A Phase 4 Trial Comparing the Cumulative Incidence of SCC After Treatment With Ingenol Mebutate and Imiquimod for Multiple Actinic Keratoses on Face and Scalp. A Multi-centre, Randomised, Two-arm, Open Label, Active-controlled, Parallel Group, 36-month Trial
Phase: PHASE4
Conditions: Actinic Keratosis (AK)
Sponsor: LEO Pharma

 
 
 
 
 
 
 
Page 1 of 1
 
 
 
Cover Page 
 
 
Official title: Risk of Squamous Cell Carcinoma on Skin Areas Treated With Ingenol Mebutate Gel, 0.015% and 
Imiquimod Cream, 5% 
LEO Pharma number: LP0041-63 
NCT number: NCT01926496 
Date: 13-MAR-2013 
 

Consolidated Clinical Study Protocol 
Risk of Squamous Cell Carcinoma on Skin Areas Treated with  
Ingenol Mebutate Gel, 0.015% and Imiquimod Cream, 5%   
A phase 4 trial comparing the cumulative incidence of SCC after treatment with ingenol 
mebutate and imiquimod for multiple actinic keratoses on face and scalp 
A multi-centre, randomised, two-arm, open label, active-controlled, parallel group, 36-month 
trial 
ICH GCP statement: The clinical trial will be conducted in compliance with the Clinical 
Study Protocol, GCP and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Protocol Code Number: 
LP0041-63
Global Clinical Operations 
Date: 
13-MAR-2013
Version:
FINAL
EudraCT Number: 
2012-003112-31
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1 CLINICAL STUDY PROTOCOL APPROVAL/ACKNOWLEDGE 
1.1 APPROVAL STATEMENT LEO PHARMA A/S 
On behalf of LEO Pharma A/S, only the head of Medical Department and the head of 
Biostatistics and Data Management are authorised to approve the Clinical Study Protocol and 
Consolidated Clinical Study Protocol(s) comprising any subsequent amendment(s). 
The following persons have approved this Clinical Study Protocol using electronic signatures 
as presented on the last page of this document: 
 
Head of Biostatistics and Data Management 
 
Head of Medical Department 
1.2 APPROVAL STATEMENT INTERNATIONAL CO-ORDINATING 
INVESTIGATOR 
It is the responsibility of the international co-ordinating investigator to approve the Clinical 
Study Protocol and Consolidated Clinical Study Protocol(s) comprising any subsequent 
amendment(s). 
The following person has approved this Clinical Study Protocol by manually signing the 
International Co-ordinating Investigator Clinical Study Protocol Approval Form adjoined as a 
separate page to this document: 
Prof Rolf Markus Szeimies 
International co-ordinating investigator 
1.3 ACKNOWLEDGE STATEMENT INVESTIGATOR(S) 
Each participating investigator must agree to the approved Clinical Study Protocol and 
Consolidated Clinical Study Protocol(s) comprising any subsequent amendment(s) by signing 
the Investigator (Consolidated) Clinical Study Protocol Agreement Form.  
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2 PROTOCOL STATEMENT 
2.1 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This Clinical Study Protocol is designed to comply with the guideline produced by the 
International Conference on Harmonisation (ICH) on the topic Good Clinical Practice (GCP) 
as well as other relevant guidelines issued by ICH, primarily the efficacy guidelines. 
3 PROTOCOL SYNOPSIS 
Name of finished/ 
investigational product: 
Ingenol mebutate gel, 0.015% 
Name of active substance: 
Ingenol mebutate 
Title of trial/ 
protocol code number: 
Risk of Squamous Cell Carcinoma on skin areas treated 
with  Ingenol Mebutate Gel, 0.015% and Imiquimod 
Cream 5% 
LP0041-63 
Co-ordinating  
investigator(s): 
International-co-ordinating investigator:  Prof Rolf 
Markus Szeimies, Germany 
National co-ordinating investigators will be appointed in 
each participating country. 
Estimated number of trial  
sites and distribution: 
Approximately 17 sites in France, 15 sites in Germany 
and 16 sites in the United Kingdom 
Trial period: 
First subject first visit planned Q2 2013 
Last subject last visit planned Q2 2018 
Main objective(s): 
Primary Objective: 
To compare the cumulative incidence of squamous cell 
carcinoma (SCC) after treatment with ingenol mebutate 
gel and imiquimod cream. 
Secondary Objectives 
To compare the cumulative incidence of neoplasia and the 
short-term and 12-month efficacy of ingenol mebutate gel 
with imiquimod cream. 
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Methodology: 
This is a phase 4, multi-centre, randomised, two-arm, 
open label, active-controlled, parallel group, 36-month 
trial.  
All subjects who qualify for inclusion in this trial are to 
have 5 to 9 clinically typical, visible and discrete actinic 
keratosis (AK) lesions (confirmed by histopathology of 
one of the AKs prior to randomisation) within a contigu-
ous 25 cm2 treatment area on the face or scalp. This area 
of skin will be referred to as the ‘selected treatment area’. 
Subjects will be randomised in a 1:1 ratio to the following 
treatment arms: 
•
Arm A: Ingenol mebutate gel 0.015% applied daily
for 3 consecutive days to the selected treatment area
followed by 8 weeks’ rest. Retreatment for another 3
consecutive days if the treatment field is not com-
pletely cleared of AKs at Week 8
•
Arm B: Imiquimod 5% cream applied 3 days per
week for 4 weeks to the selected treatment area fol-
lowed by 4 weeks’ rest. Retreatment for 4 weeks if
the treatment field is not completely cleared of AKs
at Week 8.
Study visits will take place at Screening (Visit 1), during 
the treatment period on Days 1 and 4, Weeks 2, 4 and 8 
(Visits 2 to 6) for initial treatment and, if retreatment is 
required, on Week 8+3 days and Weeks 10, 12, and 16 
(Visits 7 to 10). During the Follow-up period visits will 
take place at Week 20 and Months 12, 18, 24, 30 and 36 
(Visits 11 to 16).  
At the Screening (Visit 1) subjects will sign the study-
specific consent form in the presence of the 
(Sub)investigator and subject’s eligibility will be checked 
and the selected treatment area will be identified. A 3-4 
mm punch biopsy will be taken of one AK lesion in the 
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selected treatment area for histological confirmation of 
AK. 
Treatment Period (Day 1 to Week 16) 
At Day 1 (Visit 2), the subject eligibility will be con-
firmed and subjects will be randomised to treatment with 
either ingenol mebutate gel or imiquimod cream. The 
selected treatment area will be marked on the skin and the 
first dose will be applied under the supervision and 
management of the trial personnel. Subsequent doses will 
be applied at home. At the next visits (Day 4 and Weeks 2 
and 4; Visits 3 to 5) a clinical assessment of neoplasia in 
the selected treatment area will be performed. If there is 
suspicion of SCC, basal cell carcinoma (BCC), or other 
neoplasia when clinical assessment is performed, a 3-4mm 
punch biopsy will be taken and trial treatment will be 
stopped but the subject will remain in the trial. The 
selected treatment area will be assessed for local skin 
responses (LSRs) and any adverse events (AEs).  At Week 
8 (Visit 6), a clinical assessment of the selected treatment 
area will be performed as for previous visits. An AK 
count in the selected treatment area will also be con-
ducted.  
At Week 8, subjects who are completely cleared in the 
selected treatment area will continue into the Follow-up 
Period. Subjects, who are not completely cleared in the 
selected treatment area will have a second treatment cycle 
and will attend visits at Week 8+3 days and Weeks 10, 12, 
and 16 (Visits 7 to 10). The assessments will be the same 
as during the first treatment cycle. After the second 
treatment cycle (Week 16) subjects will enter the Follow-
up Period.  
Until the first visit of the follow-up period (Week 20), no 
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other treatments and procedures are allowed in, and within 
5 cm of the selected treatment area. Outside the selected 
treatment area (up to within 5 cm), procedures such as 
cryotherapy will be allowed; field therapy (e.g. imiqui-
mod) will not be allowed. 
Follow-up Period (Visits from Week 20 to Month 36).  
Visits will be performed at Week 20 and Months 12, 18, 
24, 30 and 36 (Visits 11 to16), at which a clinical 
assessment of neoplasia in the selected treatment area will 
be performed. If there is suspicion of SCC, BCC, or other 
neoplasia when clinical assessment is performed, a 3-4mm 
punch biopsy will be taken. An AK count in the selected 
treatment area will be conducted.  
From Week 20 until Month 36 procedures such as 
cryotherapy will be allowed in, and within 5 cm of the 
selected treatment area. Further, at the discretion of the 
Investigator and according to nationally available product 
and treatment guidelines, the same treatment as originally 
administered is allowed (imiquimod or ingenol mebutate). 
Cross-over between imiquimod and ingenol mebutate is 
not allowed. Investigators will be encouraged to pursue 
these treatment options where clinically relevant before 
employing other treatments. 
Outside the selected treatment area (up to within 5 cm) all 
treatments will be allowed, although investigators will be 
encouraged to avoid cross-over between imiquimod and 
ingenol mebutate.  
Unscheduled/Early Termination 
Upon completion of the last visit or during the study, an 
unscheduled visit may be required for any subject with a 
severe reaction, suspected pregnancy or an unresolved 
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treatment-related AE or LSR (Local Skin Responses), if 
deemed clinically significant by the investigator. Only 
assessments that require follow-up will be conducted if 
the subject is continuing in the trial. For early termination 
all trial assessments scheduled should be performed.  
Number of subjects  
entered: 
A total of 480 subjects will be enrolled in the trial and 
randomised in a 1:1 ratio to the two treatment groups. 
With 240 patients in each treatment group an adequate 
precision of the 3-year incidence rate can be obtained. 
Assuming a 3-year rate of 1.0%, the upper 95% confi-
dence limit will on average be 2.26%, and assuming a 
2.5% rate, the upper 95% confidence limit will on average 
be 4.48%, 
Main criteria for inclusion: 
1. Following verbal and written information about the
trial, subject must provide informed consent docu-
mented by signing the Informed Consent Form (ICF)
prior to any trial-related procedures
2. Subjects with 5 to 9 clinically typical, visible and
discrete AKs within a contiguous 25 cm2 treatment
area on the face or scalp. Actinic keratosis should be
confirmed by histopathology of one of the AKs prior
to randomisation
3. Subject at least 18 years of age.
Main criteria for exclusion: 
1. Location of the selected treatment area:
•
on the periorbital skin
•
on the perioral skin/around the nostrils
•
within 5 cm of an incompletely healed wound
•
within 10 cm of a suspected BCC or SCC or other
neoplasia
2. Selected treatment area lesions that have atypical
clinical appearance (e.g., hypertrophic, hyperkeratotic
or cutaneous horn)
3. History of SCC, BCC, malignant melanoma or other
neoplasia in the selected treatment area
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4. History or evidence of skin conditions other than the
trial indication that would interfere with evaluation of
the trial medication in the selected treatment area (e.g.,
eczema, unstable psoriasis, xeroderma pigmentosum)
5. Use of ingenol mebutate and/or imiquimod in and
within 5 cm of the selected treatment area within 2
years prior to Screening (Visit 1).
Investigational product: 
Ingenol mebutate gel, 0.015%, supplied in a kit of 3 single 
use, unit dose tubes for topical application. 
Reference product: 
Imiquimod 5% cream supplied in a kit of 12 single use, 
unit dose sachets for topical application 
Duration of treatment: 
Each subject will receive a maximum of 2 treatment 
cycles during the treatment period (Day 1 to Week 16). 
The Follow-up period will start at Week 16 and continue 
until Month 36. Each subject will attend a minimum of 12 
visits (16 visits if a second treatment cycle is required). 
Planned duration: 
•
Treatment period: 16 weeks including an Initial
Treatment Cycle of 8 weeks and a Second Treatment
Cycle of 8 weeks (only given when AKs are observed
after completion of the First Treatment Cycle).
•
Follow-up Period: up to 32 months (from Week 16 to
Month 36)
Assessments: 
Identification of the selected treatment area and derma-
tologic assessments of the selected treatment area must be 
performed by a dermatologist (board-certified or equiva-
lent). The same dermatologist should attempt to perform 
all dermatologic examinations of each individual subject. 
Investigator assessment 
Identification of the selected treatment area 
Identification of the selected treatment area and documen-
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tation on a study transparency using a three-point 
landmark technique (See Appendix IV). 
Biopsy and histological confirmation of one AK lesion 
prior to randomisation. 
Clinical assessment of the selected treatment area 
Clinical assessment of the selected treatment area. Biopsy 
if there is suspicion of SCC or other neoplasia. All visits. 
 Local skin responses 
At all visits from baseline up to Week 20, assessments of 
LSRs in the selected treatment area using the LSR 
Grading Scale (See Appendix III).  
AK lesion count 
Recording of the number of clinically visible AK lesions 
identified in the selected treatment area on Day 1, Weeks 
8, 16 (if retreated), and 20, and Months 12, 18, 24, 30 and 
36. 
Adverse events 
Recording of the adverse events at all visits. Adverse 
events to be reported during the different phases of the 
trial are detailed in section 10.7.5.1. 
Laboratory assessment: 
- Biopsy and histological confirmation of one AK lesion
prior to randomisation.
- Biopsy if there is suspicion of SCC or other neoplasia.
All visits.
Primary end point/ 
response criterion: 
Diagnosis of SCC (defined as invasive SCC i.e. excludes
SCC in situ) in treatment field across the 3-year trial
period.
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Secondary end point/ 
response criterion: 
1.
Diagnosis of SCC and other neoplasia in the treat-
ment field over a 3-year period.
2.
Complete clearance after the last treatment cycle (at
Week 8 or 16)
3.
Partial (at least 75%) clearance after the last treatment
cycle (at Week 8 or 16)
4.
Complete clearance at 12 months, defined as no AKs
at any time in the selected treatment area at any time
from the last treatment cycle at Week 8 or 16 through
to Month 12.
Safety evaluation: 
Incidence of Local Skin Responses (LSRs) 
Incidence of adverse events (AEs) 
Incidence of serious adverse events (SAEs) 
Statistical methods: 
Analysis of Primary Endpoint 
The 3-year cumulative incidence will be calculated for 
each treatment group using methods of survival analysis 
for estimation of cumulative incidence in the presence of 
censored time-to-event data. Annual incidence rates will 
also be presented for each group. The cumulative 
incidence rates will be presented for the event of SCC as 
primary endpoint and for SCC and other neoplasia as 
secondary. No formal test comparing the two arms will be 
performed. For descriptive purposes, as an additional 
analysis, the difference in cumulative incidence rates 
between the two arms will be estimated and presented 
together with its confidence interval. 
Analysis of Secondary Endpoints 
Complete clearance and partial clearance will be esti-
mated and compared between treatment groups using the 
Cochran–Mantel–Haenszel test. 
Adverse Events 
The primary analysis will be performed on adverse events 
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occurring within initial treatment cycle, i.e. within 8 
weeks of the start of treatment. 
Local Skin Responses 
The incidence and grade of LSRs will be summarised by 
treatment arm overall at each visit and by anatomical 
location (face/scalp). Local skin response grades will be 
summarised by frequency counts and descriptive statistics 
by treatment arm for each of the six individual LSRs: 
erythema, flaking/scaling, crusting, swelling, vesicula-
tion/pustulation, and erosion/ulceration. 
An interim analysis of trial data, obtained when approxi-
mately half of the trial period has elapsed, will be 
conducted (approximately 3 years after study start). The 
interim analysis will not impact the conduct of this trial. 
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3.1 SCHEDULE/CHART OF TRIAL PROCEDURES 
3.1.1 Screening and Treatment Period 
Screening
Treatment Period
Visit Number
1
2
3
4
5
6
7¹
8¹
9¹
10¹
Day/Week
(window)
(-42 to 
-14 days)
Day 
1
Day 
4 
(+2 
days)
Week 
2 
Day 
15 
 (±2 
days)
Week 
4 
Day 
29
(± 3 
days)
Week 
8 
Day 
57 
(±3 
days)
3 days 
after 
Visit 6 
(+2 
days)
Week 
10 
14 
days 
after
Visit 
6 (±2 
days)
Week 
12 
28  
days 
after 
Visit 
6
(± 3 
days)
Week 
16 
56 
days 
after 
Visit 
6 (± 3 
days)
Informed 
consent
X2 
In-/exclusion 
criteria
X
X3 
Medical/surgical 
History
X
Concurrent 
diagnosis
X
X3 
AK and SCC 
treatment 
history
X
Concomitant 
medications, 
treatments, 
procedures
X
X
X
X
X
X
X
X
X
X
Brief physical 
exam4 
X
X
X
X
Vital signs
X
Demographics
X
Height and 
weight
X
Fitzpatrick skin 
type
X
Urine pregnancy 
test5 
X
X
X
Identify selected 
treatment area
X
Mark selected 
treatment area 
on skin
X
 
