Clinical trial NCT02575950
Conditions: Acne Vulgaris
Sponsor: LEO Pharma
Start date: 2016-06-01; Completion date: 2017-04-01
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An exploratory Phase 2, single, centre, prospective, randomized, placebo-controlled, double-blinded, split-pace (left/right) design trial to evaluate the efficacy and tolerability of LEO 43204 in adults with moderate to severe acne.

Detailed description:

Arms: arm 1: Experimental drug arm 2: Placebo
Interventions: intervention 1: LEO43204 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Consolidated Clinical Trial Protocol 
 
 
Explorative trial evaluating the efficacy, tolerability and safety of LEO 
43204 applied in a split-face (left/right) topical design in adults with 
moderate to severe acne 
 
Phase 2a, single-centre, prospective, randomised, vehicle-controlled, double-blind, split-face 
(left/right) design trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICH GCP statement: The clinical trial will be conducted in compliance with the clinical trial 
protocol, GCP and the applicable regulatory requirement(s). 
 
 
 
 
 
 
LEO Pharma A/S 
Trial ID: 
EXP-1223 
Date: 
15-Sep-2016 
Version: 
5.0 
 
eDoc-00624671 - Version 1.0 


 
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1 Clinical Trial Protocol Statement 
1.1 Approval Statement LEO Pharma A/S 
The following persons have approved this clinical trial protocol by using electronic signatures 
as presented on the last page of this document: 
 
PPD 
 
Biostatistics Lead, Global Clinical Operations 
 
PPD 
 
Head of Translational Medicine 
 
 
1.2 Approval Statement International Coordinating Investigator 
The international coordinating investigator approves the clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by manually 
signing the International Coordinating Investigator Clinical Trial Protocol Approval Form, 
which is a separate document adjoined to this document. 
 
The following person has approved this clinical trial protocol: 
 
 
 
Hala Koudsi, MD 
International Coordinating Investigator 


 
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Table of Contents 
1 Clinical Trial Protocol Statement ........................................................................................... 2 
1.1 
Approval Statement LEO Pharma A/S .............................................................................. 2 
1.2 
Approval Statement International Coordinating Investigator ........................................... 2 
Table of Contents ........................................................................................................................ 3 
2 Trial Identification ................................................................................................................. 8 
3 Introduction and Rationale .................................................................................................... 8 
3.1 
Acne Vulgaris Introduction ............................................................................................... 8 
3.2 
Experience with Investigational Product ........................................................................... 8 
3.3 
Trial Rationale ................................................................................................................... 8 
3.3.1 
Dose Selection ............................................................................................................. 10 
3.4 Ethical Consideration Statement ..................................................................................... 10 
4 Trial Objectives .................................................................................................................... 12 
4.1 
Primary Objective ............................................................................................................ 12 
4.2 
Secondary Objectives ...................................................................................................... 12 
4.3 
Explorative Objectives .................................................................................................... 12 
5 Trial Endpoints .................................................................................................................... 13 
5.1 
Primary Endpoint ............................................................................................................. 13 
5.2 
Secondary Endpoints ....................................................................................................... 13 
5.3 
Exploratory Endpoints ..................................................................................................... 13 
6 Trial Design ......................................................................................................................... 14 
6.1 
Overall Trial Design ........................................................................................................ 14 
6.2 
Sample Size ..................................................................................................................... 18 
6.3 
Randomisation ................................................................................................................. 18 
6.4 
Blinding ........................................................................................................................... 19 
7 Trial Population and Withdrawal ......................................................................................... 19 
7.1 
Subject Eligibility ............................................................................................................ 19 
7.2 
Inclusion Criteria ............................................................................................................. 19 
7.3 
Exclusion Criteria ............................................................................................................ 20 
7.4 
Subject Enrolment Log .................................................................................................... 22 
7.5 
Subject Identification List ............................................................................................... 23 
7.6 
Restrictions during Trial ........................................................................................................ 23 


 
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7.7 
Withdrawal Criteria ......................................................................................................... 24 
8 Trial Schedule and Assessments .......................................................................................... 25 
8.1 
Schedule of Trial Procedures ........................................................................................... 25 
8.2 
Subject Eligibility ............................................................................................................ 26 
8.3 
Demographics .................................................................................................................. 26 
8.4 
Height and Weight .................................................................................................................. 27 
8.5 
Vital Signs ....................................................................................................................... 27 
8.6 
Physical Examination ...................................................................................................... 27 
8.7 
Medical History ............................................................................................................... 27 
8.8 
Acne vulgaris specific medical history ........................................................................... 27 
8.9 
Concomitant Medication ................................................................................................. 28 
8.10 Pregnancy Test ........................................................................................................................... 28 
8.11 Laboratory Assessments .................................................................................................. 28 
8.11.1 Urine collection for pregnancy test ............................................................................. 28 
8.11.2 Microbiome and Biomarker ........................................................................................ 29 
8.12 Adverse Events ................................................................................................................ 29 
8.13 Other Safety Assessments ................................................................................................ 29 
8.14 Subject Reported Outcomes ............................................................................................ 29 
8.15 Investigator Assessments ................................................................................................. 29 
8.16 Dispensing of IP ........................................................................................................................... 30 
8.17 Return of IP and Compliance .......................................................................................... 31 
8.18 End of Trial Form ............................................................................................................ 31 
9 Adverse Events .................................................................................................................... 31 
9.1 
Collection of Adverse Events .......................................................................................... 31 
9.1.1 
Local Skin Responses .................................................................................................. 31 
9.2 
Reporting of Adverse Events in the eCRF ...................................................................... 32 
9.2.1 
Actions Taken as a Consequence of an AE ................................................................. 32 
9.3 Other Events to be Reported............................................................................................ 32 
9.3.1 
Pregnancy .................................................................................................................... 32 
9.3.2 
Overdose ...................................................................................................................... 33 
9.3.3 
Medication Error ......................................................................................................... 33 
9.3.4 
Misuse ......................................................................................................................... 33 
9.3.5 
Abuse ........................................................................................................................... 33 
9.3.6 
Aggravation of Condition ............................................................................................ 34 


 
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9.3.7 
Lack of Efficacy .......................................................................................................... 34 
9.3.8 
Adverse Events of Special Interest .............................................................................. 34 
9.4 
Additional Reporting Requirements for Serious Adverse Events ................................... 35 
9.4.1 
Investigator Reporting Responsibilities ...................................................................... 35 
9.4.2 
LEO Reporting Responsibilities .................................................................................. 35 
9.5 Follow-up for Final Outcome of Adverse Events ............................................................ 36 
10 Investigational Product(s) .................................................................................................... 37 
10.1 Investigational Product Description ................................................................................ 37 
10.2 Administration of Investigational Products ..................................................................... 38 
10.2.1   Trial Medication Application ....................................................................................... 38 
10.3 Precautions/Over dosage ................................................................................................. 39 
10.3.1 Skin exposure .............................................................................................................. 39 
10.3.2 Ocular Exposure .......................................................................................................... 40 
10.3.3 Other Exposure ............................................................................................................ 40 
10.4 Packaging of Investigational Products ............................................................................ 41 
10.5 Storage of Investigational Products ................................................................................. 41 
10.6 Treatment Assignment ..................................................................................................... 41 
10.6.1 Randomisation Code List ............................................................................................ 41 
10.7 Drug Accountability and Compliance Checks ................................................................ 41 
10.7.1 
Drug Accountability .................................................................................................... 41 
10.7.2 
Trial Product Destruction ............................................................................................ 42 
10.7.3 
Treatment Compliance ................................................................................................ 42 
10.8  Emergency Unblinding of Individual Subject Treatment ................................................ 42 
11 Statistical Methods .............................................................................................................. 42 
11.1 Determination of Sample Size ......................................................................................... 42 
11.2 Definition of Trial Analysis Sets ..................................................................................... 43 
11.3 Statistical Analysis .......................................................................................................... 43 
11.3.1 Disposition of Subjects ................................................................................................ 43 
11.3.2 Demographics and other Baseline Characteristics ...................................................... 43 
11.3.3 Exposure and Treatment Compliance ......................................................................... 44 
11.3.4 Analysis of Primary Endpoints .................................................................................... 44 
11.3.4.1 Total lesion count ..................................................................................................... 44 
11.3.5 Analysis of Secondary Endpoints ................................................................................ 44 
11.3.5.1 
Lesion counts ........................................................................................................... 44 
11.3.5.2 
Investigator’s Global Assessment ............................................................................ 44 
11.3.6 Analysis of Exploratory Endpoints ............................................................................. 44 


 
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11.3.6.1 
Lesion counts by clinical evaluation. ....................................................................... 44 
11.3.6.2 
Treatment success according to IGA ....................................................................... 45 
11.3.6.3 
Inflammatory cytokine expression .......................................................................... 45 
11.3.6.4 
Microbiome profile .................................................................................................. 45 
11.3.6.5 
Subject evaluation of Acne QoL .............................................................................. 45 
11.3.6.6 
Subject evaluation of TSQM II ................................................................................ 45 
11.3.6.7 
Subject Global Cosmetic Score ............................................................................... 45 
11.3.7 Analysis of Safety ....................................................................................................... 45 
11.3.8 Adverse Events ............................................................................................................ 46 
11.3.9 Other Specific Safety Assessments ............................................................................. 46 
11.3.9.1 
Composite and component LSR score ..................................................................... 46 
11.3.9.2 
Vital Signs and Physical Findings ........................................................................... 47 
11.3.9.3 
Clinical Laboratory Evaluation ................................................................................ 47 
11.3.10 Interim Analysis ........................................................................................................... 47 
11.3.11 General Principles ....................................................................................................... 48 
11.3.12 Handling of Missing Values ................................................................................................ 48 
12 Trial Committees ................................................................................................................. 49 
13 Electronic Case Report Forms and Data Handling .............................................................. 51 
13.1 Electronic Case Report Forms (eCRFs) .......................................................................... 51 
13.2 Data Handling .................................................................................................................. 51 
13.3 Source Data ..................................................................................................................... 52 
13.4 Trial Monitoring .............................................................................................................. 52 
14 Handling of an Urgent Safety Measure ............................................................................... 53 
15 Quality Assurance/Audit ...................................................................................................... 53 
16 Completion of Trial ..................................................................................................................... 54 
16.1 Trial Completion Procedures ........................................................................................... 54 
16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site ................................ 54 
16.2 Provision for Subject Care Following Trial Completion ................................................. 54 
16.3 Archiving of Trial Documents ......................................................................................... 54 
17 Ethics and Regulatory Authorities ....................................................................................... 55 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and 
Regulatory Authorities .................................................................................................... 55 
17.2 Ethical Conduct of the Trial ............................................................................................ 55 
17.3 Subject Information and Informed Consent .................................................................... 55 
17.4 Processing of Personal Data ............................................................................................ 55 


 
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18 Insurance .............................................................................................................................. 56 
19 Use of Information ............................................................................................................... 56 
20 Publication ........................................................................................................................... 57 
21 Responsibilities .................................................................................................................... 57 
22 List of Abbreviations ........................................................................................................... 58 
23 References ........................................................................................................................... 60 
24 List of Appendices ............................................................................................................... 63 
25 Appendix 1: Protocol Summary .......................................................................................... 64 
26 Appendix 2: Tape lifting procedure and biomarker analyses ............................................... 67 
27 Appendix 3: Skin photography ............................................................................................ 68 
28 Appendix 4: Microbiome collection and profile analysis .................................................... 69 
29 Appendix 5: Subject Global Cosmetic Score ....................................................................... 70 
30 Appendix 6: Local Skin Response Grading Scale ............................................................... 71 
31 Appendix 7: Definitions of Adverse Events and Serious Adverse Events ........................... 73 
31.1 Adverse Event Definition ................................................................................................ 73 
31.2 Serious Adverse Event Definition ................................................................................... 73 
32 Appendix 8: Classification of Adverse Events .................................................................... 75 
32.1 Severity ............................................................................................................................ 75 
32.2 Causality .......................................................................................................................... 76 
32.3 Outcome .......................................................................................................................... 77 
33 Appendix 9: Contact list of LEO, protocol authors, vendors, trial committees and 
coordinating investigators .................................................................................................... 78 
34 Appendix 10: Identifying and Documenting the Treatment Area ........................................ 80 
35 Appendix 11: Acne QoL ...................................................................................................... 81 
36 Appendix 12: TSQM II ........................................................................................................ 84 


 
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2 Trial Identification 
IND number: 118384 
 
CT.gov number: NCT02575950 
 
3 Introduction and Rationale 
3.1 Acne Vulgaris Introduction 
Acne vulgaris, commonly referred to as acne, is a very common chronic inflammatory skin 
disease affecting approximately 80- 90% (50 million) of adolescents and young adults in the 
United States (1, 2, 3). Increased production of sebum and colonization of the bacteria 
Propionibacterium acnes (P. acnes) in the sebaceous glands are key factors in the 
development of acne vulgaris. Retention of sebum results in formation of comedones which 
may become inflamed and develop into pustules or deep-seated nodules in more severe cases. 
Moderate to severe acne vulgaris can reduce the quality of life and self-esteem and result in 
disfiguring persistent scarring and dyspigmentation (4, 5). Current available topical and 
systemic treatment options for acne vulgaris often require therapy for 3 to 6 months and are 
often associated with some degree of local side effects during the treatment period (e.g., 
dryness, skin irritation, scaling). This often reduces compliance, and consequently leads to 
disease relapse and disappointing treatment outcomes. 
 
3.2 Experience with Investigational Product 
LEO 43204 gel is a novel ingenol derivative being developed for field treatment of actinic 
keratosis (AKs) on face, balding scalp and treatment areas of up to 250 cm2 (40 in2) on the 
chest. LEO 43204 gel is in phase 3 of its clinical development program. 
 
Please refer to the Investigator's Brochure of 43204 gel in Actinic Keratosis Edition 4 or any 
updates hereof for all relevant non-clinical and clinical information. Refer to the 
Investigator’s Brochure Addendum for Acne Vulgaris for additional information pertaining to 
this exploratory trial. 
 
3.3 Trial Rationale 
There is an unmet medical need for safe acne vulgaris treatments of short duration with good 
efficacy and the ability to improve the patient’s disease related quality of life. 
 
The clinical rationale for investigating the efficacy of LEO 43204 gel on acne vulgaris is 
based on two case reports indicating a beneficial effect of ingenol mebutate on acne vulgaris, 
and the hypothesis that the effect of ingenol mebutate gel on the sebaceous gland (6) may be 


 
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similar to the effects observed for photodynamic therapy (PDT) in combination with 
aminolaevulinic acid (ALA) in the treatment of acne vulgaris (7). 
 
The first case indicating beneficial effects of ingenol mebutate involved a female employee at 
an ingenol mebutate manufacturing site suffering from acne. The employee accidentally 
became exposed to a large dose of dry-powder ingenol mebutate in the face. Following 
complete resolution of a severe facial skin response, the pre-existing acne vulgaris also 
cleared. In the second case, a female laboratory technician at an academic research laboratory 
was accidentally exposed in the face to an ingenol containing extract from the E. peplus plant. 
She also recovered completely from a severe skin response and later reported that her pre- 
existing acne vulgaris had cleared. 
 
The scientific rationale for investigating LEO 43204 gel as a treatment for acne vulgaris is 
based on the observation that ingenol mebutate has a stronger local skin response (LSR) 
around the hair follicles (6), suggesting accentuated cell death and inflammation in the 
pilosebaceous unit (refer to the Investigator's Brochure of 43204 gel in Actinic Keratosis 
Edition 4 or any updates hereof for details on mode of action). This could reduce the size of 
the sebaceous gland and possibly have a beneficial effect on acne vulgaris similar to the effect 
of PDT with ALA (7). 
 
In ALA-PDT the ALA serves as a precursor for the photosensitizer protoporphyrin IX. This 
molecule has significant phototoxic effects in the epidermis and pilosebaceous unit when 
irradiated with the appropriate wavelength of light (8, 9). Histologically, ALA-PDT therapy 
induces severe cell damage and cell death in the sebaceous gland epithelium resulting in a 
reduced gland size and sebum production (7). Studies have shown improvement of acne 
vulgaris disease severity for up to 20 weeks after therapy (7,10, 11). Clinically the ALA-PDT 
therapy is associated with transient erythema, crusting edema, temporary changes in 
pigmentation and pustular eruptions (11) similar to the local skin responses observed after 
treatment with ingenol mebutate. 
 
Based on this, we hypothesize that the inflammation and local skin response induced by LEO 
43204 gel may improve acne vulgaris by reducing 1) the size of the sebaceous glands, 2) the 
sebum production and 3) the colonisation of P.acnes. 
 
The objective of this explorative trial is to evaluate efficacy, safety and tolerability of LEO 
43204 gel in the treatment of moderate to severe acne vulgaris. Efficacy will be evaluated by 
an acne lesion count and investigator’s global assessment (IGA) of the treatment areas. In 
addition, the effects of LEO 43204 gel on inflammatory biomarkers, microbiome profile and 
cosmetic skin appearance will be investigated. 


 
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3.3.1 Dose Selection 
LEO 43204 gel has not previously been administered to subjects between 18 and 35 years of 
age with acne vulgaris. Previous clinical trials with field treatment for actinic keratosis (AK) 
in the face included only subjects over 40 years of age and Fitzpatrick skin type I-III. These 
trials have shown good tolerability and safety of LEO 43204 gel 0.018% when used in a 3- 
day once daily dosing regimen (refer to Investigator's Brochure of LEO 43204 gel in Actinic 
Keratosis, Edition 4 or any updates hereof) and is currently under development for AK. In this 
clinical trial the same strength of LEO 43204 gel 0.018% is selected for once daily treatment 
for up to three consecutive days. 
 
