, SELECTIVEMetoprolol 3 16.7 1 4.8 3 15.8Atenolol 0 0.0 1 4.8 2 10.5ATC4 total 3 16.7 2 9.5 5 26.3

ACE INHIBITORS, PLAINLisinopril 2 11.1 0 0.0 4 21.1Enalapril 0 0.0 1 4.8 0 0.0Quinapril 0 0.0 1 4.8 0 0.0ATC4 total 2 11.1 2 9.5 4 21.1

BIGUANIDESMetformin 2 11.1 2 9.5 4 21.1ATC4 total 2 11.1 2 9.5 4 21.1

16NOV15:11:24:26 LP0084 1077 t10 conmed.doc Continued...


Table 1-10: Concomitant medication at baseline: safety analysis set, continued

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


THYROID HORMONESLevothyroxine sodium 1 5.6 1 4.8 2 10.5Levothyroxine 2 11.1 0 0.0 1 5.3Thyroid 1 5.6 0 0.0 0 0.0ATC4 total 4 22.2 1 4.8 3 15.8

VITAMIN D AND ANALOGUESErgocalciferol 1 5.6 3 14.3 1 5.3Colecalciferol 2 11.1 1 4.8 0 0.0ATC4 total 3 16.7 4 19.0 1 5.3

ANGIOTENSIN II ANTAGONISTS, PLAINLosartan 1 5.6 1 4.8 4 21.1Olmesartan medoxomil 0 0.0 1 4.8 0 0.0ATC4 total 1 5.6 2 9.5 4 21.1

OTHER LIPID MODIFYING AGENTSFish oil 0 0.0 1 4.8 3 15.8Docosahexaenoic acid

w/eicosapentaenoic acid/ 3 16.7 0 0.0 0 0.0

ATC4 total 3 16.7 1 4.8 3 15.8

OTHER ANALGESICS AND ANTIPYRETICSGabapentin 3 16.7 2 9.5 1 5.3ATC4 total 3 16.7 2 9.5 1 5.3

SELECTIVE SEROTONIN REUPTAKE INHIBITORSSertraline 0 0.0 1 4.8 1 5.3Citalopram 1 5.6 0 0.0 0 0.0Escitalopram 0 0.0 0 0.0 1 5.3Paroxetine 0 0.0 1 4.8 0 0.0Sertraline hydrochloride 1 5.6 0 0.0 0 0.0ATC4 total 2 11.1 2 9.5 2 10.5

OTHER ANTIINFLAMMATORY AND ANTIRHEUMATIC AGENTS, NGlucosamine 0 0.0 0 0.0 2 10.5Glucosamine w/chondroitin

sulf./mangan./vit c 0 0.0 0 0.0 1 5.3

Nabumetone 0 0.0 0 0.0 1 5.3Other antiinflammatory and

antirheumatic agen 1 5.6 0 0.0 0 0.0




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


OTHER ANTIINFLAMMATORY AND ANTIRHEUMATIC AGENTS, NATC4 total 1 5.6 0 0.0 4 21.1

PIPERAZINE DERIVATIVESCetirizine hydrochloride 1 5.6 2 9.5 1 5.3Levocetirizine 0 0.0 0 0.0 1 5.3ATC4 total 1 5.6 2 9.5 2 10.5

PROPIONIC ACID DERIVATIVESIbuprofen 0 0.0 0 0.0 3 15.8Naproxen 0 0.0 0 0.0 2 10.5Naproxen sodium 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 5 26.3

VITAMIN B12 (CYANOCOBALAMIN AND ANALOGUES)Cyanocobalamin 3 16.7 1 4.8 1 5.3ATC4 total 3 16.7 1 4.8 1 5.3

ALPHA-ADRENORECEPTOR ANTAGONISTSTamsulosin 0 0.0 1 4.8 1 5.3Tamsulosin hydrochloride 1 5.6 0 0.0 1 5.3ATC4 total 1 5.6 1 4.8 2 10.5

DIHYDROPYRIDINE DERIVATIVESAmlodipine 2 11.1 1 4.8 1 5.3ATC4 total 2 11.1 1 4.8 1 5.3

GLUCOCORTICOIDSFluticasone propionate 0 0.0 0 0.0 2 10.5Fluticasone 0 0.0 0 0.0 1 5.3Prednisone 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 3 15.8

No ATC4 codeAllium sativum 0 0.0 1 4.8 0 0.0Antipyrine w/benzocaine 0 0.0 0 0.0 1 5.3Cranberry berco 0 0.0 1 4.8 0 0.0Mineral supplements 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 2 9.5 1 5.3




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


ASCORBIC ACID (VITAMIN C), PLAINAscorbic acid 2 11.1 0 0.0 1 5.3ATC4 total 2 11.1 0 0.0 1 5.3

BENZODIAZEPINE DERIVATIVESClonazepam 0 0.0 0 0.0 1 5.3Diazepam 1 5.6 0 0.0 0 0.0Temazepam 0 0.0 1 4.8 0 0.0ATC4 total 1 5.6 1 4.8 1 5.3

BENZODIAZEPINE RELATED DRUGSZolpidem tartrate 0 0.0 0 0.0 2 10.5Zolpidem 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 3 15.8

FIBRATESFenofibrate 1 5.6 0 0.0 1 5.3Gemfibrozil 1 5.6 1 4.8 0 0.0ATC4 total 1 5.6 1 4.8 1 5.3

MULTIVITAMINS WITH MINERALSAscorbic acid w/biotin/calcium

pantothenate/c 2 11.1 0 0.0 1 5.3

ATC4 total 2 11.1 0 0.0 1 5.3

MULTIVITAMINS, OTHER COMBINATIONSMultivitamins 1 5.6 1 4.8 1 5.3ATC4 total 1 5.6 1 4.8 1 5.3

NICOTINIC ACID AND DERIVATIVESNicotinic acid 0 0.0 0 0.0 3 15.8ATC4 total 0 0.0 0 0.0 3 15.8

OTHER ANTIDEPRESSANTSBupropion 1 5.6 0 0.0 0 0.0Duloxetine hydrochloride 0 0.0 1 4.8 0 0.0Trazodone 1 5.6 0 0.0 0 0.0ATC4 total 2 11.1 1 4.8 0 0.0




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


SULFONAMIDES, PLAINFurosemide 1 5.6 1 4.8 0 0.0Chlortalidone 0 0.0 0 0.0 1 5.3ATC4 total 1 5.6 1 4.8 1 5.3

3-OXOANDROSTEN (4) DERIVATIVESTestosterone 0 0.0 0 0.0 2 10.5ATC4 total 0 0.0 0 0.0 2 10.5

ADRENERGICS AND OTHER DRUGS FOR OBSTRUCTIVE AIRWAYBudesonide w/formoterol fumarate 1 5.6 0 0.0 0 0.0Seretide 0 0.0 0 0.0 1 5.3ATC4 total 1 5.6 0 0.0 1 5.3

CALCIUMCalcium 0 0.0 2 9.5 0 0.0ATC4 total 0 0.0 2 9.5 0 0.0

DOPAMINE AGONISTSPramipexole 1 5.6 1 4.8 0 0.0ATC4 total 1 5.6 1 4.8 0 0.0

FOLIC ACID AND DERIVATIVESFolic acid and derivatives 0 0.0 0 0.0 2 10.5ATC4 total 0 0.0 0 0.0 2 10.5

NATURAL OPIUM ALKALOIDSHydrocodone 0 0.0 0 0.0 1 5.3Vicodin 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 2 10.5

OTHER ANTIEPILEPTICSGabapentin 0 0.0 0 0.0 1 5.3Lamotrigine 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 1 5.3

OTHER ANTIHISTAMINES FOR SYSTEMIC USEFexofenadine hydrochloride 0 0.0 0 0.0 1 5.3




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


OTHER ANTIHISTAMINES FOR SYSTEMIC USELoratadine 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 2 10.5

SELECTIVE BETA-2-ADRENORECEPTOR AGONISTSSalbutamol 0 0.0 0 0.0 2 10.5ATC4 total 0 0.0 0 0.0 2 10.5

SULFONAMIDES, UREA DERIVATIVESGlimepiride 1 5.6 0 0.0 0 0.0Glipizide 0 0.0 0 0.0 1 5.3ATC4 total 1 5.6 0 0.0 1 5.3

VITAMINS, OTHER COMBINATIONSOcuvite lutein & zeaxanthin 0 0.0 1 4.8 0 0.0Vitamins, other combinations 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 2 9.5 0 0.0