X1
Biopsy of one 
AK lesion
X
Biopsy if 
suspicion of 
SCC etc.
X
X
X
X
X
X
X
X
Randomisation
X
AK count 
X
X
X
X
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Screening
Treatment Period
Visit Number
1
2
3
4
5
6
7¹
8¹
9¹
10¹
Day/Week
(window)
(-42 to 
-14 days)
Day 
1
Day 
4 
(+2 
days)
Week 
2 
Day 
15 
 (±2 
days)
Week 
4 
Day 
29
(± 3 
days)
Week 
8 
Day 
57 
(±3 
days)
3 days 
after 
Visit 6 
(+2 
days)
Week 
10 
14 
days 
after
Visit 
6 (±2 
days)
Week 
12 
28  
days 
after 
Visit 
6
(± 3 
days)
Week 
16 
56 
days 
after 
Visit 
6 (± 3 
days)
Dispense 
medication 
X
 
X1
Return 
medication
X7
X6
X7
X6 
Compliance
X
X6
X6
X
X6 
X6 
Field assess-
ment for SCC, 
BCC or 
neoplasia
X
X
X
X
X
X
X
X
Local skin 
response (LSR)
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
1.
Only for subjects who are not completely cleared in the selected treatment area at Week 8. Subjects who
have cleared should proceed to the Follow –up period at Visit 11
2.
Can be performed prior to Visit 1
3.
To be checked at Visit 2
4.
Including general appearance, regional lymph nodes and dermatologic examination of the skin in general
5.
Females of childbearing potential only
6.
Imiquimod only
7.
Ingenol mebutate only
3.1.2 Follow-up Period 
Visit Number 
11 
12
13 
14 
15 
16
Week/Month 
(window) 
Week 20 
(±14 days) 
Month 12 
(±14 days) 
Month 18 
 (±28 days) 
Month 24 
 (±28 days) 
Month 30 
 (±28 days) 
Month 36 
(± 28 days) 
Concomitant 
medications, 
treatments, 
procedures 
X
X
X
X
X
X
Field assessment for 
SCC, BCC or 
neoplasia 
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
AK count
X
X
X
X
X
X
Brief physical exam4
X
X
X
X
X
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Note: Unscheduled/Early Termination 
Upon completion of the last visit or during the study, an unscheduled visit may be required 
for any subject with a severe reaction, suspected pregnancy or an unresolved treatment-
related AE or LSR, if deemed clinically significant by the investigator. Only assessments that 
require follow-up will be conducted if the subject is continuing in the trial. For early termina-
tion all trial assessments scheduled should be performed if possible. 
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TABLE OF CONTENTS 
1 CLINICAL STUDY PROTOCOL APPROVAL/ACKNOWLEDGE ............................. 2
1.1 APPROVAL STATEMENT LEO PHARMA A/S .............................................................. 2
1.2 APPROVAL STATEMENT INTERNATIONAL CO-ORDINATING 
INVESTIGATOR ............................................................................................................... 2
1.3 ACKNOWLEDGE STATEMENT INVESTIGATOR(S) ................................................... 2
2 PROTOCOL STATEMENT ................................................................................................ 3
2.1 COMPLIANCE WITH GOOD CLINICAL PRACTICE .................................................... 3
3 PROTOCOL SYNOPSIS ..................................................................................................... 3
3.1 SCHEDULE/CHART OF TRIAL PROCEDURES .......................................................... 12
3.1.1 Screening and Treatment Period ..................................................................................... 12
3.1.2 Follow-up Period ............................................................................................................. 13
TABLE OF CONTENTS ....................................................................................................... 15
TABLE OF TABLES ............................................................................................................. 19
TABLE OF FIGURES ........................................................................................................... 19
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................... 20
4.1 LIST OF ABBREVIATIONS ............................................................................................ 20
4.2 DEFINITION OF TERMS ................................................................................................. 21
5 ETHICS ................................................................................................................................ 24
5.1 INDEPENDENT ETHICS COMMITTEES (IECS) OR INSTITUTIONAL REVIEW 
BOARDS (IRBS) .............................................................................................................. 24
5.2 ETHICAL CONDUCT OF THE TRIAL ........................................................................... 24
5.3 ETHICAL CONSIDERATION STATEMENT ................................................................. 24
5.4 SUBJECT INFORMATION AND INFORMED CONSENT ........................................... 26
5.5 HANDLING OF PERSONAL DATA ............................................................................... 27
6 TRIAL ADMINISTRATIVE STRUCTURE ................................................................... 27
6.1 SPONSOR .......................................................................................................................... 27
6.2 LEO PHARMA A/S AFFILIATES AND CRO(S) ............................................................ 27
6.3 LEO PHARMA A/S PERSONNEL ................................................................................... 29
6.3.1 International Clinical Trial Manager (ICTM) ................................................................. 29
6.3.2 National Lead CRAs (NLCRAs) ..................................................................................... 29
6.3.3 Sponsor’s Medical Expert ............................................................................................... 29
6.3.4 Safety Scientist/Safety Physician, Global Pharmacovigilance ....................................... 29
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6.3.5 Study Statistician ............................................................................................................. 29
6.3.6 Study Data Manager ........................................................................................................ 30
6.4 PROTOCOL AUTHOR(S) ................................................................................................ 30
6.5 INVESTIGATORS AND TRIAL COMMITTEES ........................................................... 30
6.5.1 International Co-ordinating Investigator ......................................................................... 30
6.5.2 National Co-ordinating Investigator(s) ........................................................................... 31
6.5.3 Investigators .................................................................................................................... 31
6.5.4 Trial Committees ............................................................................................................. 31
6.6 AGREEMENTS ................................................................................................................. 31
7 INSURANCE ....................................................................................................................... 31
8 INTRODUCTION AND RATIONALE ............................................................................ 31
8.1 ACTINIC KERATOSIS ..................................................................................................... 32
8.2 INVESTIGATIONAL PRODUCT DESCRIPTION ......................................................... 33
8.2.1 Ingenol Mebutate ............................................................................................................. 33
8.2.2 Imiquimod ....................................................................................................................... 34
8.3 TRIAL RATIONALE ........................................................................................................ 35
9 TRIAL OBJECTIVES ........................................................................................................ 36
9.1 PRIMARY OBJECTIVE ................................................................................................... 36
9.2 SECONDARY OBJECTIVES ........................................................................................... 36
10 INVESTIGATIONAL PLAN ........................................................................................... 37
10.1 TRIAL DESIGN .............................................................................................................. 37
10.1.1 Overall Design ............................................................................................................... 37
10.1.2 Individual Phases ........................................................................................................... 37
10.1.3 Individual Visits ............................................................................................................ 39
10.1.4 Study Design Diagram .................................................................................................. 45
10.2 TIME SCHEDULE .......................................................................................................... 45
10.3 NUMBER OF SUBJECTS/SAMPLE SIZE .................................................................... 45
10.4 CRITERIA FOR SUBJECT SELECTION (IN- AND EXCLUSION) ........................... 46
10.4.1 Inclusion Criteria ........................................................................................................... 46
10.4.2 Exclusion Criteria .......................................................................................................... 47
10.4.3 Subject Screening Log .................................................................................................. 48
10.4.4 Subject Registration ...................................................................................................... 48
10.5 WITHDRAWAL CRITERIA .......................................................................................... 48
10.6 INVESTIGATIONAL PRODUCTS ................................................................................ 49
10.6.1 Ingenol Mebutate ........................................................................................................... 49
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10.6.2 Imiquimod ..................................................................................................................... 50
10.6.3 Packaging of Investigational Products .......................................................................... 51
10.6.4 Storage of Investigational Products ............................................................................... 51
10.6.4.1 Ingenol mebutate gel .................................................................................................. 51
10.6.4.2 Imiquimod cream ....................................................................................................... 51
10.6.5 Administration of Investigational Products ................................................................... 52
10.6.5.1 Ingenol Mebutate ........................................................................................................ 52
10.6.5.2 Imiquimod .................................................................................................................. 53
10.6.5.3 Instructions to be followed by Site Personnel ............................................................ 53
10.6.5.4 Trial Medication Application ..................................................................................... 54
10.6.6 Precautions/Overdosage ................................................................................................ 55
10.6.6.1 Ingenol Mebutate ........................................................................................................ 55
10.6.6.2 Imiquimod .................................................................................................................. 56
10.6.6.3 Reproductive Precautions ........................................................................................... 57
10.6.6.4 Hypersensitivity ......................................................................................................... 57
10.6.7 Treatment Assignment .................................................................................................. 57
10.6.7.1 Randomisation Code List ........................................................................................... 57
10.6.7.2 Subject Identification List .......................................................................................... 57
10.6.8 Blinding of the Trial ...................................................................................................... 58
10.6.9 Breaking the Randomisation Code ................................................................................ 58
10.6.9.1 Un-blinding of Individual Subject Treatment ............................................................ 58
10.6.9.2 Un-blinding of the Clinical Trial ................................................................................ 58
10.6.10 Drug Accountability and Compliance Checks ............................................................ 58
10.6.10.1 Sponsor-Investigator Drug Accountability .............................................................. 58
10.6.10.2 Investigator-Subject Drug Accountability ............................................................... 58
10.6.10.3 End of Trial Drug Accountability ............................................................................ 59
10.6.10.4 Treatment Compliance ............................................................................................. 59
10.6.11 Prior and Concomitant Treatment ............................................................................... 59
10.7 TRIAL PROCEDURES ................................................................................................... 63
10.7.1 Schedule of Trial Procedures ........................................................................................ 63
10.7.2 Subject Eligibility .......................................................................................................... 65
10.7.3 Clinical Assessment ...................................................................................................... 66
10.7.3.1 Investigator Assessments ........................................................................................... 66
10.7.3.2 Subject assessments .................................................................................................... 67
10.7.4 Laboratory Assessments ................................................................................................ 67
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10.7.4.1 Central Analysis ......................................................................................................... 67
10.7.4.2 Local Analysis ............................................................................................................ 68
10.7.5 Adverse Events .............................................................................................................. 68
10.7.5.1 Reporting of Adverse Events ..................................................................................... 70
10.7.5.2 Other events to be reported ........................................................................................ 74
10.7.6 Serious adverse events .................................................................................................. 74
10.7.6.1 Reporting of Serious Adverse Events ........................................................................ 74
10.7.7 Source Data ................................................................................................................... 76
10.8 EFFICACY EVALUATION ............................................................................................ 77
10.8.1 Secondary Efficacy Response Criteria .......................................................................... 77
10.9 SAFETY EVALUATION ................................................................................................ 78
10.9.1 Primary Response Criterion .......................................................................................... 78
10.9.2 Secondary Safety Response Criterion ........................................................................... 78
10.9.3 Safety Evaluation .......................................................................................................... 78
10.9.4 Evaluation of (Serious) Adverse Events ....................................................................... 78
10.9.5 Evaluation of Laboratory Data ...................................................................................... 78
10.10 STATISTICAL ANALYSIS .......................................................................................... 78
10.10.1 Subject Qualification for Analysis .............................................................................. 78
10.10.2 Subjects Disposition .................................................................................................... 79
10.10.3 Baseline Characteristics .............................................................................................. 79
10.10.4 Analysis of Efficacy .................................................................................................... 79
10.10.5 Stratification ................................................................................................................ 79
10.10.6 Safety Analysis ............................................................................................................ 80
10.10.6.1 Analysis of Primary and Secondary Safety Endpoints ............................................. 80
10.10.6.2 Adverse Events ......................................................................................................... 80
10.10.6.3 Local Skin Responses ............................................................................................... 81
10.10.6.4 Laboratory Safety Examinations .............................................................................. 82