It is unknown whether the subjects with acne in this trial will have a different safety profile 
and LSR profile compared to the subjects investigated in the AK clinical trials. To ensure the 
safety of the subjects with acne vulgaris in this trial, additional safety measures (described in 
section 6.1 and section 12) have been adapted to ensure early detection of unexpected severe 
adverse events (AEs), LSRs and poor tolerability. 
 
The safety and tolerability data will be reviewed by a Safety Review Committee (SRC) during 
the trial (section 12). 
 
3.4 Ethical Consideration Statement 
Subjects under the age of 18 or vulnerable subjects incapable of giving informed consent will 
not be enrolled in this clinical trial. Furthermore pregnant, breastfeeding women or women 
planning on becoming pregnant during the trial will not be enrolled. Women of child bearing 
potential have to agree to use a highly effective method of contraception to prevent pregnancy 
during the clinical trial and until end of trial. In addition, all female subjects of child bearing 
potential will have a pregnancy test performed before, during and at End of Trial to ensure 
that no pregnant women are exposed to LEO 43204 gel. Female partners of male subjects are 
not required to use contraception as described in section 7.3.6 of the Investigator's Brochure 
of LEO 43204 gel in Actinic Keratosis, Edition 4 or any updates hereof. 
 
Only adult subjects with acne vulgaris who are otherwise healthy will be enrolled in this trial 
investigating efficacy and safety of LEO 43204 gel. 
 
Prior to any trial activities subjects must have signed the informed consent form (refer to 
section 17.3). The informed consent will highlight that LSR and treatment related AEs (such 
as pruritus and pain) are common events. In addition, the subjects will be informed that both 
the acne vulgaris disease severity and skin appearance (including texture, pigmentation, scars) 


 
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may appear different when comparing the left and right side of the face after end of trial. This 
difference may persist for several months or longer. 
 
As noted in section 3.3.1, all safety data on LEO 43204 gel stems from studies in subjects 
older than 40 years of age, with Fitzpatrick skin type I-III and the diagnosis of AK. In these 
subjects clinical findings following treatment are localised application site reactions (e.g., 
pruritus, pain, irritation) and local skin responses (LSRs), particularly erythema, oedema, 
flaking and scaling. These LSRs are transient and typically resolve without sequelae within 2- 
4 weeks of application. Furthermore, these local events do not have a tendency to become 
infected or cause scarring and generally do not cause pain beyond the first few days. No data 
involving young adults or individuals with pre-existing inflammation in the treatment area are 
available and it is thus unknown whether the LSRs will be different in this trial. 
 
To limit the number of exposed subjects, this early phase explorative clinical trial is designed 
as a left/right comparison within-subject. This design requires fewer subjects to achieve 
statistical power to detect a difference between treatments than a trial with comparison of 
treatments between-subjects. The vehicle gel control serves as an external validity check of 
the trial results and shows what an agent-free therapy contributes in terms of efficacy and 
safety. 
 
Moreover, to mitigate the risk of unexpected severe LSRs and AEs, the trial includes a small 
treatment escalation cohort with continuous safety review (refer to section 6.1), and 3 
subsequently treated cohorts separated by interim analysis of safety and tolerability data by a 
Safety Review Committee (refer to section 12). 
 
Subjects participating in this trial will be under the supervision of an experienced investigator 
during the course of the trial. The subject’s safety will be monitored daily (Day 1 to Day 4) 
and closely during the follow up-period until 12 weeks after treatment. 
 
Lastly only subjects with skin type I-III will be included due to lack of safety data from 
subjects with darker skin types and a potential higher risk of post-inflammatory 
hyperpigmentation. 
 
There are no invasive procedures in this clinical trial. 
 
All randomized subjects in Cohort 2, 3 and 4 will have biomarkers and microbiome samples 
collected by a tape-lifting procedure and standard bacterial swab, respectively (Appendix 2). 
This will be done at visit 2, 7, 8, 9 and 10. Both procedures may cause minor transient redness 
(less than 1 hour) and without long-term risks. 


 
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All subjects in cohort 3 and 4 will have photographs taken at screening for documentation of 
eligibility. 
 
All randomized subjects in cohort 1, 2 and 3 will have digital photographs taken at Day 1 and 
all subsequent visits (Appendix 3). These are used for documentation. 
 
The FDA guidance for developing drugs for acne vulgaris (12) recommends 12 weeks of 
treatment and 4 weeks of follow-up after end of treatment. These recommendations are not 
considered relevant for this trial in which the treatment period is only once daily for up to 3 
days due to the mode of action of LEO 43204. The efficacy endpoints (total lesion count and 
investigator global assessment) are chosen in accordance with the FDA guideline, but 
evaluated at follow-up after end of treatment at Week 2, 4, 8 and 12. The primary endpoint at 
Week 12 is chosen based on the expectation of efficacy lasting several months. 
 
In conclusion, it is considered safe and without unacceptable risks to test topical application 
of LEO 43204 gel, 0.018%, once daily, for one, two or three consecutive days on the cheeks 
in the face of adults (18 to 35 years inclusive) with Fitzpatrick skin types I-III to investigate 
whether LEO 43204 gel may be a new treatment strategy for acne vulgaris. 
 
4 Trial Objectives 
4.1 Primary Objective 
To assess the efficacy of treatment with LEO 43204 gel and vehicle gel on acne vulgaris 
disease severity 12 weeks after end of treatment. 
 
Treatment is defined as once daily application of LEO 43204 gel and vehicle gel for up to 3 
days. 
 
4.2 Secondary Objectives 
To assess the safety and tolerability of treatment with LEO 43204 gel and vehicle gel 12 
weeks after end of treatment. 
 
4.3 Explorative Objectives 
To evaluate the time course of clinical efficacy of LEO 43204 gel and vehicle gel and, based 
on this, define a time point for evaluation of the effect on expression of inflammatory 
biomarkers and skin microbiome. 


 
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To assess subject-reported outcomes using the acne-specific quality of life questionnaire 
(Acne-QoL, (13, 14)) and the treatment satisfaction questionnaire for medication (TSQM II, 
(15)). 
 
To assess the effect of LEO 43204 gel and vehicle gel on subject-evaluated change in 
cosmetic skin appearance using a Subject Global Cosmetic Score questionnaire. 
 
5 Trial Endpoints 
5.1 Primary Endpoint 
Total lesion count (inflammatory and non-inflammatory) in the treatment area for LEO 43204 
gel and vehicle gel at Week 12. 
5.2 Secondary Endpoints 
• Inflammatory lesion count in the treatment area for LEO 43204 gel and vehicle gel at 
Week 12. 
 
• Non-inflammatory lesion count in the treatment area for LEO 43204 gel and vehicle 
gel at Week 12. 
 
• Investigator’s Global Assessment of the treatment area for LEO 43204 gel and vehicle 
gel at Week 12. 
 
• Composite and component LSR score at all visits 
 
• Occurrence of unacceptable LSR scores or unacceptable safety and tolerability events 
at all visits (as described in section 12) 
 
5.3 Exploratory Endpoints 
• Total lesion count in the treatment area at Day 1 and Week 2, 4, 8 and 12 (time 
course). 
• Inflammatory lesion count in the treatment area at Day 1 and Week 2, 4, 8 and 12 
(time course). 
• Non-inflammatory lesion count in the treatment area at Day 1 and Week 2, 4, 8 and 12 
(time course). 
• Investigator’s Global Assessment of the treatment area at Day 1 and Week 2, 4, 8 and 
12 (time course). 


 
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• Treatment success, i.e. at least a two grade improvement of IGA at week 12 compared 
to baseline 
 
• Inflammatory cytokine expression at time points defined after evaluation of the 
clinical data. 
 
• Microbiome profile at time points defined after evaluation of the clinical data. 
 
• Subject evaluation of Acne-QoL at screening and Day 1 and Week 12. 
 
• Subject evaluation of TSQM II at Week 12. 
 
• Subject Global Cosmetic Score at Week 12 (Appendix 5). 
 
6 Trial Design 
6.1 Overall Trial Design 
This is an exploratory clinical (phase 2a), single-centre, prospective, randomised, vehicle- 
controlled, double-blinded, intra-individual comparison, split-face model (left/right design) 
trial. Subjects with moderate to severe acne vulgaris will be treated with LEO 43204 gel 
0.018% and vehicle gel (i.e. the Investigational Products (IPs)). The IPs are administered as a 
thin wet layer to each treatment area (TA) on the left (TAleft) and right (TAright) cheeks of the 
face, each area corresponding to approximately 36 cm2 (refer to section 10.2.1). Assessments 
during the trial are outlined in section 8.1. 
 
The subjects will be enrolled sequentially into 4 cohorts (n=40 total). 
 
Progression from one cohort to the next will be decided after a review of LSRs, safety and 
tolerability by the Safety Review Committee after Week 2 (Visit 7). 
 
Handling of LSRs, safety or tolerability deemed unacceptable is described in section 12. 
 
Cohort 1 (n=3): Treatment escalation with once daily application of IPs for one, two and 
three days respectively for each of the first three subjects. 
 
Subjects will enter treatment sequentially such that the second and third subjects only are 
exposed after a safety evaluation of the preceding subject is done. The first subject will be 
dosed for one day only, the second subject up to two days and the third subject up to three 
days. 


 
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The safety evaluation that allows the next subject to be dosed consists of the maximal LSR 
score from evaluations at days 1, 2, 3, 4, 8 and week 2 or until considerable reduction of LSR 
score and any treatment related AEs has been observed. 
 
 
For subjects two and three, the second and third treatment day depends on the following 
criteria: 
 
• The subject not reporting intolerable response to treatment. 
• The investigator not evaluating LSRs or treatment-related AEs to be unacceptable. 
• The LSR scores not exceeding predefined criteria (see Table 1, section 6.1). 
 
Subjects not receiving the optional treatment on Day 2 and/or Day 3 due to severe LSRs or 
treatment related AEs will remain in the trial and attend the scheduled follow up visits. 
 
Cohort 2 (n=6): Once daily treatment for three days with the second and third day optional 
dependent on predefined criteria (see ‘Treatment Phase’ below) Two subjects may initiate 
treatment per week. The subjects will follow the same scheduled visits as in cohort 1. 
 
Cohort 3 (n=6): Once daily treatment for three days with the second and third day optional 
dependent on predefined criteria (see ‘Treatment Phase’ below). Subjects may be enrolled 
without restrictions to the number of subjects per week. The subjects will follow the same 
scheduled visits as in cohort 1. 
 
Cohort 4 (n=25): Once daily treatment for three days with the second and third day optional 
dependent on predefined criteria (see ‘Treatment Phase’ below). Subjects may be enrolled 
without restrictions to the number of subjects per week. The visit on Day 8 will be conducted 
as a phone call visit. 
 
The trial consists of the following phases: 
Screening Phase (Day -28 to Day -1) 
Following careful information about the protocol, LSRs and other risks, the subjects willing 
to participate in this clinical trial must sign the trial specific informed consent. Screening and 
Day 1 may be combined. 


 
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At the screening visit, the diagnosis of acne vulgaris will be confirmed by the 
(sub)investigator and the overall disease severity will be assessed using the IGA of the full 
face (Table 4 in section 8.15). 
 
Two symmetrically located TAs on the left (TAleft) and right (TAright) cheeks of the face will 
be identified by the (sub)investigator and documented on individual transparent film(s) using 
a three-point landmark technique as (described in Appendix 10). The (sub)investigator will 
assess disease severity in TAleft and TAright by the IGA scale and lesion counts. In addition, the 
symmetry of the total lesion count when comparing TAleft and TAright will be assessed (refer to 
criteria 4 in section 7.2). 
 
The subject’s eligibility for the trial will be checked according to inclusion and exclusion 
criteria. 
 
If a subject is ineligible due only to current or recent use of prohibited therapies, he/she may 
be re-screened after a washout period. A decision to stop an ongoing therapy should always be 
discussed and approved by the (sub)investigator. 
 
If the subject is eligible, assessments listed in section 8.1 will be performed and recorded in 
the eCRF. Females will have a urine pregnancy test performed. 
 
Pre-treatment Phase (Day 1) 
 
If the Day 1 (Visit 2) is not combined with the Screening (Visit 1), eligibility must be 
confirmed by review of inclusion and exclusion criteria prior to randomization. Following 
randomization, the subject must complete the AcneQoL questionnaire before any other 
assessments are undertaken in addition to safety assessments. 
 
Women of childbearing potential must have a urine pregnancy test performed. 
 
In Cohort 2, 3 and 4, non-invasive samples from the skin will be taken for evaluation of 
inflammatory markers, skin microbiome profile (For details see Appendix 2 and Appendix 4). 
 
Subjects in Cohort 1, 2 and 3 will be photographed at all site visits from Day 1 and onwards 
for documentation of physical appearance (Appendix 3). Photographs will be taken at 
screening for Cohort 3 and 4 for documentation of eligibility. 
 
Each subject will be left/right randomised to receive active treatment on TAleft or TAright. The 
other side will be treated with vehicle gel. 
 
Treatment Phase (Day 1, 2 and 3) 


 
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During the treatment phase, trial visits will be performed on Day 1, Day 2 and Day 3. 
The individual transparent film(s) will be used to locate the TAs. 
LSR scores for the TAs will be recorded and any new or on-going AEs, and changes in 
medication will be recorded. 
 
Criteria for treatment on Day 2 and Day 3: 
 
• The subject not reporting intolerable response to treatment. 
• The (sub)investigator not evaluating LSRs or treatment-related AEs to be unacceptable. 
• The LSR scores not exceeding predefined criteria (see Table 1). 
 
Table 1. LSR score criteria for not administering second or third treatment. 
 
LSR component(s) 
Score on Day 2 and/or 3 
Erosion/ulceration 
≥2 
Vesiculation/pustulation 
≥3 
Any LSR component 
=4 
Flaking/scaling + crusting 
≥5 (sum) 
Flaking/scaling + crusting + vesiculation/pustulation 
≥6 (sum) 
 
 
The reason not to treat is recorded in the eCRF. Subjects will remain in the trial and attend the 
follow-up visits according to the protocol. 
The IPs are to be applied to the TAs by the site staff as per the randomization schedule at all 
three treatment visits (Visit 2, 3 and 4). Subjects will be carefully instructed in how long the 
IP must remain on the skin and how it can be washed off. Moreover, the subjects will be 
reminded about the precautions regarding accidental transfer of the IP to eyes and other areas 
(refer to section 10.3.2). 
 
Post-treatment assessment (Day 2, 3, 4 and 8) 
 
If the subject is not treated on Day 2 or Day 3, trial procedures will follow the trial schedule 
as described in Section 8.1. LSR scores for the TAs will be recorded and any new or ongoing 
AEs, and changes in medication will be recorded in the eCRF. 
 
On Day 8 subjects in cohort 1, 2 and 3 will have a site visit, while subjects in cohort 4 will be 
contacted by phone to inquire about tolerability (i.e. subjective evaluation), AEs and 
concomitant medication. Should the subjects in cohort 4 express worsening of LSR or 


 
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treatment related AEs at Day 8, it will be decided by the (sub)investigator whether an 
unscheduled trial site visit for evaluation is required. 
 
Post-treatment assessment (Week 2, 4, 8 and 12) 
 
At Week 12 the subject must complete the Acne QoL (Appendix 11), TSQM II (Appendix 12) 
and the Subject Global Cosmetic Score (Appendix 5) before any other assessments are 
undertaken. 
 
The individual transparent film(s) will be used to locate each TA for assessments. Clinical 
assessment of TAleft and TAright including IGA scoring, inflammatory and non-inflammatory 
lesion counts, LSR will be recorded in the eCRF. For biomarker assessments and microbiome 
analyses, tape-lifts and swabs from TAleft and TAright will be taken at Week 2, 4, 8 and 12 after 
all other assessments have been completed (Appendix 2 and Appendix 4). 
 
Concomitant medication, new and ongoing AEs will be reported at these visits. 
 
Trial periods: 
 
Screening phase: 1 Week (Day -28 to -1) 
Treatment phase: 3 days 
Post treatment assessment: 12 Weeks 
 
Planned date of enrolment of first subject: Q2-2016 
Planned date of completion of last subject: Q4-2016 
 
6.2 Sample Size 
A total of 40 subjects (male and female) will be randomised. Subjects withdrawn after 
randomization will not be replaced. 
 
The expected statistical properties of the primary endpoint are described in section 11.3.4. 
 
6.3 Randomisation 
Subjects will be randomised to either treatment with LEO 43204 gel 0.018% on the treatment 
area on the left cheek of the face, TAleft, and vehicle gel on the treatment area on the right 
cheek of the face, TAright, or vice versa in a 1:1 ratio. 


 
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6.4 Blinding 
All staff involved in the conduct of the trial and all subjects should remain blinded to 
treatment allocation for the entire duration of the trial. 
 
The packaging and labeling of the investigational products must contain no evidence of the 
allocated treatment. It is not considered possible to differentiate between the investigational 
products solely by sensory evaluation. Consequently, it is expected that the subjects and the 
site staff remain unaware of the individual treatment assignments during the conduct of the 
clinical trial. 
 
7 Trial Population and Withdrawal 
7.1 Subject Eligibility 
The (sub)investigator should only enroll subjects who meet all eligibility criteria, who are not 
put at undue risk by participating in the trial, and can be expected to comply with the 
protocol. 
 
The subject’s eligibility for the clinical trial must be checked according to the inclusion and 
exclusion criteria at the screening visit and at Day 1 as specified in “Schedule of Trial 
Procedures” in Section 8.1. 
 