ACETIC ACID DERIVATIVES AND RELATED SUBSTANCESEtodolac 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

ALPHA AND BETA BLOCKING AGENTSCarvedilol 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

ANGIOTENSIN II ANTAGONISTS, OTHER COMBINATIONSTribenzor 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

ANILIDESParacetamol 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

ANTIDIARRHEAL MICROORGANISMSBifidobacterium lactis 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

AROMATASE INHIBITORSAnastrozole 0 0.0 0 0.0 1 5.3




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


AROMATASE INHIBITORSATC4 total 0 0.0 0 0.0 1 5.3

BULK PRODUCERSPolycarbophil calcium 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

CENTRALLY ACTING SYMPATHOMIMETICSAmfetamine 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

COMBINATIONS OF ORAL BLOOD GLUCOSE LOWERING DRUGSVelmetia 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

CORTICOSTEROIDS, MODERATELY POTENT (GROUP II)Triamcinolone 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

DIAZEPINES, OXAZEPINES, THIAZEPINES AND OXEPINESAsenapine maleate 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

DIPHENYLMETHANE DERIVATIVESHydroxyzine 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

DRUGS USED IN ERECTILE DYSFUNCTIONVardenafil hydrochloride 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

ELECTROLYTE SOLUTIONSHydrochloric acid 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

ENEMASBisacodyl 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


H2-RECEPTOR ANTAGONISTSRanitidine hydrochloride 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

MAGNESIUMMagnesium 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

MELATONIN RECEPTOR AGONISTSMelatonin 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

NATURAL AND SEMISYNTHETIC ESTROGENS, PLAINEstradiol 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

OTHER AGENTS FOR TREATMENT OF HEMORRHOIDS AND ANALDiltiazem hydrochloride 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

OTHER ANTINEOPLASTIC AGENTSCelecoxib 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

OTHER ANTIPSYCHOTICSAripiprazole 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

OTHER ANTITHROMBOTIC AGENTSRivaroxaban 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

OTHER BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINSLiraglutide 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

OTHER CARDIAC PREPARATIONSUbidecarenone 0 0.0 1 4.8 0 0.0




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


OTHER CARDIAC PREPARATIONSATC4 total 0 0.0 1 4.8 0 0.0

OTHER CENTRALLY ACTING AGENTSCyclobenzaprine 0 0.0 0 0.0 1 5.3Tizanidine 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

OTHER CHEMOTHERAPEUTICSMetronidazole 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

OTHER DRUGS FOR FUNCTIONAL BOWEL DISORDERSSimeticone 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

OTHER LAXATIVESLinaclotide 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

OTHER OPIOIDSTramadol 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

OTHER PERIPHERAL VASODILATORSCilostazol 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

OTHER PLAIN VITAMIN PREPARATIONSTocopherol 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

OTHER POTASSIUM-SPARING AGENTSTriamterene 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

POTASSIUMPotassium 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


PREPARATIONS INHIBITING URIC ACID PRODUCTIONAllopurinol 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

PROSTAGLANDIN ANALOGUESLatanoprost 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

THIAZIDES, PLAINHydrochlorothiazide 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

THIAZOLIDINEDIONESPioglitazone hydrochloride 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

URINARY CONCREMENT SOLVENTSPotassium citrate 0 0.0 1 4.8 0 0.0ATC4 total 0 0.0 1 4.8 0 0.0

VARIOUS ALIMENTARY TRACT AND METABOLISM PRODUCTSThioctic acid 0 0.0 0 0.0 1 5.3Ubidecarenone 0 0.0 0 0.0 1 5.3ATC4 total 0 0.0 0 0.0 1 5.3

VITAMIN B-COMPLEX, PLAINVitamin b-complex, plain 1 5.6 0 0.0 0 0.0ATC4 total 1 5.6 0 0.0 0 0.0

Total number of concomitant medications3

72 69 114


16NOV15:11:24:26 LP0084 1077 t10 conmed.doc

1) Classification according to WHO Drug Dictionary version Q3, 2012. 2) N=Number of subjects. 3) Drugs with the same Anatomical Therapeutic Chemical (ATC) classification level 4 code and generic name/preferred term name which have been taken by the same subject have been counted as one.


Table 1–11: AK count at baseline by site: safety analysis set

Total AK count by site

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)




17NOV15:14:58:01 LP0084 1077 t11 AKcount.doc

PPD

PPD


Table 1–12: Vital signs at baseline: safety analysis set

VisitVital sign

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Screening Systolic Blood Pressure (mmHg)

Mean 131.7 128.4 136.0 SD 20.9 13.9 12.7 Median 130.0 131.0 132.0 Minimum 91.0 109.0 125.0 Maximum 168.0 162.0 173.0 Number 18 21 19 Diastolic Blood Pressure (mmHg)

Mean 76.2 78.6 77.6 SD 10.5 8.9 8.7 Median 75.5 81.0 78.0 Minimum 56.0 56.0 60.0 Maximum 97.0 91.0 90.0 Number 18 21 19 Heart Rate (Beats/min)

Mean 73.4 70.3 66.6 SD 10.9 10.8 11.8 Median 75.0 73.0 67.0 Minimum 51.0 47.0 50.0 Maximum 90.0 91.0 89.0 Number 18 21 19 Temperature (C)

Mean 36.7 36.8 36.7 SD 0.2 0.3 0.2 Median 36.7 36.8 36.7 Minimum 36.3 36.2 36.2 Maximum 37.4 37.5 37.1 Number 18 21 19

16NOV15:11:24:36 LP0084 1077 t12 vitals.doc


Table 1–13: Age, height, weight and BMI by site: PK analysis set

Face0.018% (n=15)

Arm0.1%

(n=20)

Scalp0.037% (n=15)






PPD


Table 1-13: Age, height, weight and BMI by site: PK analysis set, continued

Face0.018% (n=15)

Arm0.1%

(n=20)

Scalp0.037% (n=15)






PPD


Table 1-13: Age, height, weight and BMI by site: PK analysis set, continued

Face0.018% (n=15)

Arm0.1%

(n=20)

Scalp0.037% (n=15)

Total





17NOV15:15:54:57 LP0084 1077 t13_age_height_weight_bmi.doc


Table 1–14: Sex, race, ethnicity and skin type by site: PK analysis set

Face0.018% (n=15)

Arm0.1% (n=20)

Scalp0.037% (n=15)

N1 % N1 % N1 %


Race White 8 100.0 11 100.0 4 100.0 Total 8 100.0 11 100.0 4 100.0




Race White 7 100.0 9 100.0 11 100.0 Total 7 100.0 9 100.0 11 100.0




PPD

PPD


Table 1-14: Sex, race, ethnicity and skin type by site: PK analysis set, continued

Face0.018% (n=15)

Arm0.1% (n=20)

Scalp0.037% (n=15)

N1 % N1 % N1 %

Total


Race White 15 100.0 20 100.0 15 100.0 Total 15 100.0 20 100.0 15 100.0






Table 1–15: Compliance by visit: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Visit Treatment according to protocol N1 % N1 % N1 %

Visit 2/Day 1 Yes 18 100.0 21 100.0 19 100.0 Total 18 100.0 21 100.0 19 100.0

Visit 3/Day 2 Yes 15 83.3 21 100.0 17 89.5 No 3 16.7 2 10.5 Total 18 100.0 21 100.0 19 100.0

Visit 4/Day 3 Yes 16 88.9 20 95.2 15 78.9 No 2 11.1 1 4.8 4 21.1 Total 18 100.0 21 100.0 19 100.0

16NOV15:11:25:02 LP0084 1077 t15 compliance.doc



Table 1–16: Total drug usage: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Total amount used (g) Mean 3.56 3.69 3.58 SD 0.64 0.20 0.83 Median 3.78 3.72 4.11 Minimum 1.35 3.34 1.38 Maximum 4.05 3.97 4.13 Number 18 19 17

05JAN16:09:40:16 LP0084 1077 t16 drug usage.doc


Table 1–17: Total drug usage by site: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Total amount used (g)



05JAN16:09:40:34 LP0084 1077 t17 drug usage site.doc

PPD

PPD


71

21

Visit 1 (screening)

Visit 2 (Day 1)



21Visit 3 (Day 2)

21Visit 4 (Day 3)

21Visit 5 (Day 4)

21Visit 6 (Day 15)