10.10.7 Interim Analysis .......................................................................................................... 82
10.11 TRIAL COMMITTEES ................................................................................................. 82
10.12 QUALITY ASSURANCE/AUDIT ................................................................................ 82
10.12.1 Trial Monitoring .......................................................................................................... 82
10.13 CASE REPORT FORM BOOKS AND DATA HANDLING ....................................... 83
10.13.1 Case Report Forms (CRFs) ......................................................................................... 83
10.13.2 Data Handling ............................................................................................................. 84
10.14 PROTOCOL AMENDMENTS ...................................................................................... 84
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10.15 COMPLETION OF TRIAL ........................................................................................... 85
10.15.1 Trial Completion Procedures ...................................................................................... 85
10.15.2 Provision for Subject Care Following Trial Completion ............................................ 85
10.15.3 Archiving of Trial Documents .................................................................................... 85
11 USE OF INFORMATION ................................................................................................ 86
12 PUBLICATION................................................................................................................. 86
13 REFERENCES .................................................................................................................. 88
14 LIST OF APPENDICES................................................................................................... 92
TABLE OF TABLES 
Table 1:
Prohibited concomitant treatments from the start of treatment until Week 20 ....... 60
Table 2: 
Adverse Event Reporting for Visits until Week 20 ................................................ 70
Table 3: 
Adverse Event Reporting for Visits after Week 20 ................................................ 71
Table 4:
Conversion of LSRs to MedDRA Preferred Terms ................................................ 81
TABLE OF FIGURES 
Figure 1 Study Design .............................................................................................................. 45
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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
4.1 LIST OF ABBREVIATIONS 
5-FU
5-fluorouracil
ADR
Adverse Drug Reaction
AE
Adverse Event
AK
Actinic Keratosis
BCC
Basal Cell Carcinoma
CRF
Case Report Form
CRO
Contract Research Organisation
CMO
Contract Manufacturing Organisation
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GPV
Global Pharmacovigilance
ICH
International Conference on Harmonisation
ICTM
International Clinical Trial Manager
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IWR
Interactive Web Response System
LSR
Local Skin Response
NLCRA
National Lead Clinical Research Associate
NMSC
Non-Melanoma Skin Cancer
RDC
Remote Data Capture
SAE
Serious Adverse Event
SCC
SmPC
Squamous Cell Carcinoma
Summary of Product Characteristics
SOP
Standard Operating Procedure
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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UVA 
Ultraviolet light A 
UVB 
Ultraviolet light B 
WMA 
World Medical Association 
4.2 DEFINITION OF TERMS 
Assessment 
A (cluster of) characteristic(s) measured and/or recorded for a subject. 
Certified Copy 
A certified copy is a copy of original information that has been verified, as indicated by a 
dated signature, as an exact copy having all of the same attributes and information as the 
original (FDA Guidance for Industry, Computerized Systems Used in Clinical Investigations, 
May 2007). 
Concomitant Medication 
Any medication taken by a subject during the clinical trial apart from the investigational 
product. 
Enrolled Subject 
A subject for whom informed consent has been obtained and a CRF number assigned. 
Fraud 
Fabrication of data, selective and undisclosed rejection of undesired results, substitution with 
fictitious data, deliberately incorrect use of statistical methods for the purposes of reaching 
other conclusions than those warranted by the data, misinterpretation of results and conclu-
sions, plagiarism of results or entire articles from other researchers, misrepresentation of other 
researchers’ results, unwarranted authorship, and misleading application for positions or 
funds. 
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International Clinical Trial Manager (ICTM) 
The person appointed by LEO Pharma A/S to be the main international representative 
responsible for all aspects of a clinical trial as outlined in Global Clinical Operations SOPs. 
Clinical trial agreement 
A contract between on the one hand LEO Pharma A/S and/or a Contract Research Organisa-
tion (CRO) and on the other hand an investigator and/or the institution specifying the 
conditions for the co-operation in the clinical trial and the investigator’s and/or the institu-
tion‘s responsibilities. 
Investigator Staff Signature Form 
A form used: 
1.
for the investigator to delegate trial related tasks/duties
2.
for trial site staff to sign and date to accept delegation
3.
for trial site staff to document signature and initials
4.
for the investigator to authorise tasks/duties delegated
Investigator Trial File 
The collection of trial documents required by Global Clinical Operations SOPs LEO Pharma 
A/S, ICH Guidelines and/or regulatory requirements to be on file at the trial site. 
LEO Pharma A/S 
LEO Pharma A/S refers to the sponsor of the clinical trial. 
LEO Pharma A/S affiliate 
An affiliated company of LEO Pharma A/S authorised to manage certain clinical trial related 
activities for LEO Pharma A/S. 
Monitor 
A person appointed by LEO Pharma A/S to carry out monitoring of a clinical trial. 
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National Lead CRA (NLCRA) 
The person appointed by LEO Pharma A/S to be the national representative responsible for all 
aspects of a clinical trial within a country as outlined in Global Clinical Operations SOPs. 
Randomisation Code List 
A list of (sequential) numbers to each of which a treatment is allocated (assigned). Treatment 
may be revealed as a code letter (e.g. A, B, …) or by directly revealing the specific treatment 
(investigational product). 
Response Criterion 
An assessment or a transformation of the assessment(s) described on a subject level for which 
a statistical analysis is performed, i.e. a p-value or a confidence interval is stated, or for which 
tabulation serves as important supportive evidence of efficacy/safety. 
Subject Identification List 
A summary list kept by the investigator in the Investigator Trial File which records the names 
of all subjects enrolled and the date of enrolment in the trial at that trial site. The list includes 
each subject’s corresponding CRF number to allow the investigator/institution to reveal the 
identity of any subject if required. 
Subject Screening Log 
A document kept by the investigator which identifies patients/subjects who have signed the 
informed consent. 
Subject Screening Log is synonymous with Patient Screening Log. 
Subject Study Card 
A card given to a subject by the trial site at the time trial medication is first dispensed to a 
subject to identify that the subject is having treatment with an investigational product. 
Writing committee 
An appointed committee participating in the writing of a multi-centre publication. 
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5 ETHICS 
5.1 INDEPENDENT ETHICS COMMITTEES (IECs) OR INSTITUTIONAL REVIEW 
BOARDS (IRBs) 
The clinical trial must be approved by/receive favourable opinion from relevant Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs) prior to the enrolment of 
subjects. 
Any amendments to the approved clinical trial must likewise, as required, be approved 
by/receive favourable opinion from relevant IRBs/IECs prior to implementation. 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial, as 
required. 
5.2 ETHICAL CONDUCT OF THE TRIAL 
This clinical trial will be conducted to conform to the principles of the World Medical 
Association (WMA), Declaration of Helsinki, Ethical Principles for Medical Research 
Involving Human Subjects adopted by the 18th WMA General Assembly, Helsinki, Finland, 
June 1964 and last revised in Seoul in October 2008 by the WMA General Assembly (see 
Appendix II). 
5.3 ETHICAL CONSIDERATION STATEMENT 
Actinic keratosis (AK) is a common skin condition which is linked to the development of 
squamous cell carcinoma (SCC) (1), and both conditions share specific gene expression (2). 
Current treatment options for AK lesions consist of cryotherapy, photodynamic therapy, and 
topical products.  Cryotherapy and photodynamic therapy can be painful and cryotherapy 
often leaves areas of hyper- or hypopigmentation (3, 4). Curettage (with or without electro-
surgery) and excisional surgery are alternatives to cryotherapy (5). Topical products include 
5-fluorouracil (5-FU), diclofenac, and imiquimod, and are commonly used as field treatment
for multiple lesions over larger skin areas (6, 7, 8, 9, 10, 11, 12, 13, 14). The duration of
treatment required for these topical products ranges from 2 to 16 weeks. It has been previ-
ously documented that longer treatment durations reduce patient compliance (15).
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A new topical product, ingenol mebutate gel, has been developed for the treatment of actinic 
keratosis on both head (face and scalp) and non-head locations (trunk and extremities). The 
duration of treatment with ingenol mebutate gel is once daily for either 2 or 3 consecutive 
days (for non-head and head locations respectively) which provides an advantage for treat-
ment compliance and patient convenience in those subjects treated with ingenol mebutate gel. 
Ingenol mebutate gel has been approved in the US in January 2012, in Brazil in July 2012 and 
in the European Union (EU) and Australia in November 2012 under the trade name Picato®.  
Imiquimod cream is a topical immune response modifier and a 5% formulation has been 
approved for the treatment of AKs in the US and Europe (Aldara® ) with different dosage 
regimens. The safety and efficacy of imiquimod has been demonstrated in controlled clinical 
trials for both dose regimens (16, 17, 19, 18, 20). In this study, subjects in the imiquimod 
group will be treated according to the EU dosage regimen corresponding to one application on 
3 days per week for 4 weeks, with a 4-week treatment pause followed, if necessary, by 
another 4-week treatment period. 
The clinical programme for the development of ingenol mebutate gel for the face and scalp 
has initially focused on one treatment cycle of 3 days. Since the label for imiquimod already 
includes an option to repeat treatment after the first treatment cycle (12, 14), the present trial 
will extend the treatment regimen of ingenol mebutate gel to two cycles for patients who have 
recalcitrant disease. Whereas the clinical development program used only one cycle compris-
ing 2 or 3 days of treatment, the present trial will allow retreatment with at least one extra 
cycle of treatment if clinically indicated. In an ongoing trial of repeat use of ingenol mebutate 
140 subjects have been randomized 2:1 to either a repeat cycle of ingenol mebutate or vehicle, 
i.e. approximately 95 subjects have been subjected to repeat cycles of ingenol mebutate (study
code LP0041-22). The trial is ongoing with no safety concerns raised.
Since AK is a chronic disease and neither imiquimod nor ingenol mebutate are universally 
effective, need will arise in many subjects after the randomised treatment period for other 
treatment(s) than the intervention stipulated by the protocol. In such cases the choice should 
be to repeat the initial treatment (imiquimod or ingenol mebutate) as previously given to the 
subject (cross-over between imiquimod and ingenol mebutate is not allowed) or apply lesion-
based cryotherapy. In order to avoid confounding of the results, other treatments should be 
avoided for as long as medically permissible. 
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The safety of ingenol mebutate gel has been established in an extensive clinical programme 
(21). Localised application site disorders (e.g., pruritus, pain, irritation) and LSRs, particularly 
erythema and flaking/scaling are the main characteristics of the safety profile of ingenol 
mebutate gel. The application site disorders were generally mild or moderate in intensity.  
Subjects enrolled in this trial will be limited as to what concomitant medications/procedures 
they may receive, depending on the trial period and whether they require treatment inside or 
outside the selected treatment area. In particular, cross-over for any one subject between 
ingenol mebutate gel and imiquimod is not allowed. Every effort has been made to ensure that 
subjects may at all times receive relevant treatment for their condition, alternative options for 
concomitant treatment have been provided. These restrictions are therefore not considered to 
be a risk to subject safety since treatment options are still available. 
Actinic Keratosis lesions are usually diagnosed clinically rather than histologically. But when 
there is doubt as to the clinical differentiation between AKs and SCCs, histological confirma-
tion may be necessary (23). In this trial, biopsies will be performed in order to confirm the 
clinical assessment of AK at screening and also if there is suspicion of SCC/BCC or other 
neoplasia.  
In order for the necessary biopsies to be associated with as little discomfort as possible, the 
area will be anaesthetised. All the test procedures will be performed at the study centre. The 
biopsies taken if SCC/BCC or other neoplasia is suspected will be sent to a central laboratory 
for assessment. The results will be emailed to the investigator as soon as possible so that they 
can be discussed with the subject. In case of a local skin response, the affected skin areas will 
be closely monitored and appropriate medical care administered if required to minimise the 
discomfort, if any, for the subject. 
In order to ensure safety, particularly in order to capture development of SCC in any subject 
in due time for the subject to receive further treatment, all subjects participating in the trial 
will be under careful supervision of an experienced investigator during the entire course of the 
trial. 
5.4 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 
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be given 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.  
A Study Subject Card will be given to a subject by the site personnel at the time investiga-
tional product is first dispensed, to identify that the subject is having treatment with an 
investigational product.  
5.5 HANDLING OF PERSONAL DATA 
Subjects shall be asked to consent that their personal data are recorded, collected, processed 
and may be transferred to EU and non-EU countries in accordance with any national legisla-
tion regulating privacy and data protection. 
Personal data shall be handled and processed by all relevant parties involved in the clinical 
trial in accordance with any national legislation regulating privacy and data protection as well 
as in accordance with the general terms and conditions of the authorisation granted by the 
Danish Data Protection Agency to LEO Pharma A/S as set forth in the attached Appendix I. 
LEO Pharma A/S is considered data controller for this clinical trial. 
6 TRIAL ADMINISTRATIVE STRUCTURE 
6.1 SPONSOR 
LEO Pharma A/S is the sponsor of the clinical trial. 
6.2 LEO PHARMA A/S AFFILIATES AND CRO(S) 
LEO Pharma A/S has transferred certain clinical trial related activities to the LEO Pharma 
A/S affiliate(s) and/or to the CRO(s) relevant for the conduct of the clinical trial. 
LEO Pharma, France 
LEO Pharma GmbH, Germany 
LEO Laboratories, UK 
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The manufacture of investigational product ingenol mebutate is performed at either of the two 
manufacturing sites: 
LEO Laboratories Ltd., 285 Cashel Road, Crumlin, Dublin 12, Ireland 
or 
DPT Laboratories Ltd., 307 E. Josephine Street, San Antonio, Texas 78215, United States 
Dispensing of components for the manufacture of ingenol mebutate gel at DPT Laboratories 
Ltd. is performed at: 
DPT Laboratories Ltd., 3300 Research Plaza, San Antonio, Texas 78235, United States 
The manufacture of investigational product imiquimod is performed at: 
MEDA AB, Pipers väg 2A, 170 73 Solna, Sweden. 
Almac Clinical Services, 9 Charlestown Road, Seagoe Industrial Estate, Craigavon BT63 
5PW, United Kingdom will be responsible for drug storage, packaging, labelling, distribution 
and destruction of investigational product as agreed to in a Service Agreement/Contract. 
Almac Clinical Technologies, Seagoe Industrial Estate, Craigavon BT63 5UA, United 
Kingdom, will be responsible for the Interactive Web Response (IWR) System for allocation 
of trial medication kit numbers and randomisation, as agreed to in a Service Agree-
ment/Contract. 
ACM Global Central Laboratory, 23 Hospital Fields Road, York, YO10 4ZD, UK will be 
responsible for provision of kits and shipment of the skin punch biopsies as agreed to in a 
Service Agreement/Contract. 
, MD, Department of Dermatology, Medical University of Graz, Auen-
bruggerplatz 8, A-8036 Graz, Austria will be responsible for histological assessment of the 
skin punch biopsies as agreed to in a Service Agreement/Contract. 
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6.3 LEO PHARMA A/S PERSONNEL 
6.3.1 International Clinical Trial Manager (ICTM) 
, PhD, Clinical Trial Manager, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel :
, Fax :
, email:
  