Randomisation (Day 1, Visit 2) should be performed within 28 days after the Screening Visit 
(Visit 1). Re-screening is allowed if the visit window cannot be complied with for practical 
reasons or if required due to recent or current use of prohibited therapy (refer to section 6.1, 
screening phase). Re-sampling or re-screening is not allowed if the subject has failed 
eligibility according to inclusion or exclusion criteria (except prohibited therapy). 
 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial must be ensured and described in the submission documentation to authorities/ethics 
committees, as applicable. 
 
7.2 Inclusion Criteria 
1. Following verbal and written information about the trial, the subject has to provide 
signed and dated informed consent before any trial-related activities are carried out 
2. Subjects should be diagnosed with acne vulgaris of the face. 
3. Acne vulgaris disease severity in the full face and in the TA should be scored as 
moderate to severe (grade 3-4) according to the Investigator’s Global Assessment 
(IGA) Scale (Table 4, section 8.15). 


 
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4. Disease severity and total lesion count should be similar in both TAs (with a maximal 
2 fold difference in total lesion count). 
5. Fitzpatrick skin types I-III (Table 2, section 8.3) 
6. Age 18 to 35 years inclusive. 
7. Male or female subjects who are otherwise in overall good health including well- 
controlled diseases (e.g. hypertension, diabetes and thyroid disease) as determined by 
medical history, physical examination, vital signs (blood pressure, heart rate). 
8. Female subjects: 
• of non-childbearing potential, i.e. have a confirmed clinical history of sterility 
(e.g. the subject is without a uterus or has tubal litigation) 
OR 
• of child-bearing potential* provided there is a confirmed negative pregnancy 
test prior to trial treatment to rule out pregnancy AND willing to use effective 
contraception at trial entry and until completion of the trial. 
*Female subjects are considered of child-bearing potential unless they have had a 
hysterectomy or have undergone tubal ligation. 
Effective contraception is defined as follows: 
 
• Abstinence (when this is in line with the preferred and usual life style of the 
subject). 
• Vasectomised partner (given that the subject is monogamous). 
• An intrauterine device. 
• Double barrier method defined as two distinct methods (two actual barrier 
methods). 
• Hormonal contraceptive (oral hormonal birth control, oestrogenic vaginal ring, 
percutaneous contraceptive patches, implants and injectables) for at least one 
menstrual cycle prior to enrolment. 
9. Able to communicate with the (sub)investigator and understand and comply with the 
requirements of the trial. 
7.3 Exclusion Criteria 
1. Subjects with nodulocystic acne, acne conglobata, acne fulminans, secondary acne 
(e.g. chlor-acne, drug-induced acne). 


 
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2. Subjects with previous history of keloid formation or post-inflammatory 
hyperpigmentation. 
3. Fitzpatrick skin types IV-VI. 
4. Subjects in whom the (sub)investigator would recommend systemic therapy to prevent 
risk of scarring due to current disease severity of acne vulgaris. 
5. Subjects with excessive facial hair, facial skin disorders or skin reactions that may 
interfere with trial assessments (including but not limited to AK, eczema, psoriasis, 
seborrheic dermatitis, rosacea, acute or recent sunburn). 
6. Subjects with a clinical diagnosis, history or evidence of any medical condition that 
would expose the subject to an undue risk of severe AE or interfere with assessments 
of safety and efficacy during the course of the trial, as determined by the investigator's 
clinical judgment. 
7. Supine BP at Visit 1 (screening) > 140/90 mmHg or < 90/50 mmHg and/or heart rate 
at Visit 1(screening) > 100 beats per minute (bpm) or < 50 bpm after up to 15 min of 
rest. 
8. Subjects with Herpes simplex (type 1 and/or type 2) with recurrent outbreaks (6 or 
more outbreaks per year), or a recent (within 2 months) or current outbreak. 
9. Subjects known to be infected with Human Immunodeficiency Virus (HIV). 
10. Subjects with any haematological malignancies. 
11. Use of cosmetic or therapeutic products and procedures which could interfere with the 
assessments of the treatment areas. 
12. Known sensitivity or allergy to any of the ingredients in the vehicle gel or IP. 
13. Subjects who have been treated with ingenol mebutate gel in the face within the last 
12 months. 
14. Change of use of hormonal oral contraceptives within the last 6 months prior to the 
randomisation. 
15. Subjects who are known or, in the opinion of the (sub)investigator, are unlikely to 
comply with the Clinical Trial Protocol (e.g. due to alcoholism, drug abuse or 
psychotic state) or who are impossible to contact in case of emergency. 
16. Current participation in any other interventional clinical trial or previously enrolled in 
an interventional clinical trial, which in the opinion of the (sub)investigator may 
interfere with the interpretation of the trial results. 
17. Close affiliation with the (sub)investigator (e.g. a close relative) or a persons working 
at the trial sites or as an employee of the sponsor. 
18. Female subjects who are pregnant, of child-bearing potential and who wish to become 
pregnant during the trial, or who are breast feeding. 
 
Prohibited Therapies and/or Medications within 6 months prior to Day 1 (Visit 2). 


 
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19. Treatment with systemic retinoids 
20. Cosmetic or therapeutic procedures within 2 cm from the treatment area including 
ablative or non-ablative laser therapy, intense pulsed light therapy, PDT, dermabrasion, 
medium or greater depth chemical peel, or subjects who intend to have such 
procedures done within the first 6 months after Day 1. 
 
Prohibited Therapies and/or Medications within 1 month prior to Day 1 (Visit 2). 
 
21. Treatment of the face with topical retinoids. 
22. Treatment with systemic antibiotics. 
23. Treatment in the face with ultraviolet light A or ultraviolet light B or intensive solar 
exposure. 
24. Treatment in the face with light chemical peel. 
25. Treatment with any non-marketed substance (i.e. an agent which has not yet been 
made available for clinical use following registration). 
26. Treatment with systemic medications that suppress the immune system (e.g. 
cyclosporine, prednisolone). Note: inhaled, nasal, intra-articular, ophthalmic and intra- 
auricular corticosteroids are permitted. 
 
Prohibited Therapies and/or Medications within 2 weeks prior to Day 1 (Visit 2). 
 
27. Treatment within 5 cm from the treatment area with topical drugs or cosmetics 
containing benzoyl peroxide, antibiotics, keratolytic agents such as alpha- and beta- 
hydroxy acids, including glycolic acid, lactic acid and other fruit acids, salicylic acid, 
urea, soaps containing antibacterial agents such as skin fresheners/astringents or 
aftershave products) 
28. Treatment in the face within 5 cm from the treatment area with any other topical 
treatment that in the opinion of the (sub)investigator may influence the subject’s acne 
vulgaris status (e.g. topical steroids, calcineurine inhibitors, metronidazole, 
permethrin, artificial tanners). 
29. Treatment in the face within 5 cm from the treatment area with electrolysis, waxing or 
depilatories. 
 
Note: non-medicated/non-irritant lotions/creams/sunscreens are acceptable on the 
treatment area until within 3 days of Visit 2/Day 1. 
 
7.4 Subject Enrolment Log 
As a minimum, subjects who have signed the informed consent form, but who are not 
necessarily randomised in the trial/treatment assigned, should be registered on the log. 


 
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7.5 Subject Identification List 
The (sub)investigator must maintain a list of all subjects randomised/treatment assigned at the 
trial site including each subject's identity, date of enrolment and corresponding subject ID so 
that any subject may be identified if required for any reason. The list is kept by the 
investigator and must not be copied or retained by LEO. 
 
At the screening Visit, each subject must be assigned a unique subject ID to protect the 
subject's identity and which will be used in lieu of the subject's name when the 
(sub)investigator reports trial-related data. 
 
The subject ID is distinct from the randomisation code number. 
 
7.6 Restrictions during Trial 
Prohibited medication and procedures prior to trial entry are detailed in the Exclusion 
Criteria; see Section 7.3 for details. Any medication and procedures during the trial must be 
recorded along with the indication. 
 
Make-up and sunscreens are not allowed in the TAs from 3 days prior to Day 1 and until 15 
days after last IP application. Moreover, make-up and sunscreens are not allowed from the 
evening before follow up visits at Week 4, 8 and 12 until after the assessments. 
 
Non-medicated and non-irritant emollients, lotions, creams, gels or foams are not allowed in 
the TAs from 3 days prior to Day 1 and during treatment days and 3 days before trial visits. 
Note: Subjects should wash treatment areas with a mild soap before starting use of emollients, 
lotions, creams again. Eye make-up within peri-orbital area and lipstick is allowed from 1 day 
after last treatment. 
 
Subjects may be advised to use icepacks and cooling fans to attenuate burning sensation and 
pain. From experience, weak analgesics with or without antihistamine are also useful in 
treating the pain. In the case of periorbital oedema, a light and cold compression may be 
useful. In case of sleeping disorders due to pain, mild sedatives can be used. 
 
Icepacks and cooling fans will not be considered a medical intervention, but should be 
recorded in the eCRF as a concomitant medication. 
 
Use of concomitant treatment and indication must be recorded in the subject’s medical record 
and the eCRF (treatment/drug name, dose, and dates of start and stop). 
 
Subjects should not undergo any elective medical procedure without prior consultation with 
the (sub)investigator. Elective procedures (e.g. minor day-surgery, dental surgery, etc.) that 


 
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might require hospitalisation or anesthesia should be deferred during the first 15 days after 
first IP administration. 
 
7.7 Withdrawal Criteria 
Subjects may withdraw from the trial for any of the following reasons: 
 
1. Unacceptable treatment efficacy: the (sub)investigator is free to withdraw the subject at 
any time based on a medical judgment. 
2. Unacceptable AEs or LSRs: any AEe or LRS that the (sub)investigator or the subject 
considers unacceptable. 
3. Exclusion criteria: any exclusion criteria which emerge/become apparent during the 
subject’s participation in the clinical trial. 
4. Voluntary withdrawal: subjects are free to withdraw from the clinical trial at any time 
and for any reason. 
5. Subjects must withdraw from the trial for any of the following reasons: 
a. Subject becomes pregnant during the trial. 
b. Subject with positive pregnancy test at screening and/or Day 1 will be 
excluded and complete End of Trial Form. Subjects with positive pregnancy 
test at visits after treatment (Week 2, 4, 8, or 12) may remain in trial for follow 
up. 
Reason(s) for withdrawal must be recorded in the eCRF and medical records. 
 
Subjects who are discovered, after enrolment/randomisation, not to have fulfilled all in- 
/exclusion criteria at the time of enrolment should discontinue treatment unless the 
(sub)investigator, based on clinical and ethical evaluation, finds discontinuation inappropriate. 
 
Subjects who discontinue treatment after at least one treatment should remain in the trial for 
follow-up assessments. AEs should be followed up in all subjects as described in section 9.5 
 
Subjects withdrawn will not be substituted. 


 
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8 Trial Schedule and Assessments 
8.1 Schedule of Trial Procedures 
 
Screening 
Visit (SV) 
Day 0 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
8 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Visit number 
1 
2* 
3 
4 
5 
6 
7 
8 
9 
10 
Visit window 
Day -28 to 
Day 1 
±3 
Days 
±3 
Days 
±5 
Days 
±1 
Week 
Informed consent 
x 
In-/exclusion criteria1) 
x 
x 
Subject demographics 
x 
Subject height and 
weight 
x 
Identification of 
Treatment Areas (TA) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medical history and 
concurrent diagnosis 
x 
Acne Treatment History 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviated physical 
examination 
x 
x 
Vital signs 
x 
x 
Urine pregnancy test 
x 
x1) 
x 
x 
x 
x 
Clinical assessments of 
full face IGA 
x 
Clinical assessments of 
TAleft and TAright for IGA 
and lesion count 
x 
x 
x 
x 
x 
x 
Photos 
(cohort 1,2 and 3) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Photos (only cohort 3 
and 4) 
x 
Subject questionnaire 
AcneQoL 
x 
x 
Subject questionnaire 
TSQM II 
x 
Subjects Global 
Cosmetic Score 
x 
Tape lift for 
inflammatory biomarker 
analysis 4) 
x 
x 
x 
x 
x 


 
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Swab for microbiome 
collection 4) 
x 
x 
x 
x 
x 
Randomisation 
x 
Administration of trial 
medication by site staff 
x 
x** 
x** 
LSR evaluation 
x 
x 
x 
x 
x2) 
x 
x 
x 
x 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Phone Call 
x3) 
End of Trial Form 
x 
1) For women of child-bearing potential a urine pregnancy test must be performed, prior to treatment. 
2) Not applicable for cohort 4 
3) Only applicable for cohort 4 
4) Not applicable for cohort 1 
* Can be performed the same day as Screening 
** Treatment on Day 2 and/or 3 is optional as described in section 6.1. 
 
8.2 Subject Eligibility 
Refer to Sections 7.2 and 7.3. 
 
8.3 Demographics 
Subject demographics will be recorded at the Day 0 (Screening). The following will be 
recorded in the eCRF: 
 
• Date of birth 
• Sex 
• Race: American Indian or Alaska Native; Asian, Black or African American; Native 
Hawaiian or Other Pacific Islander; White; Other 
• Ethnic origin (self-reported by the subject): Hispanic or Latino, not Hispanic or Latino 
• Fitzpatrick skin type (see Table 2) 
 
Table 2: Fitzpatrick skin type 
 
Number 
Description 
I 
Always burns easily, never tans 
II 
Always burns easily, tans minimally 
III 
Burns moderately, tans gradually (light brown) 
IV 
Burns minimally, always tans well (moderate brown) 
V 
Rarely burns, tans very well (moderate brown) 
VI 
Never burns, deeply pigmented 


 
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8.4 Height and Weight 
The subject’s height must be measured or self-reported (cm or inches) and weight must be 
determined or self-reported (kg or pound) at Visit 1. 
 
8.5 Vital Signs 
Blood pressure and heart rate must be assessed after approximately 5 to 15 minutes in a 
supine position at visits indicated in Section 8.1. 
 
If an abnormal vital sign at Visit 1 (screening) is considered to be clinically significant by the 
(sub)investigator, it will be up to the (sub)investigator´s discretion if the subject should be 
enrolled into the trial. Abnormal findings of clinical relevance at Visit 1 (screening) will be 
documented as medical history in the eCRF. If an abnormal vital sign recorded at any other 
visit than Visit 1 (screening) is considered to be clinically significant by the (sub)investigator, 
it will be reported as an AE. 
 
8.6 Physical Examination 
An abbreviated physical examination including general appearance, regional lymph nodes and 
dermatologic examination of the skin must be performed at visits indicated in Section 8.1 
 
If an abnormal physical examination at Visit 1(screening) is considered by the 
(sub)investigator to be clinically significant, it will be up to the (sub)investigator´s discretion 
if the subject should be enrolled into the trial. Abnormal findings of clinical relevance in the 
physical examination at the Screening Visit will be documented as medical history in the 
eCRF. If an abnormal physical examination at Visit 10 is considered by the (sub)investigator 
to be clinically significant, it will be reported as an AE. 
 
8.7 Medical History 
Relevant medical and surgical history must be recorded at the Screening Visit 1. This includes 
previous skin disease within the treatment areas. 
 
8.8 Acne vulgaris specific medical history 
Specified relevant medical history pertaining to acne vulgaris should be recorded as detailed 
in Table 3. 


 
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Table 3: Specified medical history for acne vulgaris 
 
Detailed history 
eCRF recording 
Debut 
Age at onset 
Characteristics at debuted 
(yes/no) 
Early and more severe sebum production 
Early onset relative to menarche 
Mild facial comedones 
Current disease characteristics 
(yes/no) 
Persistent refractory disease 
Responding to standard therapies but relapsing 
Acne scarring 
Acne on trunk 
Hyperseborrheia 
Family history 
(yes/no) 
Moderate to severe acne in one parent 
Moderate to severe acne in one sibling 
Previous acne vulgaris therapy 
(yes/no) 
* used more than 1 month 
Systemic retinoids * 
Systemic antibiotics* 
Systemic hormone therapy for acne control * 
Topical retinoid monotherapy * 
Topical retinoid combination therapy * 
Other topical combination therapies * 
Topical benzoyl peroxide * 
Azealic acid * 
PDT 
Chemical peels 
Other light based therapies (specify) 
Other topical therapies (specify) 
 
 
8.9 Concomitant Medication 
Concomitant medication is defined as any medication used by a subject during the clinical 
trial apart from the investigational product. Concomitant medication including diagnoses must 
be recorded in the medical record and the eCRF at visits specified in section 8.1. 
 
8.10 Pregnancy Test 
A urine pregnancy test must be performed at the trial site in female subjects of child-bearing 
potential at visits specified in section 8.1. 
 
8.11 Laboratory Assessments 
8.11.1 Urine collection for pregnancy test 
Qualitative urine pregnancy test (dip-stick) of human chorionic gonadotropin (HCG) must be 
performed as scheduled in section 8.1. The test will be performed locally. 


 
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8.11.2 Microbiome and Biomarker 
Collection is described in Appendix 2 and Appendix 3. Handling and shipment instructions 
for the samples are provided in a separate laboratory manual. 
8.12 Adverse Events 
AEs must be assessed and recorded as specified in section 9. 
 
8.13 Other Safety Assessments 
Local Skin Responses (LSRs) 
Assessment of local skin responses in the treatment areas using the LSR Grading Scale will 
be performed at Day 1 prior to first IP application and at all subsequent visits as indicated in 
section 8.1. 
 
Local skin responses are defined as erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation and erosion/ulceration. The presence/absence and grade of each LSR 
will be recorded using the LSR Grading Scale shown in Appendix 6. This grading scale will 
also be provided as hard copy to the site. Any local skin responses identified within the 
treatment area which do not match the criteria in the LSR Grading Scale should be reported as 
AEs. 
 
8.14 Subject Reported Outcomes 
The subject must complete Acne-QoL at Visit 2 (Day 1) and Visit 10 (Week 12, End of Trial). 
 