19

19

19

19

19

18

18

18

18

18

ARM FACE SCALP

Figure 1-1: Visit attendance by treatment group


71

58Included




50PK analysis set

Enrolled

8 not fully compliant

Figure 1-2: Trial analysis sets overall


21Included


20PK analysis set

1 not fully

compliant

ARM

18

18

15

3 not fully

compliant

FACE

19

19

15

4 not fully

compliant

SCALP

Figure 1-3: Trial analysis sets by treatment group


3 Tables and Figures, Safety Data

List of Tables

Table 3–1: Overall summary of AEs: safety analysis set ....................................................... 121

Table 3–2: AEs by SOC: safety analysis set .......................................................................... 122

Table 3–3: AEs by SOC and PT: safety analysis set .............................................................. 123

Table 3–4: Most common AEs by SOC and PT: safety analysis set ...................................... 125

Table 3–5: Related AEs by SOC and PT: safety analysis set ................................................. 126

Table 3–6: Administration Site Reactions by LLT: safety analysis set .................................. 128

Table 3–7: AEs inside treatment area, excluding administration site reactions by SOC and PT: safety analysis set ........................................................................................... 129

Table 3–8: Intensity of AEs by SOC and PT: safety analysis set ........................................... 130

Table 3–9: Intensity of administration Site Reactions by LLT: safety analysis set................ 132

Table 3–10: Causality of AEs by SOC and PT: safety analysis set........................................ 133

Table 3–11: AEs leading to discontinuation of treatment by SOC and PT: safety analysis set........................................................................................................................ 134

Table 3–12: Frequency of LSR components by visit: safety analysis set .............................. 135

Table 3–13: Maximum post baseline LSR score by LSR component: safety analysis set..... 141

Table 3–14: Composite LSR score by visit: safety analysis set ............................................. 143

Table 3–15: Maximum post baseline composite LSR score: safety analysis set ................... 144

Table 3–16: Change in composite LSR score from baseline by visit: safety analysis set...... 145

Table 3–17: Summary of visit of maximum post baseline composite LSR score: safety analysis set...................................................................................................... 146

Table 3–18: Summary of visit of return to baseline for composite LSR score: safety analysis set ................................................................................................................... 147

Table 3–19: Vital signs by visit: safety analysis set ............................................................... 148

Table 3–20: Change in vital signs from baseline to Day 15: safety analysis set.................... 150

Table 3–21: Summary of Haematology parameters by visit: safety analysis set ................... 151


Table 3–22: Summary of change in Haematology parameters from baseline to visit 4: safety analysis set...................................................................................................... 159

Table 3–23: Shift tables for Haematology parameters: safety analysis set ............................ 163

Table 3–24: Summary of Biochemistry parameters by visit: safety analysis set ................... 166

Table 3–25: Summary of change in Biochemistry parameters from baseline to visit 4: safety analysis set...................................................................................................... 177

Table 3–26: Shift tables for Biochemistry parameters: safety analysis set ............................ 182

List of Figures

Figure 3-1: Maximum post baseline composite LSR score by treatment group: safety analysis set ................................................................................................................... 187

Figure 3-2: Composite LSR score – mean profiles by treatment group: safety analysis set.. 188

Figure 3-3: Composite LSR score – individual profiles by treatment group: safety analysis set........................................................................................................................ 189

Figure 3-4: LSR component scores by visit and treatment group: safety analysis set........... 190

Figure 3-5: Maximal change in composite LSR score versus total drug usage: safety analysis set ................................................................................................................... 191

Figure 3-6: Maximal composite LSR score versus total drug usage: safety analysis set....... 192

Figure 3-7: Maximal composite LSR score versus Cmax: PK analysis set ........................... 193

Figure 3-8: Cmax versus total drug usage: PK analysis set ................................................... 194

Figure 3-9: Maximal change in composite LSR score for subjects having at least one PK value above LLOQ post administration on Day 3: PK analysis set ............... 195

Figure 3-10: Maximal composite LSR score for subjects with PK values above LLOQ: PK analysis set...................................................................................................... 196


Table 3–1: Overall summary of AEs: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Adverse event category AE1,2 N3 (%) AE1,2 N3 (%) AE1,2 N3 (%)

All adverse events 29 17 ( 94.4) 35 17 ( 81.0) 36 19 (100.0) Severe adverse events 2 1 ( 5.6) 1 1 ( 4.8) 0 0 ( 0.0) Related adverse events 28 16 ( 88.9) 34 17 ( 81.0) 36 19 (100.0) AEs leading to withdrawal from trial

0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0)

SAEs 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)

16NOV15:12:45:33 LP0084 1077 t01_summary.doc

1) AE=Number 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=Number of subjects.


Table 3–2: AEs by SOC: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

System Organ Class2 N1 % N1 % N1 %

General disorders andadministration site conditions

16 88.9 17 81.0 19 100.0

Eye disorders 2 11.1 0 0.0 3 15.8Infections and infestations 0 0.0 2 9.5 0 0.0Blood and lymphatic systemdisorders

0 0.0 0 0.0 1 5.3

Investigations 1 5.6 0 0.0 0 0.0Musculoskeletal and connectivetissue disorders

0 0.0 1 4.8 0 0.0

Nervous system disorders 0 0.0 1 4.8 0 0.0Respiratory, thoracic andmediastinal disorders

0 0.0 0 0.0 1 5.3

Skin and subcutaneous tissuedisorders

0 0.0 1 4.8 0 0.0

Total number of adverseevents3

19 22 24


16NOV15:12:45:43 LP0084 1077 t02 ae soc.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) Different adverse events within the same preferred term and system



Table 3–3: AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)







1 5.6 0 0.0 0 0.0

SOC total 1 5.6 0 0.0 0 0.0 Musculoskeletal and connectivetissue disordersPain in extremity 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 0 0.0

16NOV15:12:45:53 LP0084 1077 t03_ae_soc_pt.doc Continued...


Table 3-3: AEs by SOC and PT: safety analysis set, continued

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)




Skin and subcutaneous tissuedisordersUrticaria 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 0 0.0

Total number of adverseevents3

29 35 36


16NOV15:12:45:53 LP0084 1077 t03 ae soc pt.doc




Table 3–4: Most common AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

System Organ Class (SOC)Preferred Term2,3 N1 % N1 % N1 %

General disorders and administrationsite conditionsApplication site pain 16 88.9 12 57.1 19 100.0Application site pruritus 9 50.0 11 52.4 8 42.1Application site erythema 0 0.0 3 14.3 2 10.5Chills 0 0.0 0 0.0 2 10.5Pain 0 0.0 2 9.5 0 0.0

Eye disordersEye pain 1 5.6 0 0.0 1 5.3

16NOV15:12:46:03 LP0084 1077 t04 ae soc pt most common.doc

1) N=Number of subjects.2) Classification according to MedDRA version 15.1.3) Most common adverse events are experienced by at least 2 subjects


Table 3–5: Related AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)






Musculoskeletal and connectivetissue disordersPain in extremity 0 0.0 1 4.8 0 0.0SOC total 0 0.0 1 4.8 0 0.0


16NOV15:12:46:14 LP0084 1077 t05 ae rel soc pt.doc Continued...


Table 3-5: Related AEs by SOC and PT: safety analysis set, continued

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)



Total number of related adverseevents3

28 34 36


16NOV15:12:46:14 LP0084 1077 t05_ae_rel_soc_pt.doc




Table 3–6: Administration Site Reactions by LLT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Lowest Level Term1 N2 % N2 % N2 %

Application site burning 15 83.3 10 47.6 8 42.1Application site itching 9 50.0 11 52.4 8 42.1Application site pain 7 38.9 2 9.5 17 89.5Application site stinging 7 38.9 5 23.8 3 15.8Application site erythema 0 0.0 3 14.3 2 10.5Application site tenderness 1 5.6 0 0.0 3 15.8Application site allergy 1 5.6 0 0.0 0 0.0 Total number of adverse events3 40 31 41 Total number of subjects 16 88.9 17 81.0 19 100.0

16NOV15:12:46:24 LP0084 1077 t06 app soc llt.doc

1) Classification according to MedDRA version 15.1.2) N=Number of subjects.3) Different adverse events within the same LLT and system organ

class and involving the same subject have been counted as one. A single subject could appear in multiple classes.