6.3.2 National Lead CRAs (NLCRAs) 
, Clinical Research Associate, LEO Pharma France, 2, rue René Cau-
dron, 78960 Voisins Le Bretonneux, France, Tel.:
, Fax: 
, 
email: 
 
, National Clinical Trial Manager, Clinical Operations, LEO Pharma GmbH, 
Frankfurter Straße 233, A3, D-63263 Neu-Isenburg, Germany, Tel.: 
, Fax: 
, e-mail: 
, Senior Clinical Research Associate, LEO Laboratories Limited, Longwick 
Road, Princes Risborough, Buckinghamshire HP27 9RR, United Kingdom, Tel. 
 
, Fax: 
, e-mail: 
 
6.3.3 Sponsor’s Medical Expert 
, MD, Senior Medical Advisor, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: 
, email:
 
6.3.4 Safety Scientist/Safety Physician, Global Pharmacovigilance 
, MSc PhD, Principal PV Scientist, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: 
, Fax: 
, e-mail: 
 
6.3.5 Study Statistician 
, PhD Stat, Senior Biostatistician, LEO Pharma A/S, Industriparken 55, 
2750 Ballerup, Denmark, Tel.: +
, e-mail:
 
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6.3.6 Study Data Manager 
, MSc, Clinical Data Manager, Biostatistics and Data Management, LEO 
Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark, Tel.: 
, Fax: 
, e-mail: 
6.4 PROTOCOL AUTHOR(S) 
, MSc, Clinical Trial Manager, LEO Pharma France, 2, rue René Caudron, 
78960 Voisins Le Bretonneux, France, 
, e-mail: 
 
, PhD Stat, Senior Biostatistician, LEO Pharma A/S, Industriparken 55, 
2750 Ballerup, Denmark, Tel.: 
, e-mail: 
 
, MD, Senior Medical Advisor, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: 
, email: 
 
 MD, Klinik für Dermatologie und Allergologie, Klinikum Vest 
GmbH, Behandlungszentrum, Knappschaftskrankenhaus Recklinghausen, Dorstener Str. 151 
45657 Recklinghausen, Germany, Tel.: 
  