The subject must complete TSQM II and Subject Global Cosmetic Score at Visit 10 (Week 
12, End of Trial). 
 
Subject-reported outcome measures should be completed prior to any other assessments at the 
respective trial visits in the following order: Acne QoL, TSMQ II and Subject Global 
Cosmetic Score. The subjects should be encouraged to answer all questions in the 
questionnaires. 
 
8.15 Investigator Assessments 
The investigator assessments will be conducted by an experienced and qualified 
dermatologist. All assessments of each subject at the site should preferably be performed by 
the same dermatologist. At Visit 1, identification of the treatment area should be documented 
on an individual transparent film using three-point landmark technique (refer to Appendix 10 


 
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for details). At all subsequent visits, the transparent film should be used to locate the 
treatment area for further treatment or assessments of the treated skin. 
 
The following clinical assessments must be made at visits as specified in section 8.1: 
 
1. IGA of the full face (see Table 4 for grading) at Screening to determine acne vulgaris 
severity for inclusion to the trial at Screening. 
2. IGA and non-inflammatory lesion count (open and closed comedones), and 
inflammatory lesion count ( erythematous papules and pustules) in TAleft and TAright at 
Screening and Day 1, Week 2, 4, 8, and 12. 
3. LSR assessments (see 8.13) in TAleft and TAright using the LSR Grading Scale at Day 1 
prior to IP application, and on all subsequent site visits. 
4. Skin photography at Day 1, prior to treatment, and on all subsequent site visits (only 
for cohort 1, 2, and 3). 
5. Skin photography at screening for cohort 3 and 4 
6. All other skin findings than LSRs and acne will be reported as medical history at 
Screening or as AEs at subsequent visits. 
7. Biomarker and microbiome samplings in Cohort 2, 3 and 4 at Day 1 and at Week 2, 4, 
8 and 12. See Appendix 2 and Appendix 4. Samples will be stored for later analysis. 
 
 
Table 4. Investigator’s Global Assessment Scale for Acne Vulgaris* 
 
Grade 
Description 
0 
Clear skin with no inflammatory and non-inflammatory lesions 
1 
Almost clear; rare non-inflammatory lesions with no more than one small 
inflammatory lesion 
2 
Mild severity; greater than Grade 1; some non-inflammatory lesions with no 
more than a few inflammatory lesions (papules/pustules only, no nodular 
lesions) 
3 
Moderate severity; greater than Grade 2; up to many non-inflammatory 
lesions and may have some inflammatory lesions, but no more than one 
small nodular lesions 
4 
Severe; greater than Grade 3; up to many non-inflammatory and 
inflammatory lesions, but no more than a few nodular lesions 
*The same scale will be used for full face and TA evaluation of IGA. 
 
 
8.16 Dispensing of IP 
Not applicable as this is an investigator applied IP. 


 
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8.17 Return of IP and Compliance 
Refer to Sections 10.7.1 and 10.7.3. 
 
8.18 End of Trial Form 
The End of Trial Form must be completed for all subjects who have signed informed consent. 
This includes e.g. date of last dose, last attended scheduled visit number, primary reason for 
withdrawal, etc. 
 
9 Adverse Events 
• AEs and serious AE (SAEs) are defined in Appendix 7. 
• Classification of adverse events in terms of severity, causality and outcome are defined in 
Appendix 8. 
9.1 Collection of Adverse Events 
AEs must be collected from the time of first trial-related activity after the signing of the 
informed consent form until last visit at Week 12. 
 
Abnormal findings observed at the screening visit should be recorded as diagnoses in the 
Concomitant Medication page if medication is currently being taken for the condition. If not, 
it will be documented as medical history in the eCRF. 
 
AEs must be assessed by medically qualified personnel. A qualified and experienced 
dermatologist must conduct all dermatologic examinations, LSR and AE evaluations of the 
treatment areas. 
 
For AEs recorded on the day starting treatment, it should be specified whether the AE started 
prior to or after first application of IP. 
 
At all visits, the subject will be asked a non-leading question by the (sub)investigator about 
AEs, for example: “How have you felt since I saw you last?”. No specific symptoms should 
be asked for. It is important that the (sub)investigator also observes the subject for any 
changes not reported by the subject and records these changes. 
 
9.1.1 Local Skin Responses 
Local Skin Responses which match the criteria in the LSR Grading Scale are to be reported 
on the Local Skin Response sections in the eCRF and not as AEs in the eCRF even if they 
require treatment. Skin responses other than those identified in the LSR scale must be 
recorded appropriately as AEs. 


 
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Any LSRs classified as a SAE must be added to the AE form and in addition be reported to 
LEO on the SAE Form (according to “Investigator Reporting Responsibilities”, section 9.4.1) 
 
Any treatment for a LSR must be recorded on the concomitant medication page of the eCRF 
with the most important LSR (e.g. swelling should be reported as swelling-LSR). 
 
9.2 Reporting of Adverse Events in the eCRF 
AEs reported by the subject or observed by the (sub)investigator must be recorded on the 
adverse event form of the eCRF and should be described in the following manner: 
 
The AE term will be in precise English medical terminology (i.e. not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (e.g. 
allergic contact dermatitis). 
 
For AEs, the location must be part of the adverse event description and may be described as 
“in the treatment areas”, “outside the treatment areas” or “not applicable”. For adverse events 
in treatment areas the lateral side needs to be specified also. 
 
The duration of the AE must be reported as the start date and stop date of the event. In 
addition, it must be recorded whether the AE started prior to start of trial medication. 
 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 8. 
 
9.2.1 Actions Taken as a Consequence of an AE 
Action taken with trial treatment: Any action taken with trial medication as a consequence of 
the AE must be recorded (dose not changed, dose reduced, dose increased, drug interrupted, 
drug withdrawn, not applicable, unknown). 
 
Other action taken: Any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
 
Withdrawn due to AE: It must be recorded whether the AE leads to withdrawal from the trial. 
 
9.3 Other Events to be Reported 
9.3.1 Pregnancy 
Any pregnancy occurring during the clinical trial must be reported to LEO within 24 hours of 
first knowledge using the (paper) Pregnancy Form (Part I). All such pregnancies must be 


 
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followed up until delivery or termination and final outcome must be reported on the (paper) 
Pregnancy Form (Part II) within 24 hours of first knowledge. 
 
The completed Pregnancy Forms must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO (see section 9.4.1 for contact details). 
 
Please also confer with section 7.7, Withdrawal Criteria. 
 
9.3.2 Overdose 
Overdose refers to the administration of a quantity of a medicinal product given per 
administration or per day which is above the protocol defined dosage. 
 
The term overdose must be documented on the adverse event form of the eCRF book. In 
addition, AEs originating from overdose must be documented on a separate line. 
 
9.3.3 Medication Error 
Medication error refers to any unintentional error in the dispensing or administration of a 
medicinal product while in the control of the (sub)investigator or subject. Broadly, medication 
errors fall into four categories: wrong medication, wrong dose (including strength, form, 
concentration, amount), wrong route of administration or wrong subject. 
 
The medication error must be documented on the adverse event form of the eCRF book. In 
addition, AEs originating from a medication error must be documented on a separate line 
specifying the category of error (see definitions above). 
 
9.3.4 Misuse 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
 
The term misuse must be documented on the adverse event form of the eCRF book. In 
addition AEs originating from misuse must be documented on a separate line. 
 
9.3.5 Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IP which is 
accompanied by harmful physical or psychological effects. 
 
The term abuse must be documented on the adverse event form of the eCRF book. In 
addition, AEs originating from abuse must be documented on a separate line. 


 
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9.3.6 Aggravation of Condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to baseline, must be reported as an AE. 
 
9.3.7 Lack of Efficacy 
Not applicable 
 
9.3.8 Adverse Events of Special Interest 
In the clinical trials investigating LEO 43204 gel for AK in subjects with sun-damaged skin, 
there is a special interest for adverse events regarding development of keratoacanthoma (KA) 
or squamous cell carcinoma (SCC). Moreover, KA can be difficult to distinguish clinically 
and histologically from SCC. Sun-damaged skin is also prone to development of KA as a 
response to local irritation and/or inflammation. The subjects in this trial are not expected to 
have sun-damaged skin due to younger age and are thus considered to have a very low risk of 
developing KA or SCC. 
 
To ensure that all information relevant for surveillance is collected, SCCs and KAs in the 
treatment area are considered adverse events of special interest (AESI). 
 
For SCCs and KAs in the treatment area, the relevant information will be collected in the 
eCRF. In addition, histology report should be faxed or emailed to Global Pharmacovigilance, 
once available, using the following fax number or email address: 
 
Fax number: +45 7226 3287 
 
Email address: drug.safety@leo-pharma.com 
 
SCCs and KAs in the treatment area that meet the criteria for being serious should be reported 
as SAEs (please refer to section 9.4.1 for reporting details). 
 
The pathology slides that have been used for the initial diagnosis of SCC or KA will be sent 
for central pathology review. Central pathology reports will be distributed to the investigator. 
If there are any discrepancies between the local pathology report and the central pathology 
report, there should not be any changes in the eCRF. For the central pathology review, the 
local pathology laboratory will send the relevant histology slides to the investigator who will 
forward the slides to the pathologist doing the central reading. Only if the original slides 
cannot be sent is it acceptable to use new slides made from the tissue block. 


 
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9.4 Additional Reporting Requirements for Serious Adverse Events 
9.4.1 Investigator Reporting Responsibilities 
Any Serious Adverse Event (SAE) must be reported to LEO on the (paper) Serious Adverse 
Event Form – Clinical Trials within 24 hours of first knowledge. This report should contain an 
assessment of available information on seriousness, severity, causal relationship to the IP, 
comparator or trial procedure, the action taken, the outcome to date, and a narrative 
description of the course of the event. 
 
Any LSR classified as a SAE must be added to the adverse event form in the eCRF and in 
addition reported to LEO on the SAE form. 
 
The completed SAE form must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO using the following fax number or e-mail address: 
 
Fax number: +45 7226 3287 (for Global Pharmacovigilance) 
 
E-mail address: drug.safety@leo-pharma.com (for Global Pharmacovigilance) 
 
It may be relevant for the (sub)investigator to enclose other information with the SAE form, 
such as reports of diagnostic procedures, hospital records, autopsy reports, etc. 
 
Additionally, Global Pharmacovigilance, LEO may request further information in order to 
fully assess the SAE. The (sub)investigator must forward such information to Global 
Pharmacovigilance, LEO upon request by fax or e-mail (see contact details above). 
 
The investigator must notify the local IRB(s)/IEC(s) of SAEs as required by current 
applicable legislation for the concerned country. 
 
SAEs occurring after the completion of the clinical trial including any protocol required post- 
treatment follow-up period should not be routinely sought or collected. However, such events 
should be reported to Global Pharmacovigilance, LEO (drug.safety@leo-pharma.com) if the 
(sub)investigator becomes aware of them. 
 
9.4.2 LEO Reporting Responsibilities 
Global Pharmacovigilance, LEO is responsible for assessing whether or not a SAE is 
expected. The relevant reference document for this clinical trial is: 


 
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For the IP, the Investigator’s Brochure, LEO 43204 gel, Field Therapy, Edition No. 4 
including Addendum of LEO 43204 gel in Acne Vulgaris (Exploratory Edition No. 1) and 
subsequent updates hereof must be used. 
 
Global Pharmacovigilance, LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
country. 
 
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned country. 
 
For the US, all SAEs which are assessed as causally related to the IP by LEO (Guidance for 
Industry and Investigators – Safety Reporting Requirements for INDs and BA/BE Studies) 
and which are unexpected (Serious and Unexpected Suspected Adverse Reactions (IND safety 
report)) are subject to expedited reporting to regulatory authorities and IRB(s)/IEC(s) 
according to current applicable legislation in the concerned country. Investigators will be 
notified of these on an ongoing basis. 
 
9.5 Follow-up for Final Outcome of Adverse Events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject has completed the clinical trial, LSRs as well as AEs classified as 
possibly or probably related to the IP that are deemed clinically significant should be followed 
for 2 months or until final outcome is determined, whichever comes first. 
 
SAEs must be followed up until a final outcome has been established, i.e. the follow-up may 
continue beyond the end of the clinical trial. 


 
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10 Investigational Product(s) 
10.1 Investigational Product Description 
 
Finished product (brand) name (if available)/name 
investigational product 
LEO 43204, 0.018% 
Formulation 
Gel 
Active ingredient name/concentration 
LEO 43204, 0.018% w/w 
Excipients 
CCI 
Pack size(s) 
1 g laminate tubes each containing 0.67g 
Manufacturer’s name of bulk medication (IP) 
LEO Pharma 
55 Industriparken 
2750 Ballerup 
Denmark 
Or 
LEO Laboratories LTD. 
285 Cashel Road Dublin 12 
Ireland 
Certifier’s name of bulk medication (IP) 
LEO Pharma A/S 
Supplier’s name 
LEO Pharma A/S, 
Manufacturer’s name of subject treatment packages 
CCI 
 
Certifier’s name of subject treatment packages 
LEO Pharma A/S 
Finished product (brand) name (if available)/name 
investigational product 
Vehicle gel 
Formulation 
Gel 
Active ingredient name/concentration 
Not applicable 
Excipients 
CCI 
Pack size(s) 
1 g laminate tubes each containing 0.67g 


 
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Manufacturer’s name of bulk medication (IP) 
LEO Pharma 
55 Industriparken 
2750 Ballerup 
Denmark 
Or 
LEO Laboratories LTD. 
285 Cashel Road Dublin 12 
Ireland 
Certifier’s name of bulk medication (IP) 
LEO Pharma A/S 
Supplier’s name 
LEO Pharma A/S, 
Manufacturer’s name of subject treatment packages 
CCI 
 
Certifier’s name of subject treatment packages 
LEO Pharma A/S 
 
 
10.2 Administration of Investigational Products 
 
Route of administration 
Topical administration 
Application range 
Left and right cheek treatment areas (TAleft and TAright ) 
corresponding to approximately 36 cm2 each. 
Application frequency 
Once daily for up to three consecutive days 
Daily maximum 
Approximately 1/3 of a tube per TA applied by the trial 
staff as a thin wet layer. 
Time of day for application 
No specific requirements 
Relation of time of application to dietary intake 
No specific requirements 
 
The IP will be applied to the treatment areas at the clinic by the trial site staff . 
 
10.2.1 Trial Medication Application 
At each application, a thin wet layer of trial medication should be applied evenly within the 
identified TA of approximately 36 cm2 by the trial site staff. The required total amount of IP 
to produce a thin wet layer is approximately 1/3 of a squeezed tube and equal to a pea-sized 
drop. The trial staff will be trained to dispense the correct amount of IP. Prior to application, 
the location of the TA is identified using a transparent film and a three-point landmark 
technique (Appendix 10). 
 
Trial medication should be applied according to the following procedure: 
 
1. Using standard hospital gloves, remove the cap from the unit dose tube. Squeeze a 
pea-sized drop of IP from tube onto the index finger. 


 
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2. Spread the trial medication evenly over the assigned treatment areas such that a thin 
wet layer of IP is applied. 
3. Recap the tube and store for drug account (refer to section 10.7). 
4. Dispose of gloves and wash hands with soap and water. 
5. Allow the trial medication to dry for at least 15 minutes following application. 
 
General treatment guidance: 
 
• Subjects should not shave or trim the treatment areas during the treatment days. 
• Subjects should not wash the treatment areas on the treatment days prior to IP 
application. 
• Subjects must avoid washing the treatment areas or engaging in activities that cause 
excessive sweating for at least 6 hours following IP application. 
• When subjects resume their normal washing routine, they should wash the treatment 
areas gently using a mild soap. 
• Subjects should avoid use of non-medicated/non-irritant salves/emollients on the 
treatment areas during treatment days and within 3 days prior to the first treatment 
day. 
• Subjects should avoid use of make-up and sunscreens on the treatment areas from 3 
days prior to first treatment day and 15 days after last IP application. Note: Eye-make- 
up within peri-orbital area and lipstick is allowed. 
• Subjects should be advised not to allow other persons (including children) and pets to 
come into contact with the treatment areas for a period of 6 hours following 
application. 
• Subjects should avoid contact of IP with eyes. 
• Subjects should avoid excessive sun exposure (e.g. sunbathing, tanning booths) of the 
treated area. 
 
10.3 Precautions/Over dosage 
10.3.1 Skin exposure 
The most common LSRs reported in the AK studies with LEO 43204 gel are erythema, 
flaking/scaling, and crusting. Less common LSRs include swelling/oedema, 
vesiculation/pustulation, and erosion/ ulceration. Completed clinical trials have shown LSRs 
to be transient and normally resolved within two weeks (please refer to the Investigator's 
Brochure of LEO 43204 gel in Actinic Keratosis Edition 4 or any updates hereof for further 
details). 


 
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In a low percentage of subjects treated on face or scalp, swelling around the eyes or on the 
eyelids may develop to a point where it may be considered clinical significant. In such cases 
these AEs should be recorded as peri-orbital oedema or eyelid edema. Treatment is usually 
straightforward with cold compress on the eye(s) with the subject resting in supine position 
for a few hours. 
 
The mean maximum composite LSR score in Part 2 of LP0084-1013 (face) for the doses of 
LEO 43204 gel that will be used in the current trial was 8.9 for face. Using the same doses for 
3 consecutive days (LP0084-1148), mean maximum composite scores were 10.6 for face. 
Peak value in the LP0084-1013 trial (face) was at Day 3. At Day 15, mean maximum 
composite LSR score was either at baseline value or close to baseline value in almost all 
subjects treated on face (refer to the Investigator's Brochure of 43204 gel in Actinic Keratosis 
Edition 4 or any updates hereof). 
 