Table 3–7: AEs inside treatment area, excluding administration site reactions by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)






16NOV15:12:46:29 LP0084 1077 t07 inside soc pt.doc




Table 3–8: Intensity of AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)


General disorders and administration site conditionsApplication site pain 5 10 1 4 7 1 2 17 0Application site pruritus 5 3 1 6 5 0 2 6 0Application site erythema 0 0 0 1 2 0 0 2 0Chills 0 0 0 0 0 0 2 0 0Pain 0 0 0 2 0 0 0 0 0Application sitehypersensitivity

1 0 0 0 0 0 0 0 0

Cyst 0 0 0 0 1 0 0 0 0Pyrexia 0 0 0 1 0 0 0 0 0

Eye disordersEye pain 0 1 0 0 0 0 1 0 0Dry eye 0 1 0 0 0 0 0 0 0Eye irritation 0 0 0 0 0 0 0 1 0Eyelid oedema 0 0 0 0 0 0 0 1 0

Infections and infestationsApplication site cellulitis 0 0 0 0 1 0 0 0 0Purulent discharge 0 0 0 0 1 0 0 0 0

Blood and lymphatic system disordersLymphadenopathy 0 0 0 0 0 0 1 0 0


1 0 0 0 0 0 0 0 0

Musculoskeletal and connective tissue disordersPain in extremity 0 0 0 1 0 0 0 0 0

Nervous system disordersLethargy 0 0 0 0 1 0 0 0 0

05JAN16:10:05:07 LP0084 1077 t08 ae int.doc Continued...


Table 3-8: Intensity of AEs by SOC and PT: safety analysis set, continued

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)


Respiratory, thoracic and mediastinal disordersOropharyngeal pain 0 0 0 0 0 0 1 0 0

Skin and subcutaneous tissue disordersUrticaria 0 0 0 0 1 0 0 0 0

Total number of adverse events 12 15 2 15 19 1 9 27 0

05JAN16:10:05:07 LP0084 1077 t08_ae_int.doc

1) Classification according to MedDRA version 15.1.2) Subjects with more than one AE within the same preferred term has

been counted only once in the most severe intensity group.3) Mod = Moderate. Sev = Severe.


Table 3–9: Intensity of administration Site Reactions by LLT: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Lowest Level Term1,2 Mild Mod3 Sev3 Mild Mod3 Sev3 Mild Mod3 Sev3

Application site burning 6 8 1 4 6 0 4 4 0Application site itching 5 3 1 6 5 0 2 6 0Application site pain 1 6 0 0 1 1 3 14 0Application site stinging 2 5 0 1 4 0 1 2 0Application site erythema 0 0 0 1 2 0 0 2 0Application site tenderness 0 1 0 0 0 0 2 1 0Application site allergy 1 0 0 0 0 0 0 0 0Total number of adverse events 15 23 2 12 18 1 12 29 0

05JAN16:11:34:15 LP0084 1077 t09_app_int.doc

1) Classification according to MedDRA version 15.1.2) Subjects with more than one AE within the same lowest level term

is counted only once in the most severe intensity group.3) Mod = Moderate. Sev = Severe.


Table 3–10: Causality of AEs by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

System Organ Class(SOC)Preferred Term1,2 NR3 PO3 PR3 NR3 PO3 PR3 NR3 PO3 PR3

General disorders and administration site conditions

Application site pain 0 5 11 0 6 6 0 2 17Application site pruritus 0 2 7 0 6 5 0 2 6Application site erythema 0 0 0 0 3 0 0 1 1Chills 0 0 0 0 0 0 0 1 1Pain 0 0 0 0 1 1 0 0 0Application site

hypersensitivity 0 1 0 0 0 0 0 0 0

Cyst 0 0 0 0 1 0 0 0 0Pyrexia 0 0 0 0 1 0 0 0 0

Eye disorders

Eye pain 0 1 0 0 0 0 0 1 0Dry eye 0 1 0 0 0 0 0 0 0Eye irritation 0 0 0 0 0 0 0 0 1Eyelid oedema 0 0 0 0 0 0 0 1 0

Infections and infestations

Application site cellulitis 0 0 0 0 0 1 0 0 0Purulent discharge 0 0 0 0 0 1 0 0 0

Blood and lymphatic system disorders

Lymphadenopathy 0 0 0 0 0 0 0 1 0 Investigations

Electrocardiogram QRS complex prolonged

1 0 0 0 0 0 0 0 0

Musculoskeletal and connective tissue disorders

Pain in extremity 0 0 0 0 1 0 0 0 0 Nervous system disorders

Lethargy 0 0 0 0 1 0 0 0 0 Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain 0 0 0 0 0 0 0 0 1 Skin and subcutaneous tissue disorders

Urticaria 0 0 0 1 0 0 0 0 0

16NOV15:12:46:56 LP0084 1077 t10 ae rel.doc

1) Subjects with more than one AE within the same preferred term has been counted only once in the most related group.2) Classification according to MedDRA version 15.1.3) NR=Not related, PO=Possibly related, PR=Probably related.


Table 3–11: AEs leading to discontinuation of treatment by SOC and PT: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


General disorders and administration siteconditionsApplication site pain 0 0.0 0 0.0 2 10.5SOC total 0 0.0 0 0.0 2 10.5



16NOV15:12:47:06 LP0084 1077 t11 drugwdr.doc




Table 3–12: Frequency of LSR components by visit: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Skin response parameterVisit

Grading N1 % N1 % N1 %

ErythemaVisit 2/Day 1

Not present 10 55.6 14 66.7 10 52.6 Slightly pink <50% 8 44.4 7 33.3 8 42.1 Pink or light red >50% 0 0.0 0 0.0 1 5.3 Total 18 100.0 21 100.0 19 100.0 Visit 3/Day 2

Slightly pink <50% 4 22.2 8 38.1 5 26.3 Pink or light red >50% 7 38.9 8 38.1 9 47.4 Red, restricted to treatment area 7 38.9 3 14.3 5 26.3 Red extending outside treatment

area 0 0.0 2 9.5 0 0.0

Total 18 100.0 21 100.0 19 100.0 Visit 4/Day 3


area 0 0.0 3 14.3 2 10.5

Total 18 100.0 21 100.0 19 100.0 Visit 5/Day 4


area 0 0.0 5 23.8 2 10.5

Total 18 100.0 21 100.0 19 100.0 Visit 6/Day 15

Not present 6 33.3 4 19.0 3 15.8 Slightly pink <50% 3 16.7 5 23.8 3 15.8 Pink or light red >50% 6 33.3 7 33.3 11 57.9 Red, restricted to treatment area 3 16.7 4 19.0 2 10.5 Red extending outside treatment

area 0 0.0 1 4.8 0 0.0

Total 18 100.0 21 100.0 19 100.0

16NOV15:12:47:16 LP0084 1077 t12 LSR comp visit.doc Continued...


Table 3-12: Frequency of LSR components by visit: safety analysis set, continued

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)



Flaking/ScalingVisit 2/Day 1

Not present 9 50.0 11 52.4 13 68.4 Isolated scale, specific to

lesions 9 50.0 10 47.6 6 31.6

Total 18 100.0 21 100.0 19 100.0 Visit 3/Day 2


lesions 4 22.2 8 38.1 5 26.3

Scale <50% 1 5.6 1 4.8 1 5.3 Total 18 100.0 21 100.0 19 100.0 Visit 4/Day 3


lesions 6 33.3 9 42.9 2 10.5

Scale <50% 3 16.7 1 4.8 1 5.3 Scale >50% 2 11.1 0 0.0 2 10.5 Total 18 100.0 21 100.0 19 100.0 Visit 5/Day 4


lesions 4 22.2 9 42.9 3 15.8

Scale <50% 4 22.2 1 4.8 1 5.3 Scale >50% 5 27.8 1 4.8 0 0.0 Total 18 100.0 21 100.0 19 100.0 Visit 6/Day 15


lesions 5 27.8 10 47.6 6 31.6

Scale <50% 1 5.6 7 33.3 0 0.0 Total 18 100.0 21 100.0 19 100.0

CrustingVisit 2/Day 1

Not present 18 100.0 20 95.2 12 63.2 Isolated crusting 0 0.0 1 4.8 6 31.6 Crusting <50% 0 0.0 0 0.0 1 5.3




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)



CrustingVisit 2/Day 1

Total 18 100.0 21 100.0 19 100.0 Visit 3/Day 2

Not present 14 77.8 19 90.5 16 84.2 Isolated crusting 3 16.7 2 9.5 2 10.5 Crusting <50% 1 5.6 0 0.0 1 5.3 Total 18 100.0 21 100.0 19 100.0 Visit 4/Day 3

Not present 11 61.1 15 71.4 14 73.7 Isolated crusting 6 33.3 5 23.8 2 10.5 Crusting <50% 1 5.6 1 4.8 2 10.5 Crusting >50% 0 0.0 0 0.0 1 5.3 Total 18 100.0 21 100.0 19 100.0 Visit 5/Day 4