e-mail:
, BSc (Hons) FICR, Medical Writer, Diamond Clinical Ltd, 3 Manor Courtyard, 
Hughenden Avenue, High Wycombe, HP13 5RE, United Kingdom, Tel.: 
, 
e-mail: 
6.5 INVESTIGATORS AND TRIAL COMMITTEES 
6.5.1 International Co-ordinating Investigator 
The international co-ordinating investigator is responsible for approval of the (Consolidated) 
Clinical Study Protocol, Clinical Study Protocol Addendum(s), (Consolidated) CRF and the 
Clinical Study Report on behalf of all trial investigators and as agreed to in an International 
Co-ordinating Investigator Agreement. 
Prof Rolf Markus Szeimies MD, Klinik für Dermatologie und Allergologie, Klinikum Vest 
GmbH, Behandlungszentrum, Knappschaftskrankenhaus Recklinghausen, Dorstener Str. 151 
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45657 Recklinghausen, Germany, Tel.: 
,  
e-mail: 
6.5.2 National Co-ordinating Investigator(s) 
The national co-ordinating investigator(s) are responsible for national issues relating to the 
clinical trial as agreed to in a National Co-ordinating Investigator Agreement. 
The contact details of participating national co-ordinating investigator(s) are provided outside 
the protocol. 
6.5.3 Investigators 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement. 
The contact details of each participating investigator are provided outside the protocol in the 
‘National Clinical Trial Applications’. 
6.5.4 Trial Committees  
Not applicable 
6.6 AGREEMENTS 
Before the initiation of any clinical trial related activities by the investigators/clinical trial 
committee(s)/LEO Pharma A/S affiliate(s)/CRO(s) listed above, the relevant parties must 
have entered into a written agreement regulating those activities. 
7 INSURANCE 
LEO Pharma A/S has taken out relevant insurances covering the subjects in the present 
clinical trial in accordance with applicable laws and regulations. 
8 INTRODUCTION AND RATIONALE 
This is a phase 4 trial comparing the cumulative incidence of SCC over a period of up to 3 
years after treatment with ingenol mebutate or imiquimod for multiple AKs on face and scalp. 
The trial will be conducted in approximately 48 centres in France, Germany and the United 
Kingdom in accordance with applicable national regulatory requirements. 
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8.1  ACTINIC KERATOSIS 
Actinic keratosis is a common skin condition visible as thickened, cornified, scaly lesions and 
characterised histologically by atypical epithelial proliferation (24). Actinic keratoses usually 
develop on areas that are frequently exposed to the sun (e.g., face, ears, scalp, neck, forearms, 
and back of the hands).  Patients with AK often express embarrassment, worry, and irritation 
related to the change in appearance of their skin and unsightly nature of the lesions (25, 26). 
In addition to the emotional strain, AK lesions can be painful and easily traumatised causing 
bleeding (26, 27, 28, 29). 
In population studies performed in the EU and US, reported prevalence rates for AK have 
been approximately 11-25% of the population, while estimates are higher in Australian 
studies (up to 60%) (24). Patients with AK tend to have Fitzpatrick type I or II skin (fair skin) 
which burns with sun exposure and does not tan (28).  
In the context of AK, the skin of patients with AKs shows field cancerisation, characterised 
by the epithelial surface of the photodamaged area being susceptible to the development of 
additional AKs or a malignancy. This is evidenced by the presence of multiple subclinical and 
clinically visible AK lesions as well as multifocal preneoplastic changes with genetic 
mutations (30). There is also increasing evidence that AK represents SCC in situ in its earliest 
stages (15, 24, 31). Histological evidence shows that contiguous AK is present in 97% of SCC 
lesions on sun-damaged skin (15). Actinic keratosis is linked epidemiologically to develop-
ment of SCC (1), and both conditions share specific gene expression (2). If left untreated, AK 
may regress, or alternatively, may progress to SCC, with significant morbidity and possible 
lethal outcome (15). 
Predicting which AKs may progress to SCC is not possible, nor is the conversion rate for an 
AK to SCC clear: the transformation rate from an AK lesion to SCC within one year has been 
reported to be <1:1000 (32).  Further mathematical modelling of these data has predicted that 
for an individual with an average of 7.7 AKs, the probability of at least one transforming 
within a 10-year period is approximately 10% (33). 
Diagnosis of AKs is based upon the clinical presentation (23). When there is doubt as to the 
clinical differentiation between AKs and SCCs, histological confirmation may be necessary 
(23).  
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8.2 INVESTIGATIONAL PRODUCT DESCRIPTION 
8.2.1 Ingenol Mebutate 
The formulation of ingenol mebutate gel contains ingenol mebutate as the active ingredient 
and benzyl alcohol, hydroxyethyl cellulose, isopropyl alcohol, citric acid, sodium citrate, and 
purified water as inactive ingredients. 
Ingenol mebutate is an ingenol derivative extracted from Euphorbia peplus (E. peplus), a 
member of the Spurge family. The sap of E. peplus has been used to treat a number of skin 
conditions including warts, corns, waxy growths, and skin cancer since the 1800s (34, 35, 36). 
Results from an early proof of concept study using the crude sap of E. peplus (known as study 
PEP001) confirmed anecdotal community-based evidence of activity against AK and non-
melanoma skin cancer (NMSC) when used topically.  Ingenol mebutate was identified as the 
principal active component responsible for the selective cytotoxic effects of E. peplus sap, 
based on its antitumour effects both in vitro and in vivo (37). The mechanism of action in AK 
is not fully understood.  In vivo and in vitro models have shown a dual mechanism of action 
for the effects of ingenol mebutate: 1) induction of local lesion cell death, and 2) promoting 
an inflammatory response characterised as infiltration of neutrophils and other immunocom-
petent cells (38, 39, 40, 41, 42, 43, 44). This mechanism of action distinguishes ingenol 
mebutate from current therapeutic options and provides a rationale for substantially shorter 
durations of treatment (2 to 3 days) compared to approved topical AK products. 
The clinical development programme for ingenol mebutate gel has investigated the efficacy 
and safety for the treatment of AKs in either a 3-day regimen on the face and/or scalp or 2-
day regimen on the trunk and/or extremities. Ingenol mebutate gel applied topically for 2 or 3 
days has been shown effective for field treatment of actinic keratoses (21, 22). Localised 
application site disorders (e.g., pruritus, pain, irritation) and LSRs (particularly erythema and 
flaking/scaling) are the main characteristics of the safety profile of ingenol mebutate gel. The 
application site disorders are generally mild or moderate in intensity. Local skin response data 
captured via specific LSR grading have shown that the LSRs are transient, peaking around 
Day 4 when applied on the face/scalp and between Days 3-8 when applied to 
trunk/extremities and typically resolve without sequelae within 2 or 4 weeks (on the 
face/scalp or trunk/extremities, respectively) of application (22). Furthermore, application of 
ingenol mebutate gel does not produce scarring (22). 
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Ingenol mebutate gel was first approved in the US in January 2012, in Brazil in July 2012 and 
in the EU and Australia in November 2012 under the trade name Picato®. 
With regard to the risk of development of SCC in trial subjects, it should be noted that there is 
an inherent background risk of conversion of AKs to SCC (see above, section 8.1). The trial 
objective is to further explore the incidence of SCC to examine whether there is an additional 
comparative risk following AK treatment with one or other field treatment. Data from the 
clinical development programme hitherto have not indicated such a risk for ingenol mebutate 
(the Combined Trials for Field Treatment of AK Lesions, Ningenol mebutate =1165,  Nvehicle =632):  
•
SCC with any location on the body occurred with similar frequency between groups
(11 (0.9%) vs. 5 (0.8%) for ingenol mebutate gel vs. vehicle)
•
SCC inside the selected treatment area occurred with similar frequency between groups
(3 (0.3%) vs. 2 (0.3%) for ingenol mebutate gel vs. vehicle).
Further, in the long-term follow up programme, a total of 198 patients who had demonstrated 
complete clearance of AK lesions (following treatment with ingenol mebutate gel (184 
patients) or vehicle (14 patients)) at Day 57 were followed for possible lesion recurrence and 
also for safety within the selected treatment area: no SCCs were reported for any of the 
patients in the 12-month period.This trial seeks to further examine the incidence of SCC for 
up to 3 years after treatment, within a controlled trial environment rather than as a post-
marketing surveillance exercise relying on capture of spontaneous reports. 
The trial is a phase 4 post-approval commitment to the European Medicines Agency (EMA). 
Please see the Summary of Product Characteristics (SmPC) for ingenol mebutate for further 
non-clinical and clinical information (21). 
8.2.2 Imiquimod 
Imiquimod is a topical immune response modifier and a 5% formulation has been approved 
for the treatment of AKs in the US and Europe (Aldara® cream) with a different dosage 
regimen. The dose regimen in Europe is one application 3 days per week for 4 weeks, with a 
4-week treatment pause followed, if necessary, by another 4-week treatment period. The dose
regimen in the US is two applications per week for 16 weeks. In this trial, subjects in the
imiquimod group will be treated according to the EU dosage regimen.
Imiquimod is an immune response modifier. In animal models imiquimod has been shown to 
stimulate the immune system by activating antigen-presenting cells such as monocytes⁄ 
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macrophages and dendritic cells to produce interferon and other cytokines and chemokines, 
which leads to the stimulation of the adaptive immune response.  
The safety and efficacy of imiquimod applied 3 times per week for one or two courses of 4 
weeks, separated by a 4-week treatment-free period has been demonstrated in two double-
blind vehicle controlled clinical trials , (see more information in the SmPC of Aldara®, 
Appendix V). 
The rate of progression to SCC was reported to be 1.6% (2/128 patients) within one year. 
There are no data on recurrence and progression rates beyond 1 year (Appendix V). 
8.3 TRIAL RATIONALE 
The purpose of this trial is to evaluate the risk of SCC after the treatment with ingenol 
mebutate gel. Imiquimod has been chosen for comparison as the treatment that is most 
comparable marketed field treatment with regard to efficacy. The cumulative incidence of 
SCC in a cohort of subjects with multiple AKs on the face or scalp who have been treated 
with ingenol mebutate gel or imiquimod cream will be evaluated.  
To ensure accurate diagnosis a biopsy of a representative lesion will be taken to confirm AK 
prior to randomisation. Further, the biopsy is expected to identify a number of subjects who 
have SCC at screening and are therefore not eligible for the trial. In order to increase the 
likelihood of detecting an increased risk, if any, the subjects in both groups will be treated for 
2 cycles if complete clearance is not obtained at Week 8. To obtain a reasonable number of 
SCC cases, subjects will be followed for 3 years and will be assessed for SCC (and other 
neoplasias) in the treatment area at regular intervals.  
The overall design will be a two-arm trial where patients are initially all treated with one 
cycle of either ingenol mebutate gel or imiquimod cream according to the normal treatment 
schedule for face and scalp. Subjects in the imiquimod group will be treated according to the 
approved EU dosage regimen. After 8 weeks, patients who are completely cleared of all AKs 
in the selected treatment area will continue further observation in the Follow-up period, 
whereas those who are not cleared will be retreated with a second treatment cycle. For the 
purpose of this trial the minimum period between the two treatment cycles, i.e. the period 
between the initial treatment cycle and possible retreatment, will be 8 weeks which is the time 
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when the treatment response would be evaluated in clinical practice for both products. 
Adverse events, LSRs and efficacy will also be compared between the two treatments.   
Since AK is a chronic disease and neither imiquimod nor ingenol mebutate are universally 
effective, need may arise in some subjects after the randomised treatment period for other 
treatment(s) in the selected treatment area than the intervention stipulated by the protocol. In 
such cases the choice should be to repeat the initial treatment (imiquimod or ingenol mebu-
tate) as previously given to the subject (cross-over between imiquimod and ingenol mebutate 
is not allowed) or apply lesion-based cryotherapy. In order to avoid confounding of the 
results, other treatments will be avoided for as long as medically permissible. 
9 TRIAL OBJECTIVES 
9.1 PRIMARY OBJECTIVE 
To compare the cumulative incidence of SCC after treatment with ingenol mebutate gel and 
imiquimod cream. 
The primary response criterion is diagnosis of SCC (defined as invasive SCC i.e. excludes 
SCC in situ) in the treatment field across the 3-year trial period. 
9.2 SECONDARY OBJECTIVES 
To compare the cumulative incidence of neoplasia and the short-term and 12-month efficacy 
of ingenol mebutate gel with imiquimod cream. 
The secondary response criteria are: 
1.
Diagnosis of SCC and other neoplasia in the treatment field over a 3-year period.
2.
Complete clearance after the last treatment cycle (at Week 8 or 16)
3.
Partial (at least 75%) clearance after the last treatment cycle (at Week 8 or 16)
4.
Complete clearance at 12 months, defined as no AKs in the selected treatment area at any
time from the last treatment cycle at Week 8 or 16 through to Month 12.
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10 INVESTIGATIONAL PLAN 
10.1 TRIAL DESIGN 
10.1.1 Overall Design 
This is a phase 4, multi-centre, randomised, two-arm, open label, active-controlled, parallel 
group, 36-month trial. 
All subjects who qualify for this trial are to have 5 to 9 clinically typical, visible and discrete 
AK lesions (confirmed by histopathology of one of the AKs prior to randomisation) within a 
contiguous 25 cm2 treatment area on the face or scalp. This area of skin will be referred to as 
the selected treatment area.  
In case of baldness or partial baldness, the forehead should be defined by the previous 
hairline.  
Subjects will be randomised in a 1:1 ratio to the following treatment arms: 
•
Arm A: Ingenol mebutate gel 0.015% applied daily for 3 consecutive days to the selected
treatment area followed by 8 weeks’ rest. Retreatment for another 3 consecutive days if
the treatment field is not completely cleared of AKs at Week 8
•
Arm B: Imiquimod 5% cream applied 3 days per week for 4 weeks to the selected
treatment area followed by 4 weeks’ rest. Retreatment for 4 weeks if the treatment field is
not completely cleared of AKs at Week 8.
Study visits will take place at Screening (Visit 1), during the treatment period on Days 1 and 
4, Weeks 2, 4 and 8 (Visits 2 to 6) for initial treatment and, if retreatment is required, on 
Week 8+3 days and Weeks 10, 12, and 16 (Visits 7 to 10). During the Follow-up period visits 
will take place at Week 20 and Months 12, 18, 24, 30 and 36 (Visits 11 to 16).  
10.1.2 Individual Phases 
At the Screening (Visit 1) subjects will sign the study-specific consent form in the presence of 
the investigator and subject’s eligibility will be checked and the selected treatment area will 
be identified. A biopsy will be taken of one AK lesion in the selected treatment area for 
histological confirmation of AK. 
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Treatment Period (Day 1 to Week 16) 
At Day 1 (Visit 2), the subject eligibility will be confirmed and subjects will be randomised to 
treatment with either ingenol mebutate gel or imiquimod cream. The selected treatment area 
will be marked on the skin and the first dose will be applied under the supervision and 
management of the trial personnel. Subsequent doses will be applied at home.  
At the next visits (Day 4 and Weeks 2 and 4; Visits 3 to 5) a clinical assessment of the 
selected treatment area will be performed. The selected treatment area will be assessed for 
local skin responses (LSRs) and any adverse events (AEs).  If there is suspicion of SCC, 
BCC, or other neoplasia when clinical assessment is performed, a biopsy will be taken and 
trial treatment will be stopped but the subject will remain in the trial. At Week 8 (Visit 6), a 
clinical assessment of the selected treatment area will be performed as for previous visits. An 
AK count in the selected treatment area will also be conducted.  
At Week 8, subjects who are completely cleared in the selected treatment area will continue 
into the Follow-up Period. Subjects, who are not completely cleared in the selected treatment 
area will have a second treatment cycle and will attend visits at Week 8+3 days and Weeks 
10, 12, and 16 (Visits 7 to 10). The assessments will be the same as during the first treatment 
cycle. After the second treatment cycle subjects will enter the Follow-up Period.  
Until the Follow-up period (Week 20), no other treatments and procedures are allowed in, and 
within 5 cm of the selected treatment area. Outside the selected treatment area (up to within 5 
cm), procedures such as cryotherapy will be allowed; field therapy will not be allowed. 
Follow-up Period (Week 16 to Month 36).  
Visits will be performed at Week 20 and Months 12, 18, 24, 30 and 36 (Visits 11 to16), at 
which a clinical assessment of neoplasia in the selected treatment area will be performed. If 
there is suspicion of SCC, BCC, or other neoplasia when clinical assessment is performed, a 
biopsy will be taken. An AK count in the selected treatment area will be conducted.  
From Week 20 until Month 36 procedures such as cryotherapy will be allowed in, and within 
5 cm of the selected treatment area. Further, at the discretion of the Investigator and according 
to nationally available product and treatment guidelines, the same treatment as originally 
administered is allowed (imiquimod or ingenol mebutate). Cross-over between imiquimod 
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and ingenol mebutate is not allowed. Investigators will be encouraged to pursue these 
treatment options where clinically relevant before employing other treatments. 
Outside the selected treatment area (up to within 5 cm) all treatments will be allowed, 
although investigators will be encouraged to avoid cross-over between imiquimod and 
ingenol mebutate. 
10.1.3 Individual Visits 