Investigators conducting clinical trials with LEO 43204 gel should ensure that investigational 
site staff is trained in the protocol-specified application procedure(s) and follow appropriate 
precautions. Investigators must monitor their subjects for the emergence and resolution of 
LSRs and AEs 
 
10.3.2 Ocular Exposure 
If accidental eye exposure occurs, the eye should be irrigated immediately and extensively 
with water. The subject should immediately seek medical attention by contacting the 
investigator or other medically qualified healthcare professional (e.g., in an Emergency 
Room) for assessment and treatment. All treatments are to be administered at the discretion of 
the healthcare professional (in emergency room, ophthalmologist, and/or the investigator). 
Treatment with topical cycloplegic and topical ophthalmic antibiotics is recommended. 
Topical anti-inflammatory agents and eye pads may also be useful for subject comfort. The 
subject should be monitored closely in the first few days following exposure to check for 
secondary infection and to assess visual acuity. Subjects should be warned that vision might 
worsen before improvement occurs. 
 
Any suspected ocular exposure should be documented and brought to the attention of the 
monitor 
 
10.3.3 Other Exposure 
LEO 43204 gel must not be ingested. If accidental ingestion occurs the subject should drink 
plenty of water. 


 
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10.4 Packaging of Investigational Products 
The IP will be packaged in individually numbered kits. Each kit contains 2 unit-dose tubes. 
 
Each unit-dose tube will contain LEO 43204 gel or vehicle gel to be handled in the hospital 
clinic up to three consecutive days. 
 
The label on the tubes will be colored (e.g. red and green) to instruct the site personnel on 
which site (left or right) the product should be applied. 
 
The labeling of trial products must be in accordance with Annex 13, local regulations and trial 
requirements. 
 
10.5 Storage of Investigational Products 
All LEO supplied drugs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed. 
The IP must be stored in a refrigerator between 
CCI°C and 
CCI°C (CCI °F to CCI °F). The refrigerator 
temperature must be monitored continuously and recorded. Do not freeze. 
 
10.6 Treatment Assignment 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised to receive treatment with LEO 43204 gel and 
vehicle gel to the treatment areas identified on three consecutive days. 
 
10.6.1 Randomisation Code List 
The randomisation files must be kept during the clinical trial in a secure area on the database 
server at LEO inaccessible to staff involved with the conduct and administration of the 
clinical trial until the clinical trial is unblinded. 
 
10.7 Drug Accountability and Compliance Checks 
10.7.1 Drug Accountability 
The investigator is fully responsible for the investigational products at the trial site and for 
maintaining adequate control of the investigational products and for documenting all 
transactions with them. 
 
An inventory must be kept of the investigational product given to each subject randomised in 
the trial. This inventory must be available for inspection during monitoring visits and will be 
checked by the monitor to ensure correct dispensing of the investigational product. 


 
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All investigational products supplied by the Contract Manufacturing Organisation (CMO) on 
behalf of LEO must be returned to the CMO. Prior to their return, they must be fully 
accounted for by the monitor with the help of the person responsible for dispensing the 
investigational products. Accountability must be documented by using drug accountability 
forms. 
 
Investigational products may be returned from the trial site directly to the CMO responsible 
for the running of the clinical trial. 
 
10.7.2 Trial Product Destruction 
Used and unused trial products will be destroyed by the CMO according to LEO procedures. 
 
10.7.3 Treatment Compliance 
Treatment is performed at the clinic according to the protocol by the trial site staff. 
 
10.8 Emergency Unblinding of Individual Subject Treatment 
While the safety of a subject always comes first, it is still important to seriously consider if 
unblinding is necessary to ensure subject’s safety. This section describes the procedures for 
unblinding a subject. An emergency unblinding request can be made by the (sub)investigators, 
other health care professionals or authorized LEO personnel. 
Provisions are in place for 24 hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the individual subject’s treatment assignment can be 
obtained via the IWRS. Requester without access to IWRS (Health Care Professionals), can 
contact the investigator or LEO for emergency unblinding. 
11 Statistical Methods 
11.1 Determination of Sample Size 
With a sample size of 38 subjects the power of observing a difference between active and 
vehicle gel will be 84% in a trial with intraindividual comparisons, using a paired two-sided t- 
test on a 5% level, assuming an approximate total lesion count of 36 at baseline and 
reductions at end of trial from baseline around 7.3 (20%) and 12.4 (34%) for vehicle gel and 
active respectively, and a standard deviation of the difference between treatments at end of 
treatment up to 10.4. 
 
The assumptions on sample size are that all but the two first subjects of the 40 subjects 
randomised are included in the efficacy analyses, and the assumptions on efficacy rely on 
experiences from a previous trial conducted by LEO in subjects suffering from acne vulgaris 


 
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(LP0045-01), together with an expected reduction in standard deviation of the primary 
endpoint of at least 20% due to the intraindividual comparisons. 
 
11.2 Definition of Trial Analysis Sets 
All subjects enrolled in the trial (i.e. subjects for whom informed consent has been obtained 
and who have been registered in the clinical trial) will be accounted for in the clinical trial 
report. 
 
All subjects randomised except the first two subjects with a reduced exposure are included in 
the full analysis set and will be analysed for efficacy. The size of the full analysis set will then 
be 38 subjects Exclusions from the full analysis set can be considered in special cases as 
described in ICH E9, section 5.2.1. Full Analysis Set. If it is decided to exclude a randomised 
subject from the full analysis set, a justification addressing ICH E9 will be given. 
 
A per protocol analysis set will be defined by excluding subjects from the full analysis set 
based on the review of protocol deviations before the unblinding of the trial. If it is decided to 
exclude a subject from the per protocol analysis set, a justification will be given. 
 
A safety analysis set will be defined by excluding subjects from the full analysis set who 
either received no treatment with investigational product 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 will be documented in the statistical analysis plan update before breaking the 
randomisation code. 
 
11.3 Statistical Analysis 
11.3.1 Disposition of Subjects 
The reasons for leaving the trial will be presented for all randomised subjects by last visit 
attended. 
 
11.3.2 Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
the safety analysis set. 
 
Demographics include age, sex, race, ethnicity and skin type. Other baseline characteristics 
include height, weight, BMI and, duration of acne vulgaris, concurrent diagnoses, 
concomitant medication, previous treatments for acne vulgaris. 


 
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11.3.3 Exposure and Treatment Compliance 
Descriptive statistics on treatment duration will be provided for the safety analysis set. 
 
11.3.4 Analysis of Primary Endpoints 
11.3.4.1 Total lesion count 
The evaluation of the treatment effect on total lesion count (inflammatory and non- 
inflammatory) lesions at Week 12 (primary endpoint) will be performed within the framework 
of an ANCOVA model with treatment as fixed effect, baseline total lesion count as covariate 
and subject as random effect. 
 
Comparison between active and vehicle gel will be done by means of a t-test on the estimated 
treatment contrast in the model. Estimated difference, 95% confidence limit and test 
probability will together with least square means and their 95% confidence limits be 
presented from the model. 
 
A sensitivity analysis investigating potential effect of lateral side of lesion will be performed 
by adding this effect to the above model. 
 
11.3.5 Analysis of Secondary Endpoints 
11.3.5.1 Lesion counts 
Descriptive statistics will be provided for inflammatory, non-inflammatory and their sum by 
treatment and visit. 
 
Descriptive statistics will include means, standard deviations, median and ranges. 
Furthermore mean curves over time will be made. 
 
11.3.5.2 Investigator’s Global Assessment 
Descriptive statistics will be provided for the investigator’s global assessment of disease 
severity in the treatment area, presented by treatment and visit. 
 
Descriptive statistics will show frequencies for each score. 
 
11.3.6 Analysis of Exploratory Endpoints 
11.3.6.1 Lesion counts by clinical evaluation. 
Descriptive statistics will be provided for inflammatory, non-inflammatory and their sum by 
treatment and visit for data obtained by clinical assessment. 


 
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Descriptive statistics will include means, standard deviations, median and ranges. 
Furthermore mean curves over time will be made. 
 
11.3.6.2 Treatment success according to IGA 
Rates of treatment success, defined as at least a two grade improvement in IGA at week 12 
compared to baseline, will be compared between treatments using Fisher’s exact test. 
 
11.3.6.3 Inflammatory cytokine expression 
Descriptive statistics will be presented showing means, standard deviations medians and 
ranges by treatment and time point. The results will also be shown as box-plots. 
 
If applicable data will be log transformed before deriving descriptive statistics. 
 
11.3.6.4 Microbiome profile 
The analysis of data relating to the microbiome will be specified in a separate analysis plan, 
and the reporting will be done separately. 
 
11.3.6.5 Subject evaluation of Acne QoL 
Descriptive statistics will be provided for the subject’s evaluation of Acne QoL at Day 1 and 
Week 12 for the total and each of the four domains contained within the questionnaire (self- 
perception, role-social, role-emotional and acne symptoms). 
 
11.3.6.6 Subject evaluation of TSQM II 
Descriptive statistics will be provided for the subject’s evaluation of TSQM II at Week 12 for 
the total and each of the four domains contained within the questionnaire (effectiveness, side 
effects, convenience and global satisfaction). 
 
11.3.6.7 Subject Global Cosmetic Score 
Descriptive statistics will be presented for the Subject’s Global Cosmetic Score at Week 12 
showing means, standard deviations medians and ranges by treatment. 
 
11.3.7 Analysis of Safety 
The analysis of safety will be based on the safety analysis set. 


 
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11.3.8 Adverse Events 
Treatment emergent adverse events, i.e. with an onset or intensifying after treatment start will 
be coded according to MedDRA v19.0 summarised by the following tables showing event 
counts, incidences and incident rates: 
 
• An overall summary showing statistics for all AEs, serious AE’s, AE’s with actions 
taken, AE’s stratified by severity, related AE’s by treatment, cutaneous AE’s by 
treatment 
 
• AE by system organ class and preferred term 
 
• AE’s by system organ class and preferred term stratified by disease severity 
 
• Related AE’s by system organ class and preferred term by treatment 
 
• Cutaneous AE’s by system organ class and preferred term by treatment 
 
• Serious adverse events will be evaluated separately and a narrative for each will be 
given. 
 
• AEs leading to withdrawal from trial or discontinuation of investigational product will 
be listed. 
 
11.3.9 Other Specific Safety Assessments 
11.3.9.1 Composite and component LSR score 
The incidence and grade of LSRs will be summarised by treatment and time point. LSR 
grades will be summarised by descriptive statistics including mean, standard deviation, 
median and range as well as frequency counts by treatment for each of the six individual 
LSRs: erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and 
erosion/ulceration. LSRs leading to withdrawal from trial and/or withdrawal of IP will be 
tabulated. 
 
A composite (sum) score will be obtained by summing the six individual component LSR 
scores (range 0-24) at each visit (Visit 2 to 10). The composite score and change from 
baseline will be 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 will be tabulated by treatment. 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. 


 
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11.3.9.2 Vital Signs and Physical Findings 
Observed values and changes from baseline in vital signs blood pressure, heart rate, will be 
summarised as mean, standard deviation (SD), median, minimum and maximum values. 
 
Clinically relevant physical findings will be reported as medical history or AEs as applicable. 
 
11.3.9.3 Clinical Laboratory Evaluation 
Not applicable 
 
11.3.10 
Interim Analysis 
After Week 2 (Visit 7) for specified number of subjects (refer to section 6.1) along the course 
of the trial analyses of blinded data will be performed evaluating the safety profile and the 
LSRs (refer to section 12). 
 
The analyses will include: 
 
• List of adverse event, using investigators term 
• Number of subjects with: 
 
One of the following scores on the LSR scale at any time: 
 
▪ Grade 4 crusting 
▪ Grade 4 erosion / ulceration 
▪ Grade 4 vesiculation / pustulation extending significantly outside the 
treatment area 
 
Or two or more of the following scores on the LSR scale at any time: 
 
▪ Grade 4 erythema 
▪ Grade 3 crusting 
▪ Grade 4 swelling extending significantly outside the treatment area 
▪ Grade 3 erosion / ulceration 
▪ Grade 3 vesiculation / pustulation 
 
• Descriptive statistics of composite and components of LSRs by visit and lateral side 
 
• Plots of mean and individual profiles of composite LSRs by visit and lateral side 
 
• Descriptive statistics of maximum of right and left side composite and component 
LSRs by visit 


 
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• Plots of mean and individual profiles of maximum of right and left side composite 
LSRs by visit 
 
• List of individual component LSRs 
 
11.3.11 
General Principles 
All significance tests will be two-sided using the 5% significance level. All confidence 
intervals will be presented with 95% degree of confidence. 
 
An observed cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
 
Categorical data will be summarised using the number and percentage of subjects in each 
category. Continuous data will be summarised using the mean, median, standard deviation 
(SD), minimum and maximum values. 
 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment or the statistical analysis plan update and/or 
in the clinical trial report dependent on the type of deviation. 
 
11.3.12 
Handling of Missing Values 
Subjects with missing counts of inflammatory and non-inflammatory lesions at visits 7, 8 and 
9 (weeks 2, 4 and 8) will be excluded from the analyses based on FAS and PP for these time 
points, and missing lesion counts will therefore not be imputed for these subjects. For subjects 
with missing lesion counts at visit 10 (week 12), the missing lesion counts of visit 10 will be 
imputed and the endpoints will be derived afterwards from the imputed values. 
 
A multiple imputation method will be used to handle missing data. The imputation method 
relies on the assumption that the missing data are missing at random (MAR), i.e. the 
probability that an observation is missing can depend on observed data but is unrelated to the 
data not observed. All imputations will be performed by lesion type and treatment group. 
 
Imputation of missing values for subjects with a monotone missing data pattern (i.e. there 
exist a time point for the subject where all observations before the time point are present and 
all later observations are missing) will be based on the full observed dataset excluding 
subjects with a non-monotone missing data pattern. The missing values for lesion counts at 
visit 10 will be imputed sequentially from a linear regression model with lesion counts at 
previous visits as covariates and treatment compliance (as identified by means of protocol 
deviations) as factor. 


 
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For subjects with a non-monotone missing data pattern, the lesion counts at visit 10 will be 
imputed using data from subjects without a non-monotone missing data pattern based on the 
Markov Chain Monte Carlo (MCMC) method including compliance effect, and lesion counts 
at previous visits 7, 8 and 9 as continuous variables. In case of non-convergence the 
compliance effect will be excluded from the imputation model. The imputed values at visit 10 
will be rounded to the nearest non-negative integer. 
 
Table 5 shows seed and numbers of imputations used for the multiple imputations 
 
Sensitivity analyses of the method of handling missing data will be performed for the analyses 
of the imputed endpoints: last observation carried forward (LOCF) and an observed cases 
approach. 
 
Table 5 Parameters defining imputation of lesion counts 
 
Assessment 
Seeds for Imputation 
for subjects with 
monotone pattern of 
missing data 
Seeds for Imputation 
for subjects with non- 
monotone pattern of 
missing data 
Number of imputations 
Inflammatory lesions 
255951 
897661 
100 
Non-inflammatory 
lesions 
477345 
657616 
100 
 
 
12 Trial Committees 
The Safety Review Committee will comprise the following members: 
 
• The International Coordinating Investigator 
• Sponsor’s medical expert 
• Sponsor’s Head of Translational Medicine 
• Sponsor’s pharmacovigilance expert 
• Sponsor’s Statistician 
• The ICTM 
Primary functions of the Committee: 
 
• Operate to written procedures defined by the Safety Review Committee Charter for the 
trial. 
• Document decision in the meeting minutes. 


 
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• Convene to review safety and tolerability after the last subject in cohort 1, 2 and 3 has 
completed the Week 2 follow-up visit (Visit 7). 
• Decide whether quality of data is sufficient and whether unacceptable LSRs, safety or 
tolerability events have occurred necessitating termination of the clinical trial. 
Prior to dosing of the first subject, the Safety Review Committee Charter will be finalised 
detailing the evaluation procedure and processes for immediate communication between sites. 
 
Unacceptable LSR scores, safety and tolerability events: 
 
Unacceptable safety and tolerability events in an individual subject are defined as 1) clinically 
relevant signs or symptoms observed, which in the opinion of the investigator are deemed 
unacceptable or 2) one or more of the following LSRs: 
 
• Grade 4 crusting 
• Grade 4 erosion / ulceration 
• Grade 4 vesiculation / pustulation extending significantly outside the treatment area 
Or two or more of the following: 
• Grade 4 erythema 
• Grade 3 crusting 
• Grade 4 swelling extending significantly outside the treatment area 
• Grade 3 erosion / ulceration 
• Grade 3 vesiculation / pustulation 
 
Criteria for terminating the trial: 
 
The trial will be terminated if the perception of the benefit/risk ratio (judged from clinical 
symptoms, signs and/or (S)AEs) becomes unfavorable for the continuation of the trial. 
 
• Any decision regarding premature termination of the entire trial will be made after mutual 
agreement between the Investigator and the sponsor. 
• The sponsor reserves the right to cancel the trial at any time 
• Due to the design of the trial, there are no statistical criteria for trial termination. 
• The cumulative frequencies of subjects with unacceptable LSRs, safety and tolerability 
events (as defined above ) that will strongly support the decision for trial termination are: 


 
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• 2 out of 3 subjects with unacceptable LSRs, safety and tolerability events 
after Cohort 1 
• 3 out of 9 subjects with unacceptable LSRs, safety and tolerability events 
after Cohort 2 (cumulative) 
• 5 out of 15 subjects with unacceptable LSRs, safety and tolerability events 
after Cohort 3 (cumulative) 
 
13 Electronic Case Report Forms and Data Handling 
13.1 Electronic Case Report Forms (eCRFs) 
Data will be collected by means of Electronic Data Capture (EDC). The investigator or staff 
authorised by the investigator must enter subject data into electronic CRFs. Data recorded in 
the electronic CRFs must be accessible to site staff through a secure internet connection 
immediately after entry. The eCRFs must be maintained in an up-to-date condition at all 
times. 
 