Not present 8 44.4 9 42.9 9 47.4 Isolated crusting 5 27.8 8 38.1 2 10.5 Crusting <50% 3 16.7 3 14.3 7 36.8 Crusting >50% 2 11.1 1 4.8 1 5.3 Total 18 100.0 21 100.0 19 100.0 Visit 6/Day 15

Not present 16 88.9 7 33.3 14 73.7 Isolated crusting 2 11.1 10 47.6 3 15.8 Crusting <50% 0 0.0 2 9.5 2 10.5 Crusting >50% 0 0.0 1 4.8 0 0.0 Crusting extending outside

treatment area 0 0.0 1 4.8 0 0.0

Total 18 100.0 21 100.0 19 100.0

SwellingVisit 2/Day 1

Not present 18 100.0 21 100.0 19 100.0 Total 18 100.0 21 100.0 19 100.0 Visit 3/Day 2

Not present 4 22.2 5 23.8 3 15.8 Slight, lesion specific oedema 6 33.3 13 61.9 10 52.6 Palpable oedema extending beyond

individual lesions 7 38.9 3 14.3 5 26.3

Confluent and/or visible oedema 1 5.6 0 0.0 1 5.3 Total 18 100.0 21 100.0 19 100.0




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)



SwellingVisit 4/Day 3



Confluent and/or visible oedema 4 22.2 5 23.8 1 5.3 Marked swelling extending outside

treatment area 3 16.7 1 4.8 1 5.3

Total 18 100.0 21 100.0 19 100.0 Visit 5/Day 4



Confluent and/or visible oedema 6 33.3 6 28.6 8 42.1 Marked swelling extending outside

treatment area 2 11.1 1 4.8 1 5.3

Total 18 100.0 21 100.0 19 100.0 Visit 6/Day 15



Total 18 100.0 21 100.0 19 100.0

Vesiculation/PustulationVisit 2/Day 1

Not present 18 100.0 21 100.0 19 100.0 Total 18 100.0 21 100.0 19 100.0 Visit 3/Day 2

Not present 5 27.8 12 57.1 8 42.1 Vesicles only 2 11.1 6 28.6 4 21.1 Transudate or pustules, with or

without vesicles <50% 11 61.1 2 9.5 5 26.3


0 0.0 1 4.8 2 10.5

Total 18 100.0 21 100.0 19 100.0 Visit 4/Day 3

Not present 3 16.7 5 23.8 1 5.3




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)



Vesiculation/PustulationVisit 4/Day 3

Vesicles only 4 22.2 1 4.8 2 10.5 Transudate or pustules, with or



5 27.8 8 38.1 11 57.9


3 16.7 2 9.5 1 5.3

Total 18 100.0 21 100.0 19 100.0 Visit 5/Day 4

Not present 7 38.9 3 14.3 1 5.3 Vesicles only 1 5.6 3 14.3 4 21.1 Transudate or pustules, with or



7 38.9 8 38.1 11 57.9


1 5.6 1 4.8 1 5.3

Total 18 100.0 21 100.0 19 100.0 Visit 6/Day 15

Not present 18 100.0 20 95.2 19 100.0 Vesicles only 0 0.0 1 4.8 0 0.0 Total 18 100.0 21 100.0 19 100.0

Erosion/UlcerationVisit 2/Day 1

Not present 17 94.4 21 100.0 19 100.0 Lesion specific erosion 1 5.6 0 0.0 0 0.0 Total 18 100.0 21 100.0 19 100.0 Visit 3/Day 2

Not present 11 61.1 19 90.5 13 68.4 Lesion specific erosion 3 16.7 2 9.5 4 21.1 Erosion extending beyond


Erosion >50% 0 0.0 0 0.0 1 5.3 Total 18 100.0 21 100.0 19 100.0 Visit 4/Day 3

Not present 6 33.3 9 42.9 7 36.8 Lesion specific erosion 6 33.3 9 42.9 7 36.8




Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)



Erosion/UlcerationVisit 4/Day 3

Erosion extending beyond individual lesions

5 27.8 3 14.3 3 15.8

Erosion >50% 0 0.0 0 0.0 2 10.5 Black eschar or ulceration 1 5.6 0 0.0 0 0.0 Total 18 100.0 21 100.0 19 100.0 Visit 5/Day 4



Erosion >50% 1 5.6 0 0.0 1 5.3 Total 18 100.0 21 100.0 19 100.0 Visit 6/Day 15



Total 18 100.0 21 100.0 19 100.0

16NOV15:12:47:16 LP0084 1077 t12 LSR comp visit.doc

1) N=Number of subjects.2) For parameter Vesiculation/Pustulation the value - Transudate or

pustules, with or without vesicles extending outside treatment area - is shortened.


Table 3–13: Maximum post baseline LSR score by LSR component: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


ErythemaSlightly pink <50% 3 16.7 0 0.0 0 0.0 Pink or light red >50% 2 11.1 5 23.8 4 21.1 Red, restricted to treatment area 13 72.2 10 47.6 12 63.2 Red extending outside treatment area

0 0.0 6 28.6 3 15.8

Total 18 100.0 21 100.0 19 100.0

Flaking/ScalingNot present 3 16.7 1 4.8 5 26.3 Isolated scale, specific to lesions

5 27.8 11 52.4 11 57.9

Scale <50% 5 27.8 7 33.3 1 5.3 Scale >50% 5 27.8 2 9.5 2 10.5 Total 18 100.0 21 100.0 19 100.0

CrustingNot present 4 22.2 2 9.5 4 21.1 Isolated crusting 9 50.0 11 52.4 5 26.3 Crusting <50% 3 16.7 5 23.8 8 42.1 Crusting >50% 2 11.1 2 9.5 2 10.5 Crusting extending outside treatment area

0 0.0 1 4.8 0 0.0

Total 18 100.0 21 100.0 19 100.0

SwellingNot present 1 5.6 0 0.0 1 5.3 Slight, lesion specific oedema 4 22.2 6 28.6 1 5.3 Palpable oedema extending beyond individual lesions

3 16.7 8 38.1 6 31.6

Confluent and/or visible oedema 5 27.8 6 28.6 9 47.4 Marked swelling extending outside treatment area

5 27.8 1 4.8 2 10.5

Total 18 100.0 21 100.0 19 100.0

Vesiculation/PustulationNot present 3 16.7 3 14.3 0 0.0 Vesicles only 2 11.1 1 4.8 3 15.8 Transudate or pustules, with or without vesicles <50%

2 11.1 6 28.6 2 10.5


8 44.4 9 42.9 12 63.2


3 16.7 2 9.5 2 10.5

Total 18 100.0 21 100.0 19 100.0

16NOV15:12:47:27 LP0084 1077 t13 maxlsr comp.doc Continued...


Table 3-13: Maximum post baseline LSR score by LSR component: safety analysis set,

continued

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


Erosion/UlcerationNot present 3 16.7 3 14.3 3 15.8 Lesion specific erosion 7 38.9 10 47.6 7 36.8 Erosion extending beyond individual lesions

6 33.3 8 38.1 6 31.6

Erosion >50% 1 5.6 0 0.0 3 15.8 Black eschar or ulceration 1 5.6 0 0.0 0 0.0 Total 18 100.0 21 100.0 19 100.0

16NOV15:12:47:27 LP0084 1077 t13 maxlsr comp.doc

1) N=Number of subjects.2) For parameter Vesiculation/Pustulation the value - Transudate or

pustules, with or without vesicles extending outside treatment area - is shortened.


Table 3–14: Composite LSR score by visit: safety analysis set

Composite LSR scoreVisit

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)






16NOV15:12:47:36 LP0084 1077 t14 LSR visit.doc


Table 3–15: Maximum post baseline composite LSR score: safety analysis set

Maximum post baselinecomposite LSR score

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)


16NOV15:12:47:46 LP0084 1077 t15 maxlsr.doc


Table 3–16: Change in composite LSR score from baseline by visit: safety analysis set

VisitLSR change from baseline

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Day 1 (Baseline, actual values)Mean 1.0 0.9 1.3 SD 1.1 1.0 1.0 Median 0.5 0.0 1.0 Minimum 0 0 0 Maximum 3 2 3 Number 18 21 19





16NOV15:12:47:56 LP0084 1077 t16 LSR chg visit.doc


Table 3–17: Summary of visit of maximum post baseline composite LSR score: safety analysis set

Face0.018% (n=18)

Arm0.1% (n=21)

Scalp0.037% (n=19)

Max LSR visit2 N1 % N1 % N1 %

Visit 3/Day 2 2 11.1 0 0.0 0 0.0 Visit 4/Day 3 8 44.4 8 38.1 5 26.3 Visit 5/Day 4 13 72.2 16 76.2 15 78.9 Visit 6/Day 15 0 0.0 1 4.8 0 0.0 Unscheduled 0 0.0 2 9.5 0 0.0

16NOV15:12:48:02 LP0084 1077 t17 visit maxlsr.doc

1) N=Number of subjects.2) Subjects with maximum score at more than one visit will appear at

all visits in question.