Screening (Visit 1, -42 to -14 days) 
Eligibility will be checked according to the inclusion and exclusion criteria and the subject 
will sign the study-specific consent form in the presence of the investigator or his/her 
designee prior to any screening procedures taking place.  
The following information will be recorded:  
•
Date of birth, sex, race, ethnic origin (self-report), height, weight, Fitzpatrick skin type,
relevant medical/surgical history, concurrent diagnoses, concomitant medication, AK and
SCC treatment history.
•
Abbreviated physical examination including general appearance, regional lymph nodes
and dermatologic examination of the skin in general.
•
Vital signs (resting blood pressure and heart rate) and oral or ear temperature.
The selected treatment area will be identified by the dermatologist and documented on the 
study transparency using a three-point landmark technique. Detailed instructions for the three-
point landmark technique are given in Appendix IV. 
A biopsy will be taken of one AK lesion in the selected treatment area (see 10.7.4 ) for 
histological confirmation of AK. 
Female subjects of childbearing potential will have a urine pregnancy test.   
Visit 2 (Day 1) 
Subject eligibility will be checked according to the inclusion and exclusion criteria. Once 
eligibility is confirmed, assessment of the selected treatment area, including LSRs and AK 
lesion count will be performed.  
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The subjects will be randomised to treatment with either ingenol mebutate gel or imiquimod 
cream. A trial medication kit will be assigned through an Interactive Web Response (IWR) 
System. The selected treatment area will be marked on the skin and the first dose of study 
medication will be applied under the supervision and management of the trial personnel (the 
subsequent doses will be applied at home). 
Visit 3 (Preferred on Day 4, with a visit window of +2 days) 
Visit 3 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of the selected treatment area(s) including LSRs
•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Return of trial medication (only for subjects treated with ingenol mebutate)
•
Trial medication compliance
Visit 4 (Week 2, Day 15 ± 2 days) 
Visit 4 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of treated selected treatment area(s) including LSRs
•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Trial medication compliance (for subjects treated with imiquimod)
Visit 5 (Week 4, Day 29 ± 3 days) 
Visit 5 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of the selected treatment area(s) including LSRs
•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Return of trial medication and trial medication compliance (for subjects treated with
imiquimod)
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Visit 6 (Week 8, Day 57 ± 3 days) 
Visit 6 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of the selected treatment area including LSRs and AK count.
•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Urine pregnancy test for female subjects of childbearing potential
•
An abbreviated physical examination
Subjects who are not completely cleared in the selected treatment area will be retreated with a 
Second Treatment Cycle (Visits 7 to 16). At this visit the first dose of study medication will 
be applied under the supervision and management of the trial personnel (the subsequent doses 
will be applied at home). 
Subjects, who are completely cleared in the selected treatment area (an AK count of zero), 
will continue in the Follow-up Period until trial completion at Month 36 (Visits 11 to 14). 
Visit 7 – Only if Retreatment is required (3 days after Visit 6 with a visit window of +2 days) 
Visit 7 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of the selected treatment area(s) including LSRs
•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Return of trial medication (for subjects treated with ingenol mebutate)
•
Trial medication compliance
Visit 8 – Only if Retreatment is required (Week 10, 14 days ± 2 days after Visit 6) 
Visit  will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of the selected treatment area(s) including LSRs
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•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Trial medication compliance (for subjects treated with imiquimod)
Visit 9 – Only if Retreatment is required (Week 12, 28 days ± 3 days after Visit 6) 
Visit 9 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of the selected treatment area(s) including LSRs
•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Return of trial medication and trial medication compliance (for subjects treated with
imiquimod)
Visit 10 – Only if Retreatment is required (Week 16, 56 days ± 3 days after Visit 6) 
Visit 10 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of selected treatment area including LSRs and AK count
•
Reporting of (S)AEs (see Table 2)
•
Reporting of concomitant medication, treatments and  procedures
•
Urine pregnancy test for female subjects of childbearing potential
•
Abbreviated physical examination
Visit 11 (Week 20 ± 14 days) 
Visit 11 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of selected treatment area including AK count
•
Reporting of (S)AEs (see Table 3)
•
Reporting of concomitant medication, treatments and  procedures
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Visit 12 (Month 12 ± 14 days) 
Visit 12 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of selected treatment area including AK count
•
Reporting of (S)AEs (see Table 3)
•
Reporting of concomitant medication, treatments and  procedures
•
Abbreviated physical examination
Visit 13 (Month 18 ±  28 days) 
Visit 13 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of selected treatment area including AK count
•
Reporting of (S)AEs (see Table 3)
•
Reporting of concomitant medication, treatments and  procedures
•
Abbreviated physical examination
Visit 14 (Month 24 ± 28 days) 
Visit 14 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of selected treatment area including AK count
•
Reporting of (S)AEs (see Table 3)
•
Reporting of concomitant medication, treatments and  procedures
•
Abbreviated physical examination
Visit 15 (Month 30 ± 28 days) 
Visit 15 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of selected treatment area including AK count
•
Reporting of (S)AEs (see Table 3)
•
Reporting of concomitant medication, treatments and  procedures
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•
Abbreviated physical examination
Visit 16 (Month 36 ± 28 days) 
Visit 16 will include: 
•
Clinical assessment of neoplasia in the selected treatment area (biopsy if there is suspi-
cion of SCC, BCC or other neoplasia)
•
Dermatologic examination of selected treatment area including AK count
•
Reporting of (S)AEs (see Table 3)
•
Reporting of concomitant medication, treatments and  procedures
•
Abbreviated physical examination
Unscheduled/Early Termination 
Upon completion of the last visit or during the study, an unscheduled visit may be required 
for any subject with a severe reaction, suspected pregnancy or an unresolved treatment-related 
AE or LSR, if deemed clinically significant by the investigator. Only assessments that require 
follow-up will be conducted if the subject is continuing in the trial. For early termination, 
all trial assessments scheduled should be performed if possible. 
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10.1.4 Study Design Diagram 
Figure 1 Study Design 
10.2 TIME SCHEDULE 
Planned date of first subject first visit: Q2 2013 
Planned date of last subject first visit: Q2 2015 
Planned date of completion of last subject: Q2 2018 
10.3 NUMBER OF SUBJECTS/SAMPLE SIZE 
A total of 480 subjects will be enrolled in the trial and randomised 1:1 to the two treatment 
groups. With 240 patients in each treatment group an adequate precision of the 3-year inci-
dence rate can be obtained. Assuming a 3-year rate of 1.0%, the upper 95% confidence limit 
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will on average be 2.26%, and assuming a 2.5% rate, the upper 95% confidence limit will on 
average be 4.48%. 
10.4 CRITERIA FOR SUBJECT SELECTION (IN- AND EXCLUSION) 
Following receipt of verbal and written information about the clinical trial, the subject must 
provide signed and dated informed consent before any trial related activity is carried out. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and will be described in submission documentation to authorities/ethics 
committees, as applicable. 
10.4.1 Inclusion Criteria 
1.
Following verbal and written information about the trial, subject must provide informed
consent documented by signing the Informed Consent Form (ICF) prior to any trial-
related procedures
2.
Subjects with 5 to 9 clinically typical, visible and discrete AKs within a contiguous 25
cm² treatment area on the face or scalp. Actinic keratosis should be confirmed by histopa-
thology of one of the AKs prior to randomisation.
3.
Subject at least 18 years of age
4.
Female subjects must be of either:
a.
Non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history
of sterility (e.g. the subject is without a uterus) or,
b.
Childbearing potential, provided there is a confirmed negative urine pregnancy test
prior to trial treatment, to rule out pregnancy.
5.
Female subjects of childbearing potential 1 must be willing to use highly effective
methods of contraception (Pearl index < 1%) at study entry until Week 20. These meth-
ods of contraception are defined as:
•
abstinence (when this is in line with the preferred and usual lifestyle of the subject)
•
vasectomised partner (partner should be the sole partner for the subject)
•
an intrauterine device
•
double barrier method defined as two distinct methods (either two actual barrier
methods or one actual barrier method and one hormonal method)
1 Female subjects are considered of childbearing potential unless they have been hysterectomised or have
undergone tubal ligation or have been post-menopausal for at least one year prior to first visit.. 
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•
hormonal contraceptive (oral hormonal birth control, oestrogenic vaginal ring, percu-
taneous contraceptive patches, implants and injectables) for at least one menstrual
cycle prior to enrolment.
10.4.2 Exclusion Criteria 
1.
Location of the selected treatment area:
•
on the periorbital skin
•
on the perioral skin/around the nostrils
•
within 5 cm of an incompletely healed wound
•
within 10 cm of a suspected BCC or SCC or other neoplasia
2.
Selected treatment area lesions that have atypical clinical appearance (e.g., hypertrophic,
hyperkeratotic or cutaneous horn).
3.
History of SCC, BCC, malignant melanoma or other neoplasia in the selected treatment
area.
4.
History or evidence of skin conditions other than the trial indication that would interfere
with evaluation of the trial medication in the selected treatment area (e.g., eczema, unsta-
ble psoriasis, xeroderma pigmentosum).
5.
Use of ingenol mebutate and/or imiquimod in and within 5 cm of the selected treatment
area within 2 years prior to Screening (Visit 1).
6.
Use of cosmetic or therapeutic products and procedures which could interfere with the
assessments of the treatment area.
7.
Anticipated need for hospitalisation or out-patient surgery prior to Day 15 in the initial
treatment cycle. Note that cosmetic/therapeutic procedures are not excluded if they fall
outside of the criteria detailed in Prohibited Therapies or Medications (see Exclusion Cri-
teria Nos. 18- 19).
8.
Known sensitivity or allergy to any of the ingredients in ingenol mebutate gel or imiqui-
mod cream.
9.
Organ transplant recipients
10. Immunosuppressed subjects (for example HIV patients)
11. Clinical diagnosis/history or evidence of any medical condition that would expose a
subject to an undue risk of a significant AE or interfere with assessments of safety and
efficacy during the course of the trial, as determined by the investigator’s clinical judg-
ment
12. Presence of acute sunburn within the selected treatment area
13. Current enrolment or participation in a clinical trial within 30 days of entry into this trial.
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14. Subjects previously randomised in the trial.
15. Female subjects who are breastfeeding.
16. Subjects who are institutionalised by court order or by the local authority
17. In the opinion of the investigator, the subject is unlikely to comply with the Clinical
Study Protocol (e.g. alcoholism, drug dependency or psychotic state)
Prohibited Therapies and/or Medications: within 4 weeks prior to Screening (Visit 1): 
18. Treatment with immunomodulators (e.g., azathioprine), cytotoxic drugs (e.g., cyclophos-
phamide, vinblastine, chlorambucil, methotrexate, podophyllin, camptothecin) or inter-
feron /interferon inducers.
19. Treatment with systemic medications that suppress the immune system (e.g., cyc-
losporine, prednisone, methotrexate).
10.4.3 Subject Screening Log 
A subject screening (enrolment) log will be maintained by the site during the trial. All 
subjects who sign the informed consent will be included on the screening log and in the CRF. 
10.4.4 Subject Registration 
At Visit 1, each subject will be assigned the next (ascending) CRF book number available at 
the trial site. The CRF book number is a unique subject identifier used throughout the trial, in 
lieu of the subject’s name. 
It is completely distinct from the trial medication kit number(s) assigned to the subject. 
10.5 WITHDRAWAL CRITERIA 
The investigator is free to withdraw the subject at any time for medical reasons. 
Subjects may withdraw for any of the following reasons: 
1.
Unacceptable adverse events or LSRs: any adverse event or LSR that the investigator or
the subject considers unacceptable.
2.
Exclusion criteria: any exclusion criteria which emerge/become apparent during the
subject’s participation in the clinical trial.
3.
Voluntary withdrawal: subjects will be free to withdraw from the clinical trial at any time
and for any reason.
4.
Other reasons: other reasons than stated above which requires the subject to (be)
withdraw(n) should be specified.
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Subjects, who are discovered, after randomisation, not to have fulfilled all in-/exclusion 
criteria at time of enrolment, should be withdrawn from treatment unless the investigator, 
based on clinical and ethical evaluation, finds withdrawal from treatment inappropriate. If a 
biopsy is taken for suspicion of neoplasia in the treatment area, the subject should likewise be 
withdrawn from treatment.  
Such deviation(s) from the (Consolidated) Clinical Study Protocol must be reported to LEO 
Pharma A/S (and the IEC/IRB, as appropriate) and recorded in the Clinical Study Report. 
Subjects who withdraw from the trial should be asked to complete the early termination visit. 
Reason(s) for withdrawal will be recorded in the CRF. 
Subjects withdrawn after randomisation will not be substituted. 
10.6 INVESTIGATIONAL PRODUCTS 
10.6.1 Ingenol Mebutate 
Finished product (brand) name (if avail-
able)/name investigational product 
Ingenol mebutate gel, 0.015% / 
Picato® 
Formulation
Gel
Active ingredient name/concentration 
Ingenol mebutate 0.015% w/w 
Excipients 
Isopropyl alcohol Ph. Eur. 
Hydroxyethyl cellulose Ph. Eur. 
Benzyl alcohol Ph. Eur. 
Citric acid monohydrate Ph. Eur. 
Sodium citrate dihydrate Ph. Eur. 
Purified water Ph. Eur. 
Pack size(s) 
0.47 g 
Manufacturer’s name of bulk medication 
(IP) 
LEO Laboratories Ltd, Ireland or 
DPT Laboratories Ltd., US 
Certifier’s name of bulk medication (IP) 
LEO Pharma A/S 
Supplier’s name 
Almac Clinical Services 
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Manufacturer’s name of subject treatment  
packages 
Almac Clinical Services 
Certifier’s name of subject treatment  
packages 
LEO Pharma A/S 
10.6.2 Imiquimod 
Finished product (brand) name (if avail-
able)/name investigational product 
Imiquimod Cream, 5% /  
Aldara® 
Formulation
Cream
Active ingredient name/concentration 
Imiquimod 5% w/w 
Excipients
Isostearic alcohol
Benzyl alcohol 
Cetyl alcohol 
Stearyl alcohol 
White soft paraffin 
Polysorbate 60 
Sorbitan stearate 
Glycerol 
Methyl hydroxybenzoate (E218) 
Propyl hydroxybenzoate (E216) 
Xanthan gum 
Purified water 
Pack size(s) 
250 mg  
Manufacturer’s name of bulk medication 
(IP) 
Meda AB, Sweden 
Certifier’s name of bulk medication (IP) 
Meda AB 
Supplier’s name 
Almac Clinical Services 
Manufacturer’s name of subject treatment  
packages 
Almac Clinical Services 
Certifier’s name of subject treatment  
packages 
LEO Pharma A/S 
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10.6.3 Packaging of Investigational Products 
The trial medication will be packaged individually for each subject in two separate trial 
medication kits each containing either 3 single use unit-dose tubes of Ingenol mebutate gel 
0.015% or 12 single use, unit-dose sachets of Imiquimod cream 5%. The trial medication kit 
and the unit dose tubes/sachets are intended to remain together throughout the trial. 
The trial medication kit and unit dose tubes/sachets will be identified by a label in compliance 
with national laws and regulations. 
10.6.4 Storage of Investigational Products 
10.6.4.1 Ingenol mebutate gel 
At the site, the kits will be stored in a refrigerator (2ºC – 8ºC) in a secure and restricted access 
area. Refrigerator temperature at the investigational site must be monitored continuously and 
recorded. 
Following dispensing, subjects should place the trial medication kit in the home refrigerator 
as soon as possible after returning from the Day 1 visit. The trial medication kit should be 
refrigerated and stored in a place segregated from foodstuffs to avoid exposure to the trial 
medication. The investigational products should also be refrigerated in a safe and secure 
manner inaccessible to children and pets. 
10.6.4.2 Imiquimod cream 
At the site, the kits will be stored in a cool place (below 25ºC) in a secure and restricted 
access area.  
Following dispensing, subjects should store the sachets in a cool place (below 25ºC) in a safe 
and secure manner inaccessible to children and pets. 
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10.6.5 Administration of Investigational Products 
10.6.5.1 Ingenol Mebutate 
Route of administration 
Topical on selected treatment area on face or 
scalp 
Dosing range 
One unit-dose tube 
Dosing frequency 
Once daily application for 3 consecutive days 
Daily maximum 
One unit-dose tube 
Time of day for dosing 
No specific requirements 
Relation of time of dosing to dietary intake 
No specific requirements 
Trial medication (ingenol mebutate gel, 0.015% gel) will be applied followed immediately by 
hand washing.  
The first unit dose will be applied during the Day 1 visit(s) (Visit 2 and Visit 6 in case of 
retreatment) under the supervision of trial site personnel and the second and third doses will 
be applied at home. 
At Day 1 (Visit2), the subjects will be instructed by the site personnel on how to handle and 