The investigator must electronically sign all CRFs used. This signature information (including 
date of signature) will be kept in the audit trail and cannot be altered. Any correction(s) made 
by the investigator or authorised site staff to the eCRF after original entry will be documented 
in the audit trail. Changes to data, already approved, will require the re-signature of the 
investigator. The person making the change and the date, time and reason for the change will 
be identified in the audit trail. 
 
For archiving purposes, each investigator must be supplied with a copy of the eCRFs for all 
subjects enrolled at the trial site via an electronic medium at completion of the trial and before 
access to the eCRF is revoked. Audit trail information must be included. eCRFs must be 
available for inspection by authorised representatives from LEO (e.g. audit by the quality 
assurance department), from regulatory authorities and/or IEC/IRBs. 
 
13.2 Data Handling 
Subject data should be entered into the eCRF as soon as possible after the visit in accordance 
with the time requirements described in the Clinical Trial Agreement with the site. Queries for 
discrepant data may be generated 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, will be in an electronic format. This systematic validation will ensure that 
a clean and consistent database is provided prior to the statistical analysis being performed. 


 
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13.3 Source Data 
For all data recorded, the source document must be defined in a source document agreement 
at each trial site. There must only be one source defined at any time for any data elements. 
 
The trial monitor will check the eCRFs for accuracy and completeness by verifying data 
recorded in the eCRF against source data to ensure such records are consistent. 
 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed by medically qualified (sub)investigators. 
 
• If the worksheet does not become part of the subject’s medical record, the following 
should as a minimum be added to the subject’s medical record: 
• Date(s) of conducting the informed consent process (date of enrolment) including date of 
provision of subject information 
• Subject ID 
• Randomisation code number (if applicable) 
• The fact that the subject is participating in a clinical trial in acne including treatment arms 
of LEO 43204 gel and vehicle gel once daily for up to three consecutive days 
• Other relevant medical information 
13.4 Trial Monitoring 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol 
and GCP are adhered to, that all issues have been recorded to perform source data 
verification, and to monitor drug accountability. 
 
The first monitoring visit should be performed as soon as possible after First Subject First 
Visit (FSFV) and no later than 4 weeks after. 
 
The monitoring visit intervals will depend on the trial site’s recruitment rate, the compliance 
of the trial site with the protocol and GCP. 
 
In order to perform their role effectively, monitors and persons involved in quality assurance 
and inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the monitor with signed and dated printouts. In addition, relevant 


 
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site staff should be available for discussions at monitoring visits and between monitoring 
visits (e.g. by telephone). 
 
14 Handling of an Urgent Safety Measure 
An Urgent Safety Measure is a measure taken to implement an action/protocol deviation 
under an emergency. This is defined within the EU Directive as “…the occurrence of any new 
event relating to the conduct of the trial or the development of the investigational medicinal 
product where that new event is likely to affect the safety of the subjects, the sponsor and the 
investigator shall take appropriate urgent safety measures to protect the subjects against any 
immediate hazard.” (Article 10(b) of Directive 2001/20/EC). 
 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order to protect clinical trial 
subjects from any immediate hazard to their health and safety, the investigator can do so 
without prior approval from LEO, regulatory authority(ies) or IRB(s)/IEC(s). 
 
The investigator must immediately inform LEO - by contacting the ICTM or medical expert - 
of this change in the clinical trial procedure or of the temporary halt providing full details of 
the information and the decision making process leading to the implementation of the urgent 
safety measure. 
 
LEO must act immediately upon receipt of the urgent safety measure notification in 
accordance with the internal procedures. 
 
15 Quality Assurance/Audit 
The clinical trial will be subject to audits conducted by LEO or inspections from domestic or 
foreign regulatory authorities or from IRBs/IECs. Audits and inspections may take place 
during or after the trial. The investigator and the site staff as well as LEO staff have an 
obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant 
to the clinical trial. This includes permission to examine, verify and reproduce any records 
and reports that are important to the evaluation of the trial. 
 
If the trial site is contacted for an inspection by competent authorities, LEO must be notified 
immediately. 


 
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16 Completion of Trial 
16.1 Trial Completion Procedures 
Trial enrolment will be stopped at the trial site when the total requested number of subjects for 
the clinical trial has been obtained. 
 
Upon completion of the clinical trial, LEO must undertake arrangements for the collection 
and disposal of any unused trial material that the investigator is not required to keep in his/her 
files. 
 
16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site 
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the trial, part 
of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained. 
 
If a trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. As specified by applicable regulatory 
requirements, the investigator or LEO must promptly inform IRB/IECs and provide a detailed 
written explanation. Relevant competent authorities must be informed. 
 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavorable for the continuation of the trial. 
 
16.2 Provision for Subject Care Following Trial Completion 
After the completion of the trial, the subjects will be treated at the investigator’s discretion or 
referred to other physician(s) according to standard practice. 
 
16.3 Archiving of Trial Documents 
The investigator at each trial site must make arrangements to store the essential trial docu- 
ments including the Investigator Trial File (ICH E6, Guideline for Good Clinical Practice) 
until LEO informs the investigator that the documents are no longer to be retained or longer if 
required by local regulations. 
 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (e.g. 
in case of an inspection from regulatory authorities). 


 
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The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the clinic/practice or retires before the end of the required storage period. 
 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
 
17 Ethics and Regulatory Authorities 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) and Regulatory Authorities 
Written approval or favourable opinion must be obtained from relevant IRB/IECs prior to the 
enrolment of subjects. 
 
Any amendments to the approved clinical trial must be approved by/receive favorable opinion 
from relevant IRBs/IECs and regulatory authorities as required prior to the implementation. 
 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial, as 
required. 
 
17.2 Ethical Conduct of the Trial 
This clinical trial must be conducted in accordance with the principles of the revision current 
at the start of the trial of the World Medical Association (WMA), Declaration of Helsinki, 
Ethical Principles for Medical Research Involving Human Subjects. 
 
17.3 Subject Information and Informed Consent 
All subjects shall receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
 
The subject’s signed and dated informed consent to participate in the clinical trial must be 
obtained prior to any clinical trial related procedure being carried out in accordance with ICH 
GCP (4.8) and all applicable laws and regulations. 
 
17.4 Processing of Personal Data 
This protocol specifies the personal data on trial subjects (e.g. age, gender, health condition, 
height, medical history, test results, etc.) which shall be collected as part of the trial and 
processed during and after trial completion. 


 
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Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator and LEO. 
 
Processing of personal data on behalf of LEO requires a written agreement between LEO and 
the relevant party which covers collection, processing and transfer of personal data in the 
clinical trial. In certain cases an agreement on transfer of personal data may also be required. 
 
Investigators and LEO must ensure that collection, processing and transfer of personal data 
are in compliance with national legislation on data protection and privacy. 
 
The investigator/institution may be considered as data controller when they wish to use 
personal data collected in the clinical trial for their own purpose such as publication of 
clinical trial results. 
 
Subjects must be asked to consent to the collection, processing and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities. 
 
If required, LEO has obtained the necessary authorisations for the processing by LEO of 
personal data collected in the trial. 
 
18 Insurance 
LEO has taken out relevant insurances covering the subjects in the present clinical trial in 
accordance with applicable laws and regulations. 
 
19 Use of Information 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the investigational product(s) is confidential information of LEO and 
shall not be used by the investigator for purposes other than this clinical trial. 
 
The investigator agrees that LEO may use any and all information, data and results from this 
clinical trial in connection with the development of the investigational product(s) and, 
therefore, may disclose and/or transfer information, data and/or results to other investigators, 
regulatory authorities and/or commercial partners. 


 
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20 Publication 
Basic information of this clinical trial will be posted on the website: www.clinicaltrials.gov 
before the first subject enters into the clinical trial (16, 17). 
 
Results will be made available on LEO’s web site according to LEO’s position on access to 
clinical trial information. 
 
After the clinical trial has been completed or terminated and all data have been received, 
defined as database lock of the clinical trial, the investigator shall have the right to publish the 
results from the clinical trial generated by the investigator, subject to the following notice 
requirements. 
 
Prior to submitting or presenting a manuscript relating to the clinical trial to a publisher, 
reviewer or other outside person, the investigator shall provide to LEO a copy of all such 
manuscripts, and LEO shall have rights to review and comment. Upon the request of LEO, the 
investigator shall remove any confidential information (other than results generated by the 
investigator) prior to submitting or presenting the manuscripts. The investigator shall, upon 
the request of LEO, delay the publication or presentation to allow LEO to protect its 
inventions and other intellectual property rights described in any such manuscripts. In case the 
first multi-centre publication is still ongoing and has not been made public at the time of 
notification, LEO and the Writing Committee may also delay the publication or presentation if 
the manuscript is deemed to harm the ongoing multi-centre publication. 
 
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must be followed. 
 
LEO also subscribes to the joint position of the innovative pharmaceutical industry (18) for 
public disclosure of clinical trial results in a free, publicly accessible database, regardless of 
outcome. 
 
21 Responsibilities 
The International Coordinating Investigator is responsible for the approval of the 
(Consolidated) Clinical Trial Protocol, Clinical Trial Protocol Amendment(s) and the Clinical 
Trial Report as agreed to in an international coordinating investigator agreement. 


 
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22 List of Abbreviations 
 
AESI 
Adverse Events of Special Interest 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AK 
Actinic keratosis 
ALA 
Aminolaevulinic acid 
AV 
Acne vulgaris 
CDMS 
Clinical Data Management System 
CMO 
Contract Manufacturing Organisation 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organisation 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
GPV 
Global Pharmacovigilance 
ICH 
International Conference on Harmonisation 
ICTM 
International Clinical Trial Manager 
IEC 
Independent Ethics Committee 
IGA 
Investigator Global Assessment 
IP 
Investigational Product 
IPL 
Intense pulsed light 
IRB 
Institutional Review Board 
KA 
Keratoacanthoma 
LSR 
Local Skin Response 
NLCRA 
National Lead Clinical Research Associate 
PDT 
Photodynamic therapy 
QoL 
Quality of Life 
SRC 
Safety Review Committee 
SAE 
Serious Adverse Event 
SCC 
Squamous Cell Carcinoma 
SOP 
Standard Operating Procedure 


 
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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TA 
Treatment area 
TSQM 
Treatment Satisfaction Questionnaire 
VPN 
Virtual Private Network 
WMA 
World Medical Association 


 
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23 References 
1. Ghodsi SZ., Orawa H. and Zouboulis CC. Prevalence, severity, and severity risk 
factors of acne in high school pupils: a community-based study. J Invest Dermatol. 
2009; 129:2136-2141. 
 
2. Stern RS. The prevalence of acne on the basis of physical examination. J Am Acad 
Dermatol 1992, 26: 931-935. 
 
3. White, GM. Recent findings in the epidemiologic evidence, classification, and 
subtypes of acne vulgaris. J Am Acad Dermatol 1998, 39:S34-37 
 
4. Tan, JK. Psychosocial impact of acne vulgaris: evaluating the evidence. Skin 
Therapy Lett. 2004, 9: 1-3. 
 
5. Layton AM, Henderson CA and Cunliffe WJ. A clinical evaluation of acne scarring 
and its incidence. Clin Exp Dermatol 19: 303-308, 1994 
 
6. Ulrich, M., Lange-Asschenfeldt, S., Röwert-Huber, J., Völker-C, M., Oesterdal, 
ML., Skak, K., Zibert, JR. and Stockfleth, E. Assessment of the in-vivo effects of 
ingenol mebutate 0.05 gel for the treatment of actinic field cancerization by 
reflectance confocal microscopy. Abstract 0174, WCCS Congress, 2014. 
 
7. Hongcharu, W., Taylor, CR., Chang, Y., Aghassi, D., Suthamjariya, K. and 
Anderson, RR. Topical ALA-Photodynamic therapy for the treatment of acne 
vulgaris. J Invest Dermatol115: 183-192, 2000. 
 
8. Divaris DX, Kennedy JC and Pottier RH. Phototoxic damage to sebaceous glands 
and hair follicles of mice after systemic administration of 5-aminolevulinic acid 
correlates with localized protoporphyrin IX fluorescence. Am J Pathol 136: 891- 
897, 1990 
 
9. Sakamoto FH, Lopes JD and Anderson RR. Photodynamic therapy for acne 
vulgaris: a critical review from basics to clinical practice: part I. Acne vulgaris: 
when and why consider photodynamic therapy? J Am Acad Dermatol 63: 183-193, 
2010. 
 
10. Yeung CK., Shek SY., Bjerring P., Yu CS., Kono T. and Chan HH. A comparative 
study of intense pulsed light alone and its combination with photodynamic therapy 
for the treatment of facial acne in Asian skin. Lasers Surg Med 2007, 39: 1-6. 


 
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11. Sakamoto FH, Torezan L and Anderson RR. Photodynamic therapy for acne 
vulgaris: a critical review from basics to clinical practice: part II. Understanding 
parameters for acne treatment with photodynamic therapy. J Am Acad Dermatol 63: 
195-211, 2010 
 
12. Guidance of Industry. Acne Vulgaris: Developing Drugs for Treatment. Draft 
Guidance. U.S. Department of Health and Human Services, Food and Drug 
Administration. Center for Drug Evaluation and Research. September 2005. 
 
13. Girman CJ, Hartmaier S, Thiboutot D, Johnson J, Barber B, DeMuro-Mercon C, et 
al. Evaluating health-related quality of life in patients with facial acne: 
development of a self-administered questionnaire for clinical trials. Qual Life Res. 
1996;5:481-90. 
 
14. Martin AR, Lookingbill DP, Botek A, Light J, Thiboutot D, Girman CJ. Health-related 
quality of life among patients with facial acne: Assessment of a new acne-specific QoL 
questionnaire. Clin Exp Dermatol 2001;26:380-385. 
 
15. Atkinson MJ, Kumar R, Cappelleri JC, et al. Hierarchical construct validity of the 
treatment satisfaction questionnaire for medication (TSQM version II) among 
outpatient pharmacy consumers. Value Health 2005;8 Suppl 1:S9-S24. 
 
16. De Angelis, CD., Drazen, JM., Frizelle, FA., Haug, C., Hoey, J., Horton, R. et al. 
Clinical trial registration: a statement from the International Committee of Medical 
Journal Editors. J Am Acad Dermatol 292(11):1363-4, 2004. 
 
17. De Angelis, CD. Is this clinical trial fully registered? A statement from the 
International Committee of Medical Journal Editors, available from: 
http://www.icmje.org/clin_trialup.htm. 
 
18. Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial 
Registries and Databases, available from: 
http://clinicaltrials.ifpma.org/clinicaltrials/fileadmin/files/pdfs/EN/November_10_2 
009_Updated_Joint_Position_on_the_Disclosure_of_Clinical_Trial_Information_vi 
a_Clinical_Trial_Registries_and_Databases.pdf 
 
19. Wong, R., Tran, V., Morhenn, V., Hung, SP., Anderson, B., Ito, E., Hatfield, GW., 
Benson, NR. Use of RT-PCR and DNA Microarrays to characterize RNA recovered 
by non-invasive tape harvesting of normal and inflamed skin. 
J.Invest.Dermatol.123:159-167, 2004. 


 
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20. Benson, NR., Papenfuss, J., Wong, R., Motaal, A., Tran, V., Panko, J., Krueger, GG. 
An analysis of select pathogenic messages in lesional and non-lesional psoriatic 
skin using non-invasive tape harvesting. J.Invest.Dermatol. 2006, 126:2234-2241. 


 
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24 List of Appendices 
Appendix 1: Protocol Summary 
 
Appendix 2: Tape lifting procedure and biomarker analyses 
Appendix 3: Skin photography 
Appendix 4: Microbiome collection and profile analysis 
Appendix 5: Subject Global Cosmetic Score 
Appendix 6: Local Skin Response Grading Scale 
 
Appendix 7: Definitions of Adverse Events and Serious Adverse Events 
Appendix 8: Classification of Adverse Events 
Appendix 9: Contact list of LEO, protocol authors, vendors, trial committees and coordinating 
investigators 
 
Appendix 10: Identifying and Documenting the Treatment Area 
Appendix 11: Acne QoL 
Appendix 12: TSQM II 


 
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25 Appendix 1: Protocol Summary 
 
Name of finished/ 
investigational 
product 
LEO 43204 gel 0.018% 
Name of active 
substance 
LEO 43204 
Title of trial/trial 
ID/ 
Explorative trial evaluating the efficacy, tolerability and safety of LEO 
43204 applied in a split-face (left/right) topical design in adults with 
moderate to severe acne / EXP-1223 
International 
Coordinating 
Investigator 
Hala Koudsi, M.D. 
Sponsor’s name/ 
address 
LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark 
Estimated 
number of trial 
sites and 
distribution 
Single site in USA 
Trial period 
Planned date of enrolment of first subject: Q2-2016 
Planned date of completion of last subject: Q4-2016 
Main objective(s) To assess the efficacy of treatment with LEO 43204 gel and vehicle gel 
on acne vulgaris disease severity 12 weeks after end of treatment. 
Treatment is defined as once daily application of LEO 43204 gel and 
vehicle gel for up to 3 days 
Methodology 
Phase 2a, Single centre, prospective, randomised, vehicle-controlled, 
double-blinded, split-face (left/right) design trial 
Number of 
subjects to be 
enrolled 
Planned to enroll 40 subjects 
Planned to complete 30 subjects 
Main criteria for 
inclusion 
• Subjects should be diagnosed with moderate to severe acne vulgaris 
of the face. 
• Fitzpatrick skin types I-III (due to lack of safety data for the 
investigational product in darker skin types) 
• Lesions should be relatively symmetrical in appearance on both sides 
of the face (asymmetrical disposition of acne lesions defined as: the 
number of acne lesions on any hemiface is greater than twice the 
number on the other hemiface for either inflammatory or non- 
inflammatory lesions). 
• Male or female aged 18 to 35 years inclusive. 