Table 3–18: Summary of visit of return to baseline for composite LSR score: safety analysis set

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Visit of return to baseline LSR




Visit 6/Day 15 8 44.4 3 14.3 7 36.8 Unscheduled 6.02 1 5.6 0 0.0 0 0.0 LSR not returned to baseline level

9 50.0 18 85.7 12 63.2

Total 18 100.0 21 100.0 19 100.0

16NOV15:12:48:13 LP0084 1077 t18 visit return base.doc


Table 3–19: Vital signs by visit: safety analysis set

VisitVital sign

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

ScreeningSystolic Blood Pressure (mmHg)


Mean 76.2 78.6 77.6 SD 10.5 8.9 8.7 Median 75.5 81.0 78.0 Minimum 56.0 56.0 60.0 Maximum 97.0 91.0 90.0 Number 18 21 19 Heart Rate (beats/min)

Mean 73.4 70.3 66.6 SD 10.9 10.8 11.8 Median 75.0 73.0 67.0 Minimum 51.0 47.0 50.0 Maximum 90.0 91.0 89.0 Number 18 21 19 Temperature (°C)


16NOV15:12:48:23 LP0084 1077 t19 vs visit.doc Continued...


Table 3-19: Vital signs by visit: safety analysis set, continued

VisitVital sign

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Visit 6/Day 15Systolic Blood Pressure (mmHg)


Mean 76.4 78.0 76.1 SD 7.2 8.4 7.7 Median 78.5 78.0 78.0 Minimum 59.0 65.0 60.0 Maximum 88.0 94.0 86.0 Number 18 21 19 Heart Rate (beats/min)

Mean 72.9 73.8 67.4 SD 12.3 9.9 10.1 Median 72.0 72.0 68.0 Minimum 51.0 58.0 53.0 Maximum 98.0 95.0 83.0 Number 18 21 19 Temperature (°C)


16NOV15:12:48:23 LP0084 1077 t19 vs visit.doc


Table 3–20: Change in vital signs from baseline to Day 15: safety analysis set

Vital sign

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Systolic Blood Pressure (mmHg)Mean 0.9 3.0 -4.1 SD 10.1 16.1 16.5 Median 1.5 1.0 -6.0 Minimum -21.0 -21.0 -38.0 Maximum 22.0 37.0 40.0 Number 18 21 19

Diastolic Blood Pressure (mmHg)Mean 0.2 -0.6 -1.5 SD 7.2 10.8 6.6 Median 1.0 -2.0 -2.0 Minimum -16.0 -17.0 -13.0 Maximum 12.0 22.0 11.0 Number 18 21 19

Heart Rate (beats/min)Mean -0.5 3.5 0.8 SD 10.0 7.5 6.7 Median 1.0 4.0 1.0 Minimum -27.0 -10.0 -13.0 Maximum 15.0 16.0 12.0 Number 18 21 19

Temperature (°C)Mean -0.1 -0.1 0.1 SD 0.3 0.5 0.3 Median -0.1 0.0 0.1 Minimum -0.6 -1.2 -0.5 Maximum 0.6 0.6 0.7 Number 18 21 19

16NOV15:12:48:27 LP0084 1077 t20 vs chg.doc


Table 3–21: Summary of Haematology parameters by visit: safety analysis set

ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

BasophilsScreening

Mean 0.017 0.014 0.021 SD 0.038 0.036 0.042 Median 0.000 0.000 0.000 Minimum 0.00 0.00 0.00 Maximum 0.10 0.10 0.10 Number 18 21 19 Visit 4/Day 3


Mean 0.000 0.050 SD 0.071 Median 0.000 0.050 Minimum 0.00 0.00 Maximum 0.00 0.10 Number 1 2

Basophils/LeukocytesScreening




16NOV15:12:49:12 LP0084 1077 t21_haem_visit.doc Continued...


Table 3-21: Summary of Haematology parameters by visit: safety analysis set, continued

ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

EosinophilsScreening




Eosinophils/LeukocytesScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

HematocritScreening




HemoglobinScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

LymphocytesScreening




Lymphocytes/LeukocytesScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Ery. Mean Corpuscular VolumeScreening




MonocytesScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Monocytes/LeukocytesScreening




NeutrophilsScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Neutrophils/LeukocytesScreening




PlateletsScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

ErythrocytesScreening




LeukocytesScreening




16NOV15:12:49:12 LP0084 1077 t21_haem_visit.doc


Table 3–22: Summary of change in Haematology parameters from baseline to visit 4: safety analysis set

ParameterChange from screening

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

BasophilsMean -0.020 -0.006 0.006 SD 0.042 0.057 0.024 Median 0.000 0.000 0.000 Minimum -0.10 -0.10 0.00 Maximum 0.00 0.10 0.10 Number 10 16 18

Basophils/LeukocytesMean -0.080 -0.169 -0.133 SD 0.169 0.218 0.387 Median -0.050 -0.200 -0.050 Minimum -0.30 -0.60 -1.50 Maximum 0.10 0.10 0.30 Number 10 16 18

EosinophilsMean 0.010 0.000 0.072 SD 0.088 0.115 0.089 Median 0.000 0.000 0.100 Minimum -0.10 -0.20 -0.10 Maximum 0.10 0.20 0.30 Number 10 16 18

Eosinophils/LeukocytesMean -0.390 -0.356 -0.061 SD 1.099 1.430 1.158 Median -0.100 0.150 -0.100 Minimum -2.80 -3.60 -3.80 Maximum 1.00 1.50 1.70 Number 10 16 18

HematocritMean -0.008 -0.003 0.007 SD 0.024 0.017 0.018 Median -0.009 0.000 0.006 Minimum -0.05 -0.05 -0.02 Maximum 0.05 0.02 0.04 Number 11 16 18

16NOV15:12:48:34 LP0084 1077 t22 haem chg.doc Continued...


Table 3-22: Summary of change in Haematology parameters from baseline to visit 4: safety

analysis set, continued


Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

HemoglobinMean -0.909 -1.250 1.889 SD 7.489 4.851 7.791 Median -1.000 -1.000 2.000 Minimum -12.00 -11.00 -11.00 Maximum 13.00 7.00 16.00 Number 11 16 18

LymphocytesMean 0.150 0.213 0.233 SD 0.369 0.710 0.329 Median 0.150 0.250 0.300 Minimum -0.50 -1.80 -0.40 Maximum 0.70 1.20 0.80 Number 10 16 18

Lymphocytes/LeukocytesMean -3.240 -0.363 -4.100 SD 5.662 9.569 6.659 Median -4.250 1.600 -4.100 Minimum -11.00 -30.10 -15.40 Maximum 4.90 11.70 9.40 Number 10 16 18

Ery. Mean Corpuscular VolumeMean -0.591 -0.175 0.950 SD 2.807 2.184 1.667 Median -1.600 -0.750 1.300 Minimum -3.40 -3.80 -2.20 Maximum 6.10 3.60 4.00 Number 11 16 18

MonocytesMean 0.110 0.025 0.239 SD 0.173 0.205 0.209 Median 0.150 0.000 0.200 Minimum -0.20 -0.20 -0.10 Maximum 0.40 0.50 0.80 Number 10 16 18

16NOV15:12:48:34 LP0084 1077 t22_haem_chg.doc Continued...





Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Monocytes/LeukocytesMean -0.250 -0.388 1.028 SD 1.603 2.619 2.419 Median -0.200 -0.750 0.500 Minimum -4.10 -4.80 -2.50 Maximum 1.70 4.90 6.30 Number 10 16 18

NeutrophilsMean 1.320 0.950 1.467 SD 1.171 2.321 1.570 Median 1.500 0.500 1.850 Minimum -0.50 -0.80 -2.10 Maximum 3.00 9.30 3.90 Number 10 16 18

Neutrophils/LeukocytesMean 3.960 1.275 3.267 SD 5.169 11.858 8.947 Median 4.850 -2.150 3.350 Minimum -2.60 -11.00 -12.90 Maximum 12.30 36.80 16.70 Number 10 16 18

PlateletsMean 8.636 5.667 2.000 SD 34.320 24.526 33.300 Median -8.000 9.000 -3.000 Minimum -30.00 -40.00 -34.00 Maximum 75.00 44.00 90.00 Number 11 15 14

ErythrocytesMean -0.054 -0.021 0.023 SD 0.205 0.169 0.226 Median -0.050 -0.015 0.005 Minimum -0.49 -0.37 -0.35 Maximum 0.26 0.28 0.47 Number 11 16 18

16NOV15:12:48:34 LP0084 1077 t22_haem_chg.doc Continued...





Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

LeukocytesMean 1.445 1.206 2.022 SD 1.460 1.829 1.634 Median 1.500 0.700 2.450 Minimum -0.50 -0.40 -1.10 Maximum 3.90 7.10 4.90 Number 11 16 18

16NOV15:12:48:34 LP0084 1077 t22 haem chg.doc


Table 3–23: Shift tables for Haematology parameters: safety analysis set

Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2

Lab parameter Base1 L3 N3 H3 L3 N3 H3 L3 N3 H3

Basophils NORMAL 0 10 0 0 16 0 0 18 0

Basophils/Leukocytes NORMAL 0 10 0 0 16 0 0 17 0HIGH 0 0 0 0 0 0 0 1 0

Eosinophils NORMAL 0 10 0 0 16 0 0 17 0HIGH 0 0 0 0 0 0 0 0 1

Eosinophils/Leukocytes NORMAL 0 7 0 0 13 0 0 16 0HIGH 0 2 1 0 1 2 0 1 1

Hematocrit LOW 2 0 0 1 0 0 0 2 0NORMAL 0 9 0 0 15 0 1 15 0

Hemoglobin LOW 1 1 0 0 0 0 0 2 0NORMAL 0 9 0 0 16 0 0 16 0

16NOV15:12:48:44 LP0084 1077 t23 haem shift.doc Continued...


Table 3-23: Shift tables for Haematology parameters: safety analysis set, continued

Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2


Lymphocytes NORMAL 0 10 0 2 14 0 0 18 0

Lymphocytes/Leukocytes LOW 3 0 0 0 1 0 4 1 0NORMAL 1 5 0 2 12 1 3 10 0HIGH 0 1 0 0 0 0 0 0 0

Ery. Mean Corpuscular Volume LOW 0 0 0 1 0 0 0 0 0NORMAL 0 11 0 1 14 0 0 18 0

Monocytes NORMAL 0 9 1 0 14 2 0 14 3HIGH 0 0 0 0 0 0 0 1 0

Monocytes/Leukocytes NORMAL 0 10 0 0 16 0 0 16 1HIGH 0 0 0 0 0 0 0 1 0

Neutrophils NORMAL 0 10 0 0 15 1 0 15 2HIGH 0 0 0 0 0 0 0 1 0

16NOV15:12:48:44 LP0084 1077 t23 haem shift.doc Continued...


Table 3-23: Shift tables for Haematology parameters: safety analysis set, continued

Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2


Neutrophils/Leukocytes NORMAL 0 8 2 1 13 2 0 14 2HIGH 0 0 0 0 0 0 0 1 1

Platelets NORMAL 0 10 1 0 15 0 0 14 0

Erythrocytes LOW 1 0 0 1 1 0 5 0 0NORMAL 0 10 0 2 12 0 2 11 0

Leukocytes LOW 0 0 0 0 1 0 0 1 0NORMAL 0 11 0 0 14 1 0 13 3HIGH 0 0 0 0 0 0 0 0 1

16NOV15:12:48:44 LP0084 1077 t23 haem shift.doc

1) Baseline category. Number of subjects with laboratory parameters below, within or above the reference range.2) End of Treatment category. Number of subjects with laboratory parameters below, within or above the reference

range.3) L=Low, N=Normal, H=High.


Table 3–24: Summary of Biochemistry parameters by visit: safety analysis set

ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

AlbuminScreening




Alkaline PhosphataseScreening




16NOV15:12:49:23 LP0084 1077 t24_chem_visit.doc Continued...


Table 3-24: Summary of Biochemistry parameters by visit: safety analysis set, continued

ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Alanine AminotransferaseScreening




Aspartate AminotransferaseScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

BicarbonateScreening




Direct BilirubinScreening



Mean 2.550 SD 1.202 Median 2.550 Minimum 1.70 Maximum 3.40 Number 0 2




ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

BilirubinScreening




Blood Urea NitrogenScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

CalciumScreening




ChlorideScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

CreatinineScreening




Gamma Glutamyl TransferaseScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

GlobulinScreening




GlucoseScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

PotassiumScreening




Lactate DehydrogenaseScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

MagnesiumScreening




PhosphateScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

ProteinScreening




SodiumScreening







ParameterVisit

Summary

Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

UrateScreening




16NOV15:12:49:23 LP0084 1077 t24 chem visit.doc


Table 3–25: Summary of change in Biochemistry parameters from baseline to visit 4: safety analysis set


Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

AlbuminMean 0.273 -0.118 0.474 SD 3.165 2.288 2.366 Median 1.000 0.000 1.000 Minimum -7.00 -5.00 -4.00 Maximum 5.00 4.00 4.00 Number 11 17 19

Alkaline PhosphataseMean 2.909 1.000 12.684 SD 13.247 7.882 7.103 Median 3.000 1.000 15.000 Minimum -29.00 -12.00 -1.00 Maximum 22.00 14.00 26.00 Number 11 17 19

Alanine AminotransferaseMean -0.818 -1.706 -1.053 SD 5.095 8.222 7.656 Median -1.000 -2.000 -1.000 Minimum -7.00 -17.00 -13.00 Maximum 10.00 25.00 19.00 Number 11 17 19

Aspartate AminotransferaseMean 0.000 -2.824 -1.947 SD 6.633 4.461 4.778 Median -3.000 -2.000 -2.000 Minimum -9.00 -14.00 -9.00 Maximum 12.00 5.00 12.00 Number 11 17 19

BicarbonateMean 0.909 -1.176 0.053 SD 3.590 3.187 2.223 Median 1.000 -2.000 0.000 Minimum -5.00 -5.00 -4.00 Maximum 7.00 5.00 3.00 Number 11 17 19

16NOV15:12:48:54 LP0084 1077 t25 chem chg.doc Continued...


Table 3-25: Summary of change in Biochemistry parameters from baseline to visit 4: safety



Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Direct BilirubinMean -0.309 0.213 -0.378 SD 1.276 1.074 0.932 Median 0.000 0.000 0.000 Minimum -3.40 -1.80 -1.70 Maximum 1.70 1.80 1.70 Number 11 16 18

BilirubinMean -2.491 -0.512 -1.805 SD 4.104 3.822 3.073 Median -1.700 0.000 -1.700 Minimum -10.30 -12.00 -6.90 Maximum 3.50 5.10 5.20 Number 11 17 19

Blood Urea NitrogenMean -0.555 -0.153 -0.553 SD 1.919 0.692 1.539 Median -0.300 0.000 -0.700 Minimum -3.90 -1.10 -4.60 Maximum 2.20 1.10 2.10 Number 11 17 19

CalciumMean -0.036 -0.023 -0.004 SD 0.112 0.129 0.102 Median -0.020 -0.030 0.000 Minimum -0.20 -0.25 -0.28 Maximum 0.17 0.20 0.13 Number 11 17 19

ChlorideMean -2.909 -0.647 -1.842 SD 1.921 2.262 2.089 Median -3.000 -1.000 -2.000 Minimum -6.00 -5.00 -7.00 Maximum 0.00 2.00 1.00 Number 11 17 19

16NOV15:12:48:54 LP0084 1077 t25_chem_chg.doc Continued...





Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

CreatinineMean 1.909 1.529 4.421 SD 12.565 10.554 10.668 Median 5.000 1.000 3.000 Minimum -23.00 -21.00 -17.00 Maximum 23.00 19.00 23.00 Number 11 17 19

Gamma Glutamyl TransferaseMean -1.091 -2.882 1.158 SD 5.770 14.177 7.581 Median 0.000 0.000 -2.000 Minimum -17.00 -54.00 -6.00 Maximum 5.00 11.00 26.00 Number 11 17 19

GlobulinMean 0.182 -0.176 -0.053 SD 1.401 1.425 1.810 Median 0.000 0.000 0.000 Minimum -2.00 -3.00 -3.00 Maximum 2.00 2.00 4.00 Number 11 17 19

GlucoseMean 1.673 0.335 0.574 SD 2.377 1.706 1.943 Median 0.600 0.300 0.700 Minimum -0.10 -2.20 -3.90 Maximum 6.50 5.00 5.10 Number 11 17 19

PotassiumMean -0.136 0.112 0.058 SD 0.619 0.583 0.508 Median -0.200 0.000 0.100 Minimum -1.50 -1.10 -1.10 Maximum 0.80 1.40 0.80 Number 11 17 19






Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

Lactate DehydrogenaseMean -2.818 7.588 2.105 SD 18.297 28.129 42.057 Median -2.000 3.000 -5.000 Minimum -40.00 -32.00 -65.00 Maximum 28.00 90.00 152.00 Number 11 17 19

MagnesiumMean -0.009 0.005 -0.023 SD 0.085 0.081 0.074 Median 0.000 0.000 -0.040 Minimum -0.17 -0.21 -0.17 Maximum 0.08 0.12 0.09 Number 11 17 19

PhosphateMean 0.131 0.059 0.104 SD 0.248 0.174 0.165 Median 0.090 0.060 0.100 Minimum -0.36 -0.23 -0.32 Maximum 0.65 0.30 0.36 Number 11 17 19

ProteinMean 0.455 -0.294 0.421 SD 4.108 3.274 3.849 Median 1.000 0.000 0.000 Minimum -7.00 -8.00 -7.00 Maximum 7.00 5.00 8.00 Number 11 17 19

SodiumMean -0.818 -1.294 -0.737 SD 1.401 2.024 2.232 Median -1.000 -1.000 0.000 Minimum -3.00 -6.00 -4.00 Maximum 1.00 1.00 2.00 Number 11 17 19






Face0.018% (n=18)

Arm0.1%

(n=21)

Scalp0.037% (n=19)

UrateMean -15.727 11.588 -38.895 SD 38.552 36.948 33.188 Median -12.000 12.000 -41.000 Minimum -83.00 -53.00 -107.00 Maximum 60.00 83.00 42.00 Number 11 17 19

16NOV15:12:48:54 LP0084 1077 t25 chem chg.doc


Table 3–26: Shift tables for Biochemistry parameters: safety analysis set

Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2


Albumin LOW 0 0 0 0 0 0 0 1 0NORMAL 0 11 0 0 16 0 0 18 0HIGH 0 0 0 0 1 0 0 0 0

Alkaline Phosphatase LOW 1 0 0 0 1 0 2 0 0NORMAL 1 7 0 0 10 0 0 15 2HIGH 0 0 2 0 1 5 0 0 0

Alanine Aminotransferase NORMAL 0 10 1 0 13 1 0 17 0HIGH 0 0 0 0 1 2 0 1 1

Aspartate Aminotransferase NORMAL 0 10 1 0 14 0 0 17 1HIGH 0 0 0 0 1 2 0 0 1

Bicarbonate NORMAL 0 10 0 0 15 1 0 18 1

16NOV15:12:49:04 LP0084 1077 t26 chem shift.doc Continued...


Table 3-26: Shift tables for Biochemistry parameters: safety analysis set, continued

Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2


Bicarbonate HIGH 0 0 1 0 1 0 0 0 0

Direct Bilirubin NORMAL 0 10 0 0 14 1 0 19 0HIGH 0 1 0 0 0 2 0 0 0

Bilirubin LOW 0 0 0 0 1 0 0 0 0NORMAL 2 8 0 1 12 0 1 18 0HIGH 0 1 0 0 1 2 0 0 0

Blood Urea Nitrogen NORMAL 0 8 0 0 15 0 0 13 2HIGH 0 1 2 0 1 1 0 3 1

Calcium LOW 0 0 0 0 2 0 1 0 0NORMAL 0 10 0 0 12 0 1 16 0HIGH 0 1 0 0 2 1 0 1 0

Chloride NORMAL 0 11 0 0 17 0 1 17 0




Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2


Chloride HIGH 0 0 0 0 0 0 0 1 0

Creatinine NORMAL 0 8 1 0 16 1 0 16 1HIGH 0 0 2 0 0 0 0 0 2

Gamma Glutamyl Transferase NORMAL 0 9 0 0 13 1 0 17 1HIGH 0 0 2 0 0 3 0 0 1

Globulin NORMAL 0 11 0 0 17 0 0 19 0

Glucose NORMAL 0 8 2 0 12 3 0 16 0HIGH 0 0 1 0 1 1 0 1 2

Potassium NORMAL 0 8 0 0 13 2 0 17 1HIGH 0 3 0 0 2 0 0 1 0

Lactate Dehydrogenase NORMAL 0 11 0 0 13 1 0 16 2




Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2


Lactate Dehydrogenase HIGH 0 0 0 0 2 1 0 1 0

Magnesium NORMAL 0 11 0 0 16 0 0 18 1HIGH 0 0 0 0 1 0 0 0 0

Phosphate LOW 0 0 0 0 1 0 0 0 0NORMAL 0 6 2 0 11 3 0 18 1HIGH 0 1 2 0 2 0 0 0 0

Protein LOW 0 0 0 0 0 0 0 2 0NORMAL 0 11 0 0 16 0 0 16 0HIGH 0 0 0 0 1 0 0 1 0

Sodium NORMAL 0 11 0 0 15 0 0 17 0HIGH 0 0 0 0 1 1 0 2 0




Face0.018% (n=18)

EOT2

Arm0.1%

(n=21)

EOT2

Scalp0.037% (n=19)

EOT2


Urate LOW 0 0 0 1 1 0 1 0 0NORMAL 1 8 0 0 13 1 2 12 0HIGH 0 0 2 0 1 0 0 2 2

16NOV15:12:49:04 LP0084 1077 t26 chem shift.doc

1) Baseline category. Number of subjects with laboratory parameters below, within or above the reference range.2) End of Treatment category. Number of subjects with laboratory parameters below, within or above the reference

range.3) L=Low, N=Normal, H=High.


Figure 3-1: Maximum post baseline composite LSR score by treatment group: safety analysis set


Figure 3-2: Composite LSR score – mean profiles by treatment group: safety analysis set


Figure 3-3: Composite LSR score – individual profiles by treatment group: safety analysis set


Figure 3-4: LSR component scores by visit and treatment group: safety analysis set


Figure 3-5: Maximal change in composite LSR score versus total drug usage: safety analysis set


Figure 3-6: Maximal composite LSR score versus total drug usage: safety analysis set


Figure 3-7: Maximal composite LSR score versus Cmax: PK analysis set


Figure 3-8: Cmax versus total drug usage: PK analysis set


Figure 3-9: Maximal change in composite LSR score for subjects having at least one PK value above LLOQ post administration on Day 3: PK analysis set


Figure 3-10: Maximal composite LSR score for subjects with PK values above LLOQ: PK analysis set


0 End-of-Text Listings


Table of Contents

Listing 0-1: Subjects Withdrawn from treatment due to Adverse Events....................................................................................................................................199

Treatment group=Scalp 0.037%...................................................................................................................................................................................................199

Listing 0-2: Deaths.......................................................................................................................................................................................................................200

Listing 0-3: Serious Adverse Events ............................................................................................................................................................................................201


Listing 0-1: Subjects Withdrawn from treatment due to Adverse Events

Treatment group=Scalp 0.037%

Centre/SubjectID

Preferred term/Reported term Location

Start/Stop

Duration(days) Relation Intensity

Actiontaken Outcome Serious

Days sincefirst/latestdose

/ APPLICATION SITE PAIN/Burning

Inside treatment area

/ 4 Probable Moderate Drug withdrawn

Recovered No 0/.

/ APPLICATION SITE PAIN/Severe pain on scalp

Inside treatment area

/ 9 Probable Moderate Drug withdrawn

Recovered No 0/0

19NOV2015:11:20:43 - ae(where=aeacn='DRUG WITHDRAWN')

PPI

PPDPPD PPD

PPD

PPDPPD

PPDPPD


Listing 0-2: Deaths

Date of program execution Empty List19NOV2015:11:20:43 No data for this listing

19NOV2015:11:20:43 - ae(where=aeout='FATAL')


Listing 0-3: Serious Adverse Events

Date of program execution Empty List19NOV2015:11:20:43 No data for this listing

19NOV2015:11:20:43 - ae(where=first(upcase(aeser))='Y')

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Signed by Meaning of Signature Server Date (dd-MMM-yyyy HH:mm ‘GMT’Z)

LP0084-1077 Clinical Study Report 05-Feb-2016

MedicalApproval

08-Feb-2016 13:43 GMT+01

Biostatistics Approval 08-Feb-2016 15:43 GMT+01

PPD

PPD

PPD

PPD