apply the trial medication and a Patient Safety and Study Medication Instruction Sheet will be 
provided to the subjects.  
If retreatment is required the same procedure should be followed as for the first treatment 
cycle and the site personnel should confirm that the subject has a Patient Safety and Study 
Medication Instruction Sheet and knows how to apply the trial medication. 
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10.6.5.2 Imiquimod 
Route of administration 
Topical on selected treatment area on face or 
scalp 
Dosing range 
One unit-dose sachet 
Dosing frequency 
Once daily application for 3 days/week (e.g. 
Monday, Wednesday and Friday) for 4 weeks 
Daily maximum 
One unit-dose sachet 
Time of day for dosing 
Prior to normal sleeping hours 
Relation of time of dosing to dietary intake 
No specific requirements 
Trial medication (imiquimod cream, 5%) will be applied followed immediately by hand 
washing.  
At Day 1 (Visit 2), the subjects will be instructed by the site personnel on how to handle and 
apply the trial medication and a Patient Safety and Study Medication Instruction Sheet will be 
provided to the subjects.  
The first unit dose will be applied during the Day 1 visit(s) (Visit 2 and Visit 6 in case of 
retreatment) under the supervision of trial site personnel and subsequent doses will be applied 
at home. 
If retreatment is required the same procedure should be followed as for the first treatment 
cycle and the site personnel should confirm that the subject has a Patient Safety and Study 
Medication Instruction Sheet and knows how to apply the trial medication. 
10.6.5.3 Instructions to be followed by Site Personnel 
The following guidelines should be followed by the site personnel when instructing the 
subject on how to apply trial medication prior to the application on Day 1 in each treatment 
cycle: 
1. Ensure that all evaluations have been completed prior to the dispensing of the trial
medication and that the kit number stated on the trial medication label matches the kit
number assigned by the IWR System.
2. Ensure the selected treatment area has been marked on the study transparency with a
permanent ink marker using the three-point landmark technique (see Appendix IV).
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3. Ensure the corners of the selected treatment area have been marked on the skin using the
study transparency to assist with identification of the selected treatment area, before the
first unit dose of trial medication is applied.
4. Ensure the subject understands that trial medication should be applied using a fingertip
and hands should be washed immediately after application. Contact with skin other than
the selected treatment area and application finger or inhalation of the trial medication must
be avoided.
5. Ensure the subject understands how to store the trial medication at home.
6. Ensure the subject is instructed to return the trial medication kit with all dispensed
tubes/sachets to the site at Visit 3 (for ingenol mebutate treated subjects) or Visit 5 (for
imiquimod treated subjects). In the case of retreatment, kits should be returned at Visits 7
and 9 for ingenol mebutate or imiquimod treated subjects, respectively.
7. Ensure that the subject is instructed with post-treatment guidelines and provided with a
Patient Safety and Study Medication Instruction Sheet for the relevant treatment.
8. Ensure that if the subject needs assistance with application of treatment that the subject
assisting is also instructed and that they must follow the Patient Safety and Study Medica-
tion Instructions.
10.6.5.4 Trial Medication Application 
Ingenol Mebutate 
Study medication should be applied once daily for three days in a row onto the selected 
treatment area: 
•
Open a new tube each time you use this medication. Remove the cap just before use.
•
Squeeze the entire contents of the tube onto a fingertip.
•
Gently rub the gel onto the treatment area.
•
Recap the tube and return the tube to the study medication kit.
•
Wash your hands with soap and water immediately after applying the gel.
•
Allow the treated skin area to dry for at least 15 minutes.
•
Do not apply medication immediately after taking a shower or less than 2 hours before
bedtime.
•
Do not wash the areas where you applied the gel for at least 6 hours after you apply it.
After this period, the treatment area may be washed using mild soap and water.
•
Do not touch the treatment area yourself or allow anyone or any pets to touch the
treatment area for a period of 6 hours after applying the gel.
•
Do not cover the treated area with air- or water-tight bandages after application.
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•
Avoid excessive sun exposure (e.g., sunbathing, tanning booths) and wear protective
clothing over the treated area when exposed to sunlight.
Imiquimod 
Study medication should be applied 3 times per week (eg. Monday, Wednesday and Friday) 
for 4 weeks onto the selected treatment area: 
•
Before application wash your hands and the treatment area with mild soap and water and
dry thoroughly.
•
Cream should be applied prior to normal sleeping hours.
•
Open a new sachet each time you use this medication.
•
Gently rub the cream onto the treatment area until the cream vanishes.
•
Return the used sachet to the study medication kit.
•
Wash your hands carefully after applying the cream.
•
Do not wash the area where you applied the gel for approximately 8 hours after you apply
it. After this time the treatment area should be washed with mild soap and water.
•
Do not cover the skin with air- or water-tight bandages after application.
•
Avoid excessive sun exposure (e.g., sunbathing, tanning booths) and wear protective
clothing over the treated area when exposed to sunlight.
10.6.6 Precautions/Overdosage 
A summary of the most relevant information is presented here. Further details are available in 
the SmPC for ingenol mebutate and for imiquimod (Appendix V).  
10.6.6.1 Ingenol Mebutate 
Skin Exposure 
The most common LSRs reported in the AK studies were erythema, flaking/scaling, and 
crusting. Less common LSRs included swelling/edema, vesiculation/pustulation, and erosion/ 
ulceration. The mean maximum composite LSR score for patients treated with ingenol 
mebutate gel, 0.015% was 9.1 (SD, 4.1) compared with 1.8 (SD, 1.6) for patients treated with 
vehicle, with the majority of patients having a maximum score on Day 4 and return to 
baseline by Day 29. 
Studies in healthy volunteers showed no evidence of skin sensitisation, phototoxicity, or 
photosensitisation following the application of ingenol mebutate gel. 
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Investigators conducting clinical trials with ingenol mebutate gel should ensure that investiga-
tional site staff and subjects are 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.  
Ocular Exposure 
The risk for accidental ocular exposure with ingenol mebutate gel should be minimised by 
avoiding the treatment of lesions on the periorbital skin. If accidental 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, ophthal-
mologist, 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 exposure should be documented and brought to the attention of the monitor. If 
ocular exposure does occur, the strategies discussed above for management of treatment of 
exposure are recommended. 
Other Exposure 
If ingenol mebutate is inhaled, assist the exposed person to breathe fresh air. If breathing is 
difficult, provide supplemental oxygen, if possible, and seek medical assistance. If ingenol 
mebutate is swallowed, and if the person is conscious, assist the exposed person to irrigate the 
mouth with copious amounts of water and seek immediate medical assistance. Do not induce 
vomiting. 
10.6.6.2 Imiquimod 
Rarely, intense local inflammatory reactions including skin weeping or erosion can occur 
after only a few applications of imiquimod cream. Local inflammatory reactions may be 
accompanied, or even preceded by, flu-like systemic signs and symptoms including malaise, 
pyrexia, nausea, myalgias and rigors. An interruption of dosing should be considered. 
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Contact with eyes, lips and nostrils should be avoided. Use of an occlusive dressing is not 
recommended. Imiquimod should be used with caution in subjects with reduced haematologic 
reserve. 
Following accidental ingestion, nausea, emesis, headache, myalgia and fever could occur after 
a single dose of 200 mg imiquimod which corresponds to the content of approximately 16 
sachets. The most clinically serious adverse event reported following multiple oral doses of 
200 mg was hypotension which resolved following oral or intravenous fluid administration. 
10.6.6.3 Reproductive Precautions 
Women of child-bearing potential may be considered for enrolment if they: 1) have a negative 
urine pregnancy test before study treatment to rule out pregnancy per the protocol; and 2) are 
willing to consent to use effective (i.e., as detailed in the protocol) contraception until Week 
20. All such women will be tested for pregnancy. Any woman who becomes pregnant, before
completion of the Treatment Period, will be monitored, up to and following, the birth of the
child.
10.6.6.4 Hypersensitivity 
Use of ingenol mebutate gel and imiquimod cream is contraindicated in subjects with a 
known hypersensitivity to any ingredient in the formulation.  
10.6.7 Treatment Assignment 
At Day 1 (Visit 2) subjects will be randomised centrally to treatment with ingenol mebutate 
gel or imiquimod cream in a 1:1 ratio stratified by country, anatomical location (face or scalp) 
and history of SCC (none or previous SCC) through the IWR system. The system will assign 
a unique trial medication kit number to each subject. The unique kit number assigned to each 
subject has to be recorded in the CRF.  
10.6.7.1 Randomisation Code List 
During the clinical trial, the randomisation files will be kept in a secure area at Almac Clinical 
Technologies inaccessible to staff involved with the conduct and administration of the clinical 
trial until the trial database is locked. 
10.6.7.2 Subject Identification List 
The investigator will maintain a list of all subjects included in the trial at the trial site 
including each subject's identity, date of enrolment and corresponding CRF book number so 
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that any subject may be identified if required for any reason. The list is kept by the investiga-
tor and will not be copied to LEO Pharma A/S. 
10.6.8 Blinding of the Trial 
Not applicable as this is an open-label trial. 
10.6.9 Breaking the Randomisation Code 
10.6.9.1 Un-blinding of Individual Subject Treatment 
Not applicable as this is an open-label trial. 
10.6.9.2 Un-blinding of the Clinical Trial 
Not applicable. 
10.6.10 Drug Accountability and Compliance Checks 
The investigator is fully responsible for the investigational products at the trial site. Dispens-
ing of investigational products may be delegated to, e.g. a hospital pharmacy as locally 
applicable. 
The person responsible for dispensing the investigational products will be responsible for 
maintaining adequate control of the investigational products and for documenting all transac-
tions with them. Investigational products must be stored in a safe and secure place, and proper 
dispensing arrangements must be made. 
10.6.10.1 Sponsor-Investigator Drug Accountability 
All trial medication kits supplied by Almac Clinical Services on behalf of LEO Pharma A/S 
will be returned to Almac Clinical Services and be fully accounted for by the monitor with the 
help of the person responsible for dispensing trial medication. Accountability will be docu-
mented by use of drug accountability forms, including information of number of used/unused 
tubes/sachets per kit. 
10.6.10.2 Investigator-Subject Drug Accountability 
Subjects will be instructed to return the trial medication kit (containing all dispensed 
tubes/sachets) to the site for assessment of trial medication compliance as follows: 
•
At the Day 4 visit(s) after the first application for subjects treated with ingenol mebutate
•
At the Week 4 visit(s) after the first application for subjects treated with imiquimod
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An inventory (Individual Drug Accountability Form) will be kept of the trial medication 
given to and returned by each subject enrolled 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 trial medication. 
10.6.10.3 End of Trial Drug Accountability 
Almac Clinical Services will be responsible for overall trial medication reconciliation with 
trial medication kits and destruction when the trial is completed. 
10.6.10.4 Treatment Compliance 
The subject will be asked if she/he has used the trial medication as prescribed to assess 
treatment compliance as follows: 
•
At the Day 4 visit(s) after the first application for subjects treated with ingenol mebutate
•
At the Day 4, Week 2 and Week 4 visit(s) after the first application for subjects treated
with imiquimod
If this is not the case, the degree and nature of non-compliance has to be specified and 
recorded in the CRF.  
10.6.11 Prior and Concomitant Treatment 
Prior to the trial 
Prohibited treatments and procedures prior to trial entry are detailed in the Exclusion Criteria; 
see Section 10.4.2 for full details. 
During the trial 
Use of non-marketed/other investigational products are not permitted during the entire trial 
period. 
Concomitant Medications, Treatments and Procedures from start of treatment until 
Week 20 
All concomitant medication currently being taken at time of Day 1 (Visit 2) must be recorded 
in the CRF, along with the reasons for administration of the medication or treatment as well 
as location, described as the selected treatment area, outside the selected treatment area or not 
applicable. 
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No other treatments and procedures are allowed in, and within 5 cm of the selected treatment 
area. Treatment for SCC or any other malignancy is allowed.  
Outside the selected treatment area (up to within 5 cm), procedures such as cryotherapy will 
be allowed; field therapy will not be allowed. 
Any new medication started from Day 1 (Visit 2) until Week 20 must be recorded in the CRF, 
along with the reason for administration of the medication or treatment.  
Prohibited treatments and procedures for the selected treatment area during the treatment 
period are detailed in Table 1. 
Table 1: Prohibited concomitant treatments from the start of treatment until Week 20  
Prohibited Treatment 
Location 
Cosmetic or therapeutic procedures (e.g., use of 
liquid nitrogen, surgical excision, curettage, 
dermabrasion, medium or greater depth chemical 
peel, laser resurfacing) 
within 5 cm of the selected treatment area 
Use of keratolytic topical therapeutic products 
(e.g., alpha- and beta- hydroxy acids, including 
glycolic acid, lactic acid and other fruit acids, 
salicylic acid, topical retinoids, urea or light 
chemical peels): 
within 5 cm of the selected treatment area 
Topical medicated creams, ointments, lotions, 
gels, foams or spray, including topical steroids. 
within 5 cm of the selected treatment area  
Note, may be used 12 days after last treatment 
with investigational product  
Topical non-medicated/non-irritant lo-
tions/creams/gels/sunscreens 
within 5 cm of the selected treatment area. 
Prohibited on treatment days. Subject should 
wash the treatment area with mild soap and water 
prior to use. 
Any topical medications or treatments that might 
influence the intended effects or mask the side 
effects of treatment, such as topical corticoster-
oids 
within 5 cm of the selected treatment area. 
Note, may be used 12 days after last treatment 
with investigational product 
Artificial tanners 
within 5 cm of the selected treatment area 
Treatment/therapy with UVA or UVB 
Anywhere 
Excessive or prolonged exposure to ultraviolet 
light (e.g., sunlight, tanning beds) 
Anywhere 
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5-FU, imiquimod, diclofenac sodium, ingenol
mebutate or photodynamic therapy
Anywhere (other than as study medication) 
Immunomodulators (e.g., azathioprine), cytotoxic 
drugs (e.g., cyclophosphamide, vinblastine, 
chlorambucil, podophyllin, camptothecin) or 
interferon/ interferon inducers 
Not applicable (excluded) 
Medications that suppress the immune system 
(e.g., cyclosporine, prednisone, methotrexate) 
Not applicable (excluded) 
Systemic retinoids (e.g., isotretinoin, acitretin, 
bexarotene) or biologic/monoclonal antibody 
therapies (e.g, alefacept, infliximab rituximab). 
Anywhere during the study 
Other investigational drugs, agents or devices or 
any chemotherapy for cancer treatment or any 
medications or treatments that might influence the 
intended effects or mask the side effects of trial 
medication 
Not applicable (excluded) 
Concomitant Medication, Treatments and Procedures from Week 20 in the Follow-up 
Period: 
In the Follow-up Period information will be collected regarding: 
• concomitant medications, treatments and procedures used in the selected treatment area
• all use of ingenol mebutate or imiquimod whether inside or outside the selected treatment
area
• medication or treatments which may suppress the immune system in the subjects
Procedures such as cryotherapy will be allowed in, and within 5 cm of the selected treatment 
area. Further, at the discretion of the Investigator and as according to nationally available 
product and treatment guidelines, the same treatment as originally administered is allowed 
(imiquimod or ingenol mebutate). Cross-over between imiquimod and ingenol mebutate is 
not allowed. Investigators will be encouraged to pursue these treatment options where 
clinically relevant and before employing other treatments. 
Outside the selected treatment area (up to within 5 cm) all treatments will be allowed, 
although investigators will be encouraged to avoid cross-over between imiquimod and 
ingenol mebutate.  
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No other information on concomitant medications, treatments or procedures will be collected 
for subjects. 
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10.7 TRIAL PROCEDURES 
10.7.1 Schedule of Trial Procedures 
Screening and Treatment Period 
Screening
Treatment Period
Visit Number
1
2
3
4
5
6
7¹
8¹
9¹
10¹
Day/Week
(window)
(-42 to 
-14 days)
Day 
1
Day 
4 
(+2 
days)
Week 
2 
Day 
15 
 (±2 
days)
Week 
4 
Day 
29
(± 3 
days)
Week 
8 
Day 
57 
(±3 
days)
3 days 
after 
Visit 6 
(+2 
days)
Week 
10 
14 
days 
after
Visit 
6 (±2 
days)
Week 
12 
28  
days 
after 
Visit 
6
(± 3 
days)
Week 
16 
56 
days 
after 
Visit 
6 (± 3 
days)
Informed 
consent
X2 
In-/exclusion 
criteria
X
X3 
Medical/surgical 
History
X
Concurrent 
diagnosis
X
X3 
AK and SCC 
treatment 
history
X
Concomitant 
medications, 
treatments, 
procedures
X
X
X
X
X
X
X
X
X
X
Brief physical 
exam4 
X
X
X
X
Vital signs
X
Demographics
X
Height and 
weight
X
Fitzpatrick skin 
type
X
Urine pregnancy 
test5 
X
X
X
Identify selected 
treatment area
X
Mark selected 
treatment area 
on skin
X
 