 
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Main criteria for 
exclusion 
• Subjects with nodulocystic acne, acne conglobata, acne fulminans, 
secondary acne (e.g. chlor-acne, drug-induced acne). 
• Fitzpatrick skin types IV-VI Subjects in whom the investigator 
would recommend systemic therapy to prevent risk of scarring due to 
current disease severity of acne vulgaris. 
• Subjects with excessive facial hair, facial skin disorders or skin 
reactions that may interfere with trial assessments (including but not 
limited to, actinic keratosis, eczema, psoriasis, seborrheic dermatitis, 
rosacea, acute or recent sunburn). 
• Known sensitivity or allergy to any of the ingredients in the vehicle 
gel or IP. 
• Current participation in any other interventional clinical trial 
orpreviously enrolled in an interventional clinical trial which in the 
opinion of the investigator may interfere with the interpretation of 
the trial results. 
• Female subjects who are pregnant, of child-bearing potential and 
who wish to become pregnant during the trial, or who are breast 
feeding. 
Prohibited Therapies and/or Medications within 6 Month prior to Day 1 
(Visit 2). 
1. Treatment with systemic retinoids 
Prohibited Therapies and/or Medications within 1 month prior to Day 1 
(Visit 2). 
2. Treatment of the face with topical retinoids 
3. Treatment with systemic antibiotics 
4. Treatment in the face with ultraviolet light A (UVA) or ultraviolet 
light B (UVB) or intensive solar exposure. 
5. Treatment in the face with light chemical peel 
6. Treatment with systemic medications that suppress the immune 
system (e.g. cyclosporine, prednisolone). 
Prohibited Therapies and/or Medications within 2 weeks prior to Day 1 
(Visit 2). 
7. Treatment within 5 cm from the treatment area with topical drugs 


 
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or cosmetics containing benzoyl peroxide, antibiotics, 
keratinolytic agents such as alpha- and beta- hydroxy acids, 
including glycolic acid, lactic acid and other fruit acids, salicylic 
acid, urea, soaps containing antibacterial agents such as skin 
fresheners/astringents or aftershave products) 
Investigational 
product(s) 
LEO 43204 gel 0.018%. 
Each visit kit should contain 1 tube with active gel and 1 tube with 
vehicle gel, to be handled in the hospital clinic on Day 1, Day 2 and Day 
3, respectively. The label on the tubes will be colored as green to be 
applied on the right side of the face and red to be applied on the left side 
of the face. 
Investigational 
reference 
product(s) 
Vehicle gel. Each kit will be generic and the site personnel will add the 
randomisation number when assigned to the subject. Each kit contains 2 
unit-dose tubes for topical administration 
Duration of 
treatment 
Treatment for up to 3 consecutive days with a follow-up period of 12 
Weeks 
Main assessments Acne lesion (non-inflammatory and inflammatory lesions) counts in 
treatment areas 
Investigator Global Assessment of acne severity in treatment areas 
Tolerability, safety and Local Skin Responses 
Acne related quality of life and treatment satisfaction questionnaires 
Primary endpoint Count of total (inflammatory and non-inflammatory) lesions in the 
treatment area at Week 12. 
Secondary 
endpoint(s) 
Count of inflammatory lesions in the treatment area at Week 12. 
Count of non-inflammatory lesions in the treatment area at Week 12. 
Investigator’s Global Assessment of the treatment area at Week 12. 
Statistical 
methods 
Lesion count will be analysed by a ANCOVA model with treatment, site 
and baseline count of total lesions as fixed effects and subject as random 
effect. Comparison between active and vehicle gel will be done by 
means of a t-test on the estimated treatment contrast in the model. 
Investigator Global Assessment will be analysed by descriptive statistics 
of disease severity by treatment and at Week 12. Desriptive statistics will 
show frequencies for each score. 
For submission to IEC/IRBs and/or regulatory authorities, attach schedule of trial procedures 
(Section 8.1) 


 
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26 Appendix 2: Tape lifting procedure and biomarker analyses 
Tape lifting procedure: 
 
Skin contents will be collected from the subjects as described in 8.1Schedule of Trial 
Procedures for inflammatory marker analysis, using D-squame Stripping Discs (CuDerm, 
Dallas, TX). Apply the tape strip to the treatment area, smooth side down, pressing down to 
ensure good contact with skin. Slowly and carefully peel off starting at edges, pulling toward 
center and place the strip immediately in an Eppendorf tube for storage until analysis. For 
further details refer to the Lab Manual. 
 
Biomarker analyses 
 
Expression of inflammatory mediators such as, but not limited to, IL-1, IL-6, IL-8, IL-10 and 
TNF-α will be analyzed from tape strips sampled from the treatment areas. We hypothesize 
that treatment with ingenol mebutate may modulate the levels of pro-inflammatory mediators, 
including IL-1, TNF-α and IL-8. Recently, a non-invasive method of detecting changes in 
cytokine expression in skin has been demonstrated (19). Using a similar technique, we will 
compare the changes in expression of inflammatory mediators before and after topical 
application of LEO 43204 gel or vehicle gel as one of the exploratory endpoints. Skin samples 
will be collected using a tape stripping method as described previously in a psoriasis trial 
(20). Samples will be used to isolate RNA and mRNA expression of inflammatory mediators 
will be determined by real-time PCR using the Fluidigm Platform at AROS Applied 
Biotechnology A/S, Denmark For details, see Lab Manual. 


 
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27 Appendix 3: Skin photography 
Using a standard digital camera three photographs (left side, frontal, right side) will be taken 
of the face .Exposure and distance will be controlled to provide optimal images. The site staff 
will be trained in using the camera. 
 
Images should be obtained prior to samplings for biomarkers and microbiome analyses. 
 
Images will be uploaded from the clinical site to Canfield Scientific, Inc. (253 Passaic 
Avenue, Fairfield, NJ) for quality control and de-identification. 


 
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28 Appendix 4: Microbiome collection and profile analysis 
Microbiome collection 
 
Skin contents for microbiome analyses will be collected from the subjects as described in 
8.1Schedule of Trial Procedures. The collection swab (CatchAll®Sample Collection Swab, 
Epicenter) is moistened and the treatment area is swabbed for 30s rubbing the swab back and 
forth about 50 times applying firm pressure. The swab is then stored until microbiome 
analysis. Details on collection and storage are described in the Lab Manual. 
 
Microbiome profile analysisDNA will be extracted using the MoBio UltraClean Microbial 
DNA isolation kit. Microbial sequencing will be performed on the Illumina MiSeq next 
generation sequencing platform at the UCLA Sequencing and Genotyping Core Laboratory as 
per protocol, refer to the Lab Manual. 


 
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29 Appendix 5: Subject Global Cosmetic Score 
Subject Self-assessment Questionnaire for Global Cosmetic Score 
In each row below, please check the box that most closely matches your judgement of how 
your skin looks and feels today compared to before you were treated with the trial drug in this 
clinical trial. 
Right side 
Much worsened 
Somewhat 
worsened 
No change 
Somewhat 
improved 
Much improved 
Overall 
appearance of the 
treatment areas 
Overall feel of the 
treatment areas 
 
 
Left side 
Much worsened 
Somewhat 
worsened 
No change 
Somewhat 
improved 
Much improved 
Overall 
appearance of the 
treatment areas 
Overall feel of the 
treatment areas 


 
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30 Appendix 6: Local Skin Response Grading Scale 
 


 
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31 Appendix 7: Definitions of Adverse Events and Serious Adverse Events 
31.1 Adverse Event Definition 
An adverse event is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An adverse event (AE) can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) product. (ICH Harmonized Tripartite 
Guideline for Good Clinical Practice, E6 (R1)). 
 
This definition includes: 
 
• accidental injuries, events related to trial procedures, reasons for any unfavourable and 
unplanned change in medication (drug and/or dose), clinically significant worsening of 
pre-existing conditions, or reasons for admission to hospital or surgical procedures unless 
these were planned before enrolment. It also includes AEs commonly observed and AEs 
anticipated based on the pharmacological effect of the investigational product. In addition, 
any laboratory abnormality assessed as clinically significant by the (sub)investigator must 
be recorded as an AE. 
31.2 Serious Adverse Event Definition 
A serious adverse event (SAE) is any untoward medical occurrence that 
 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation. Planned 
hospitalisation or planned prolonged hospitalisation do not fulfill the criteria for being an 
SAE but should be documented in the subject’s medical record. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
or 


 
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• is a medically important condition. Events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples 
are intensive treatment in an emergency room or at home for allergic broncospasm, blood 
dyscrasias and convulsions that do not result in hospitalization, development of drug 
dependency or drug abuse. 


 
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32 Appendix 8: Classification of Adverse Events 
32.1 Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the (sub)investigator’s clinical judgement. 
 
Mild 
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
Moderate 
An adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm 
to the subject. 
Severe 
An adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
If the severity of an AE worsens, a new AE should be recorded. 


 
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32.2 Causality 
The causal relation of the AE to the use of the investigational product should be described in 
terms of probable, possible or not related according to the following: 
 
Probably 
related 
Follows a reasonable temporal sequence from administration of the 
investigational product. 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the subject. 
Follows a known pattern of response to the investigational product. 
Disappears or decreases on cessation or reduction in dose of the 
investigational product. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
Follows a reasonable temporal sequence from the administration of the 
investigational product. 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the subject. 
Follows a known pattern of response to the investigational product. 
Not related 
Does not follow a reasonable temporal sequence from administration of the 
investigational product. 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the subject. 
Does not reappear or worsen upon re-challenge. 
Does not follow a known pattern of response to the investigational product. 


 
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32.3 Outcome 
The outcome of the event should be classified and handled as follows: 
 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved. 
Not 
recovered/ 
not resolved 
Event is still ongoing. 
Recovered 
with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to (sub)investigator, e.g. subject lost to follow-up. 


 
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33 Appendix 9: Contact list of LEO, protocol authors, vendors, trial 
committees and coordinating investigators 
Contact details for the international clinical trial manager (ICTM), national lead CRA 
(NLCRA), medical expert and safety scientist/safety physician are provided to participating 
trial sites outside the protocol on a list of LEO representatives which is included in clinical 
trial applications. 
 
Sponsor 
 
LEO Pharma A/S (referred to as ‘LEO’ in this clinical trial protocol) is the sponsor of the 
clinical trial: 
 
LEO Pharma A/S 
Industriparken 55 
DK-Ballerup 
 
Protocol Author(s) 
 
Hala Koudsi, MD, International Coordinating Investigator 
PPD 
, MD, Ph.D, UCLA 
PPD 
, ICTM, LEO Pharma A/S 
PPD 
, MD, Senior Scientist, LEO Pharma A/S 
PPD 
 , Senior Scientist, LEO Pharma A/S 
PPD 
  
, Biostatistician, LEO Pharma A/S 
PPD 
, MSc Pharm., PV Advisor, LEO Pharma A/S 
PPD 
, Medical Writer, LEO Pharma A/S 
 
 
Trial Committees 
 
Safety Review Committee members 
 
Hala Koudsi, MD, International Coordinating Investigator, Torrance Clinical Research 
Institute Inc., 25043 Narbonne Ave., Lomita, CA 90707, USA 
PPD 
, MD, Medical Expert LEO Pharma A/S, Industriparken 55, 2750 Ballerup, 
Denmark, Tel.: +45 PPD 
, email: PPD 
@ leo-pharma.com 


 
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PPD 
PPD 
 
PPD 
, MD, Head of Department, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: +45 PPD 
, email: PPD 
@leo-pharma.com 
PPD 
, PV Scientist, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, 
Denmark, Tel.: +45 PPD 
, email: PPD 
@leo-pharma.com 
PPD 
, Biostatistics, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, 
Denmark, Tel.: +45 PPD 
, email: PPD @leo-pharma.com 
PPD 
, ICTM, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark, 
Tel.: +45 PPD  
, email: PPD 
@leo-pharma.com 
 
 
Contract Research Organisations (CROs)/vendors 
 
, 
 
 
PPD , 
will be responsible for providing a portal to upload, de-identify and store digital photographs 
of treatment areas in the faces of the trial subjects , as agreed to in a Service 
Agreement/Contract 
 
, 
, 
, 
will be responsible for providing electronic data capture and IWRS 
services as agreed to in a Service Agreement/Contract. 
 
 
 
for analyzing of the Microbiome 
 
PPD 
 
 
, PPD 
 
 
, PPD 
will be responsible 
 
 
, PPD 
will be responsible for analyzing of the Biomarkers 
PPD 
PPD 
PPD 
PPD 
, PPD 
, 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 


 
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34 Appendix 10: Identifying and Documenting the Treatment Area 
Identifying and Documenting the Treatment Area 
 
On each cheek of enrolled subjects representative areas of approximately 36 cm2 (6cm ×6 cm) 
are selected as treatment areas by the investigator. 
 
These TAs area will be documented using a ‘3-point landmark technique’ on the study 
transparencies. 
 
Instructions are provided below. Transparencies and markers will be provided to the trial sites. 
Three point landmark technique for each study transparency: 
1. Complete information on the transparency using a permanent marker. 
2. Place the transparency over the treatment area and cut a hole for the nose. 
3. Map and label at least 3 anatomical landmarks on the transparency which are in the 
vicinity of the treatment area. These landmarks should not change during the trial (e.g., 
scars, moles, birthmarks, bony landmarks, etc.) 
4. Mark the outline of the treatment area on the provided transparency. 
5. Use the transparency to re-locate the treatment area for subsequent trial visits. When 
realigning the transparency, use the documented anatomical landmarks to accurately 
duplicate transparency placement. 
6. Retain the transparency as part of the subject’s source documents. 


 
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35 Appendix 11: Acne QoL 
 
Acne-Specific Quality of Life Questionnaire (Acne-QoL) 
 
(Please check one box for each question) 
 
 
1 In the past WEEK, how unattra ctive did you feel because of your facial acne? 
extremely 
very much 
quite a bit 
a good bit 
somewhat 
a little bit not at all 







2 In the past WEEK, how embarrassed did you feel because of your facial acne? 
extremely 
very much 
quite a bit 
a good bit 
somewhat 
a little bit not at all 







 
 
3 
 
Extremely 
very much quite a bit 
a good bit 
somewhat 
a little bit 
not at all 
 
 
 
 
 
extremely 
very much 
quite a bit 
a good bit 
somewhat 
 
 
 

a little 
bit 

not at 
all 





5. 
In the past WEEK, how annoyed did you feel at having to spend time every day 
cleaning and treating your face because of your facial acne? 
extremely 
very much 
quite a bit 
a good bit 
somewhat 
a little bit not at all 







6. 
In the past WEEK, how dissatisfied with your self-appearance did you feel 
because of your facial acne? 
extremely 
very much 
quite a bit 
a good bit 
somewhat 
a little bit not at all 







4 In the past WEEK, how upset were you about having facial 
. 
In the past WEEK, how self-conscious (uneasy about oneself) did you feel 
about your facial acne? 
 
 







 
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7. 
In the past WEEK, how concerned or worried were you about not looking your best 
because of your facial acne? 
extremely 

very much 

quite a bit 

a good bit 
not at all 

somewhat 

a little bit 

8. In the past WEEK, how concerned or worried were you that your acne medication/products 
were working fast enough in clearing up the acne on your face? 
extremely 

very much 

quite a bit 

a good bit 
not at all 

somewhat 

a little bit 

9. 
In the past WEEK, how bothered did you feel about the need to always have 
medication or cover-up available for the acne on your face? 
extremely 

very much 

quite a bit 

a good bit 
not at all 

somewhat 

a little bit 

10. 
In the past WEEK, how much was your self-confidence (sure of yourself) negatively 
affected because of your facial acne? 
extremely 

very much 

quite a bit 

a good bit 
not at all 

somewhat 

a little bit 

11. 
In the past WEEK, how concerned or worried were you about meeting new people 
because of your facial acne? 
extremely 

very much 

quite a bit 

a good bit 
not at all 

somewhat 

a little bit 

12. 
In the past WEEK, how concerned or worried were you about going out in public 
because of your facial acne? 
extremely 

very much 

quite a bit 

a good bit 
not at all 

somewhat 

a little bit 



 
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13. 
In the past WEEK, how much was socializing with people a problem for you because 
of your facial acne? 
extremely 
very much 
quite a bit 
a good bit 
somewhat 
a little bit not 
at all 





 
 
extremely 
very much 
quite a bit 
a good bit  somewhat a little bit 
not 
at all 
 
 
 
 
  


15. 
In the past WEEK, how many bumps did you have on your face? 
Extensive 
A whole 
A lot 
A moderate 
Some 
Very Few 
N 

lot 


amount 



o 
16. 
In the past WEEK, how many bumps full of pus did you have on your face? 
Extensive 
A whole 
A lot 
A moderate 
Some 
Very 
Few 
None lot 
amount 




 
17. 
In the past WEEK, how much scabbing from your facial acne did you have? 
Extensive 
A whole 
A lot 
A moderate 
Some 
Very 
Few 
None lot 
amount 




 


extremely 
very much 
quite a bit 
a good bit somewhat a little bit not at all 
 
 
 
 
 
 



19. 
In the past WEEK, how oily was your facial skin? 
extremely 
very much 
quite a bit 
a good bit 
somewhat 
a little bit not at all 
 
 
 


 

In the past WEEK, how much was interacting with the opposite sex (or same 
sex if gay or lesbian) a problem for you because of your facial acne? 
14. 
18. 
In the past WEEK, how concerned or worried were you about scarring from 
your facial acne? 


 
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


36Appendix 12: TSQM II 
A derived score for each of the four dimensions of the TSQM (effectiveness, side effects, 
convenience, global satisfaction) will be calculated for each subject. For each of the TSQM 
dimensions the derived score will be summarised using the mean, SD, median, minimum and 
maximum values at week 12 for each treatment group. 
 
TSQM (Version II): Treatment Satisfaction Questionnaire for Medication 
 
1. How satisfied or dissatisfied are you with the ability of the medication to prevent or treat 
the condition? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
 
 
2. How satisfied or dissatisfied are you with the way the medication relieves symptoms? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
 
 
3. As a result of taking this medication, do you experience any side effects at all? 
1. Yes 
2. No 


 
EXP-1223 
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4. How dissatisfied are you by side effects that interfere with your physical health and ability 
to function (e.g., strength, energy levels)? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Somewhat Dissatisfied 
4. Slightly Dissatisfied 
5. Not at all Dissatisfied 
 
 
5. How dissatisfied are you by side effects that interfere with your mental function (e.g., 
ability to think clearly, stay awake)? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Somewhat Dissatisfied 
4. Slightly Dissatisfied 
5. Not at all Dissatisfied 
 
 
6. How dissatisfied are you by side effects that interfere with your mood or emotions (e.g., 
anxiety/fear, sadness, irritation/anger)? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Somewhat Dissatisfied 
4. Slightly Dissatisfied 
5. Not at all Dissatisfied 
 
 
7. How satisfied or dissatisfied are you with how easy the medication is to use? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 


 
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8. How satisfied or dissatisfied are you with how easy it is to plan when you will use the 
medication each time? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
 
 
9. How satisfied or dissatisfied are you by how often you are expected to use/take the 
medication? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
 
 
10. How satisfied are you that the good things about this medication outweigh the bad things? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 


 
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11. Taking all things into account, how satisfied or dissatisfied are you with this medication? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 


 
EXP-1223 Consolidated Clinical Trial Protocol 5 15-Sep-2016 - 
English 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Electronic signature made within eDoc LEO by LEO Pharma A/S employees or employees of any LEO 
Pharma A/S affiliate located anywhere in the world, are to be considered to be legally binding 
equivalent of traditional handwritten signatures. 
 
 
 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
PPD 
 
PPD 
  
Head of Tranlsational Medicine 
Approval 
Biostatistics Lead, Biostatistical 
Approval 
15-Sep-2016 16:04 GMT+02 
 
18-Sep-2016 22:26 GMT+02 

SAP_001.pdf: 
Sponsor: Leo Pharma A/S 
EXP-1223 
Date: 19MAY2017 
Statistical Analysis Plan 
Final version 1.0 
 
 
 
 
 
 
 
 
Statistical Analysis Plan Update 
 
 
EXP-1223 
Explorative trial evaluating the efficacy, tolerability and safety of 
LEO 43204 applied in a split-face (left/right) topical design in adults 
with moderate to severe acne 
 
 
 
 
 
 
 
 
 
CRO: 
Sponsor: 
Larix A/S 
Leo Pharma A/S 
Lyskær 8b 
DK-2730 Herlev 
Denmark 
Tel.: +45 70 27 22 21 
Fax: +45 70 27 22 41 
Industriparken 55 
DK-2750 Ballerup 
 
Tel.: +45 44 94 58 88 
Fax: +45 72 26 33 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TMF-000020P2a9g0e-1Vofer9sion 1.0 


Sponsor: Leo Pharma A/S 
EXP-1223 
Date: 19MAY2017 
Statistical Analysis Plan 
Final version 1.0 
 
 
Signature page 
Author: 
Date: 
 
 
 
Signature 
PPD 
, Senior statistician, Larix A/S 
 
 
 
Reviewed and approved by: 
 
Date: 
 
 
 
Signature 
PPD 
, Biostatistic Lead 
Leo Pharma A/S 
 
 
Date: 
 
 
 
Signature 
PPD 
, Senior Director 
Translational Medicine, Medical Science & Safety 
Leo Pharma A/S 


Sponsor: Leo Pharma A/S 
EXP-1223 
Date: 19MAY2017 
Statistical Analysis Plan 
Final version 1.0 
 
 
 
 
Table of Contents 
1 
Abbreviations and definition of Terms ..................................................................................... 4 
2 
Introduction ............................................................................................................................... 4 
3 
Analysis Sets ............................................................................................................................. 4 
4 
Statistical analyses and presentation of data ............................................................................. 5 
4.1 
Disposition of subjects ............................................................................................. 5 
4.2 
Demographics and other Baseline Characteristics ................................................... 5 
4.3 
Exposure and treatment compliance ........................................................................ 5 
4.3.1 
Analysis of primary endpoint ...................................................................................... 5 
4.3.2 
Secondary Efficacy Analyses ...................................................................................... 6 
4.4 
Safety ....................................................................................................................... 7 
4.4.1 
Adverse Events ............................................................................................................ 7 
4.4.2 
Other safety endpoints ................................................................................................. 8 
5 
Programming and Quality Control............................................................................................ 8 
6 
Tables, Listings and Figures ..................................................................................................... 8 
7 
Change Log ............................................................................................................................... 9 
 


Sponsor: Leo Pharma A/S 
EXP-1223 
Date: 19MAY2017 
Statistical Analysis Plan 
Final version 1.0 
 
 
1 Abbreviations and definition of Terms 
 
Abbreviations 
Meaning of abbreviations in document 
ADaM 
Analysis Data Model (The data set structure used for analysis data sets when 
following the CDISC consortium) 
ADRG 
Analysis Data Reviewer’s Guide 
CDISC 
Clinical Data Interchange Standards Consortium 
FAS 
Full-Analysis Set 
IMP 
Investigational Medicinal Product 
LOCF 
Last Observation Carried Forward 
OC 
Observed Cases 
PP 
Per-Protocol 
SAP 
Statistical Analysis Plan 
SAPU 
Statistical Analysis Plan Update 
SAS 
Safety Analysis Set 
SDTM 
Standard Data Tabulation Model (The data set structure used for the base data 
sets when following the CDISC consortium) 
 
Terms 
Definitions 
Randomised 
Subject randomised to study treatment 
Screened 
Subject who enters the screening phase 
 
2 Introduction 
 
This SAPU is based on the Larix template for an ordinary SAP. Since Leo Pharma’s standard process is to prepare a 
SAPU instead of a SAP it was decided to also follow that approach for this study and content which is just repeating 
information from the protocol will not be included. 
 
This document expands any necessary details on statistical plans in the protocol if such expansion is needed for a 
complete description. In addition, the document will include all data driven decisions originating from the blind data 
review prior to un-blinding the study. 
 
The SAPU is based on the protocol version 5.0 of 15 September 2016. The protocol version 5.0 includes all changes 
implemented in amendments 1 to 4. 
 
 
3 Analysis Sets 
 
A total of 19 screening failures were seen but not included in the trial. 
In accordance with the design in the protocol a total of 40 subjects were enrolled and randomized as 
Cohort 1: 
3 subjects 
Cohort 2: 
6 subjects 
Cohort 3: 
6 subjects 
Cohort 4: 
25 subjects 
 
3 subjects discontinued before completion: 
 
Subject PPD from cohort 2 was lost to follow up after day 8 
Subject PPD from cohort 4 was lost to follow up after week 4 
Subject PPD from cohort 4 was lost to follow up after week 8 


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Subject PPD from cohort 4 withdrew voluntarily after day 3 (after treatment application) 
Subject PPD from cohort 4 withdrew voluntarily after day 8 
Subject PPD from cohort 4 was lost to follow up after week 4 
 
As planned in the protocol subjects PPD and PPD received 1 and 2 treatment administrations respectively and will not 
be included the FAS. Other subjects with reduced treatment administration were: 
 
Subject 
Number of treatments 
Reason 
PPD 
2 
Subject refused 3rd treatment due to local AE (i.e. intolerable response to 
treatment). 
PPD 
1 
Withdrawal by subject. According to investigator comment subject not 
interested in continuing participation. 
 
These additional 2 subjects with reduced treatment will, as described in the protocol, be included in the FAS. 
The FAS therefore include all 40 randomized subjects except subject PPD and PPD , which gives a total of 38 subjects. 
 
All randomised and exposed subjects will be included in the safety analysis set (SAS). The SAS therefore includes 
40 subjects. 
 
A PP analysis set is defined as all subjects who 
• 
complete the trial 
• 
have no other major protocol deviations deemed to influence the evaluation of efficacy 
 
Subjects PPD , PPD and PPD were treated on day 2 and/or 3 although their LSR indicated they should not have been (see 
further about separate listing on this in the safety section). This was in violation of the protocol, but it is assessed that 
with respect to efficacy evaluation this is not a problem and the subjects are retained in the PP analysis set. 
Inspecting actual visit day versus planned visit day subjects PPD and PPD had week 12 visit outside the protocol 
allowed window of +/- 7 days. The violation was +5 days for subject PPD and +2 days for subject PPD . Other 
noteworthy deviations are: subject PPD +15 days on week 8 visit, subject PPD +11 days on week 8 visit and subject 
PPD +12 days on week 4 visit. Although the last three mentioned deviations are relatively large it was decided at the 
Blind Data Review meeting not to perform visit reallocation or deletion of these data points since this would not 
necessarily improve the modelling of the recorded data and since it would add extra complication. Overall, the PP 
analysis set therefore will consist of all subjects in the FAS who completed the trial. The per protocol analysis set 
thus consists of all subjects except subjects PPD , PPD , PPD , PPD , PPD , PPD , PPD , PPD or a total of 32 subjects. 
 
4 Statistical analyses and presentation of data 
 
4.1 Disposition of subjects 
Subject disposition will be presented as described in the protocol. 
 
4.2 Demographics and other Baseline Characteristics 
Demographics and baseline characteristics will be presented as described in the protocol. Age will be presented both 
as a continuous variable and grouped into 18-20, 21-24, and 25-35 years. 
 
4.3 Exposure and treatment compliance 
Exposure and treatment compliance will be presented as described in the protocol. 
 
4.3.1 
Analysis of primary endpoint 
The analysis of the primary endpoint total lesion count at week 12 will follow the description in the protocol. The 
primary analysis will be based on the FAS analysis set. A sensitivity analysis will include the lateral side of lesion as 


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a covariate. An additional sensitivity analysis will be performed on the PP analysis set. 
 
Furthermore, if there are missing data then the above analyses will be handled with the below multiple imputation 
methods and additionally an LOCF and an OC analysis will be included. 
 
Missing data for total lesion count on day 1 or week 12 will be handled using multiple imputation as described in the 
protocol. The following additional specifications may be given: 
• 
All imputations will be performed by lesion type and treatment group. 
• 
Total lesion will be calculated by suming of inflamed and non-inflamed lesions by simulation 
 
Screening and baseline lession values are very similar. To avoid problems with identifiability in the estimations 
modeling will only be from baseline and forward. 
 
4.3.2 
Secondary Efficacy Analyses 
Additional lesion count presentations will be presented as described in the protocol. 
Investigator’s global assessment will be presented as described in the protocol. 
 
Treatment success derived from IGA will be tabulated and tested by a McNemar’s test. This is a minor deviation 
from the protocol where a Fisher’s Exact test is specified. The change in analysis plan stems from the fact that the 
McNemar’s test is designed for paired observations as is the case in this split-face design. 
 
The inflammatory cytokine expression data will be presented as described in the protocol but will due to timing be 
reported separately from the main CTR. 
 
The analysis of data relating to the microbiome will be specified in a separate analysis plan, 
and the reporting will be done separately. 
 
The subject’s self evaluation of Acne QoL will follow description in the protocol. Item scores will be coded from 0 
to 6 with zero most negative and 6 most positive. Four domains are defined by summing item scores as defined in the 
below table. Missing items will be replaced by the mean of the non-missing data within the same subject, visit and 
domain. If less than 3 items are scored within a domain the domain sum will be missing. 
 
Self Perception 
Role-emotional 
1 
Feel unattractive 
5 
Spending time treating face 
3 
Feel self-concious 
9 
Need to have meds or cover-up available 
10 
Self-confidence affected 
8 
Meds won’t clear face fast enough 
2 
Feel embarrassed 
7 
Not looking your best 
6 
Dissatisfied with self appearance 
4 
Feel upset 
Role-Social 
Acne Symptoms 
12 
Going out in public 
15 
Bumps on face 
11 
Meeting new people 
16 
Bumps full of pus 
14 
Interacting with opposite sex (or same sex if 
gay) a problem 
17 
Scabbing from acne 
13 
Socializing with people a problem 
18 
Concerned with scarring 
19 
Oily skin 
 
 
The subject’s self evaluation of TSQM II will follow description in the protocol. Item scores will be coded from 1 to 
7 with 1as the most negative and 7 as the most positive. Four domains are defined by summing item scores as 
defined in the below table. The domain scores will be scaled from 0 to 100, with 0 as the lowest possible score and 
100 as the highest possible score. For domains with 3 items one item may be missing and then the domain score is 
based on the two non-missing items. For domains with two items both of these must be present for a domain score to 
be calculated. 


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Effectiveness 
Side effects 
1 
How satisfied or dissatisfied are you with the 
ability of the medication to prevent or treat 
the condition? 
4 
How dissatisfied are you by side effects that 
interfere with your physical health and ability 
to function (e.g., strength, energy levels)? 
2 
How satisfied or dissatisfied are you with the way 
the medication relieves symptoms? 
5 
How dissatisfied are you by side effects that 
interfere with your mental function (e.g., 
ability to think clearly, stay awake)? 
6 
How dissatisfied are you by side effects that 
interfere with your mood or emotions (e.g., 
anxiety/fear, sadness, irritation/anger)? 
Convenience 
Global satisfaction 
7 
How satisfied or dissatisfied are you with how 
easy the medication is to use? 
10 
How satisfied are you that the good things about 
this medication outweigh the bad things? 
8 
How satisfied or dissatisfied are you with how 
easy it is to plan when you will use the 
medication each time? 
11 
Taking all things into account, how satisfied or 
dissatisfied are you with this medication? 
9 
How satisfied or dissatisfied are you by how often 
you are expected to use/take the 
medication? 
 
 
 
The subject’s global cosmetic score will be presented as described in the protocol. The following transformation 
from the eCRF categories to numerical ratings will be used: 
 
Category 
Rating 
Much worsened 
0 
Somewhat worsened 
1 
No change 
2 
Somewhat improved 
3 
Much improved 
4 
 
 
4.4 Safety 
Safety parameters will be evaluated for the safety analysis data set. 
 
4.4.1 
Adverse Events 
The treatment emergent adverse events will be tabulated in the following categories: 
• 
Cutaneous 
o 
Outside of treatment area 
o Leo 43204 Gel 0.018% 
o 
Vehicle 
• 
Non-cutaneous 
 
The split between cutaneous and non-cutaneous will be based on the MedDRA preferred term text as follows: 
• 
Cutaneous 
o 
Application site plain 
o 
Application site pruritus 
• 
Non-cutaneous 


Sponsor: Leo Pharma A/S 
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Statistical Analysis Plan 
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o 
Headache 
o 
Nausea 
 
Frequencies, incidences and incidence rates for treatment emergent adverse events will be presented in the following 
tables 
• 
Overall summary table of adverse events 
• 
Adverse events presented by system organ class and preferred term 
• 
Adverse events presented by system organ class and preferred term and severity 
• 
Related adverse events presented by system organ class and preferred term 
All adverse events will be listed split by treatment emergent and non-treatment emergent. Adverse events leading to 
withdrawal or discontinuation of treatment will be listed. 
A listing of unacceptable LSR events, following section 11.3.10 in the protocol, and LSR scores for not administer- 
ing the 2nd or 3rd treatment (table 1 in protocol) will be shown together with reason for no treatment. 
 
4.4.2 
Other safety endpoints 
Vital signs will be presented as described in the protocol. 
 
5 Programming and Quality Control 
 
SDTM data sets are received from the data management provider Novella (formerly TKL). Larix will review the 
SDTMs and inform Novella and Leo of any deficiencies and discrepancies. 
Larix will prepare ADaM data sets, ADRG and define file. ADaM data sets will be QCed by double programming. 
Tables, listings and figures will be independently code reviewed by a qualified programmer (statistician for analysis 
programs) according to Larix SOPs. 
ADaM data sets, tables, listings and figures will be produced by SAS ver. 9.4 following Larix’ SOPs on program- 
ming. 
 
6 Tables, Listings and Figures 
 
The table shells are presented in a separate document. 
 
 
The following figures will be prepared: 
1. Mean and individual lesion count profiles 
2. Plots of mean and individual profiles of composite LSRs by visit and lateral side 
3. Plots of mean and individual profiles of maximum of right and left side composite LSRs by visit 
 
 
All data will be listed by subject, visit and treatment (if relevant). 


Sponsor: Leo Pharma A/S 
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Statistical Analysis Plan 
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7 Change Log 
 
 
 
Edition 
Effective on 
Reason for revision 
1.0 
19MAY2017 
New version 


 
 
 
Signature Page for TMF-000020290 v1.0 
 
 
 
 
Signature Page for TMF-000020290 v1.0 
Management / Lead Approver Verdict(s) 
Name: PPD 
                
Capacity: Biostatistics 
Date of signature: 31-Aug-2017 07:36:20 
GMT+0000 
Approver Verdict(s) 
Name: PPD 
         
Capacity: Quality Control 
Date of signature: 31-Aug-2017 08:22:26 
GMT+0000 
Reason for signing: Approved 
Reason for signing: Approved