X1
Biopsy of one 
AK lesion
X
Biopsy if 
suspicion of 
SCC etc.
X
X
X
X
X
X
X
X
Randomisation
X
AK count 
X
X
X
X
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Screening
Treatment Period
Visit Number
1
2
3
4
5
6
7¹
8¹
9¹
10¹
Day/Week
(window)
(-42 to 
-14 days)
Day 
1
Day 
4 
(+2 
days)
Week 
2 
Day 
15 
 (±2 
days)
Week 
4 
Day 
29
(± 3 
days)
Week 
8 
Day 
57 
(±3 
days)
3 days 
after 
Visit 6 
(+2 
days)
Week 
10 
14 
days 
after
Visit 
6 (±2 
days)
Week 
12 
28  
days 
after 
Visit 
6
(± 3 
days)
Week 
16 
56 
days 
after 
Visit 
6 (± 3 
days)
Dispense 
medication 
X
 
X1
Return 
medication
X7
X6
X7
X6 
Compliance
X
X6
X6
X
X6 
X6 
Field assess-
ment for SCC, 
BCC or 
neoplasia
X
X
X
X
X
X
X
X
Local skin 
response (LSR)
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
1.
Only for subjects who are not completely cleared in the selected treatment area at Week 8. Subjects who
have cleared should proceed to the Follow –up period at Visit 11
2.
Can be performed prior to Visit 1
3.
To be checked at Visit 2
4.
Including general appearance, regional lymph nodes and dermatologic examination of the skin in general
5.
Females of childbearing potential only
6.
Imiquimod only
7.
Ingenol mebutate only
Follow-up Period 
Visit Number 
11 
12
13 
14 
15 
16
Week/Month 
(window) 
Week 20 
(±14 days) 
Month 12 
(±14 days) 
Month 18 
 (±28 days) 
Month 24 
 (±28 days) 
Month 30 
 (±28 days) 
Month 36 
(± 28 days) 
Concomitant 
medications, 
treatments, 
procedures 
X
X
X
X
X
X
Field assessment for 
SCC, BCC or 
neoplasia 
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
AK count
X
X
X
X
X
X
Brief physical exam4 
X
X
X
X
X
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Note: Unscheduled/Early Termination 
Upon completion of the last visit or during the study, an unscheduled visit may be required 
for any subject with a severe reaction, suspected pregnancy or an unresolved treatment-
related AE or LSR, if deemed clinically significant by the investigator. Only assessments that 
require follow-up will be conducted if the subject is continuing in the trial. For early termina-
tion all trial assessments scheduled should be performed if possible. 
10.7.2 Subject Eligibility 
Subject eligibility for the clinical trial will be checked according to the inclusion and exclu-
sion criteria as specified in 10.4.1 and 10.4.2 at screening (Visit 1) and confirmed at Day 1 
(Visit 2).  
At Screening (Visit 1) subjects’ demographic details (date of birth, sex, race, ethnic origin, 
height, weight, Fitzpatrick skin type) will be recorded. The subject will self-report their 
ethnicity (Hispanic or Latino, not Hispanic or Latino), and race (American Indian or Alaska 
Native; Asian, Black or African American; Native Hawaiian or Other Pacific Islander; White, 
Other). Relevant medical/surgical history, concurrent diagnosis, skin diseases and AK and 
SCC treatment history will also be recorded. 
The subject’s height will be measured without shoes and weight will be determined with 
indoor clothing and without shoes. 
The abbreviated physical examination will include general appearance, regional lymph nodes 
and dermatologic examination of the skin in general. 
Vital signs (resting blood pressure and heart rate) and oral or ear temperature will be re-
corded.   
For female subjects of childbearing potential a urine pregnancy test will be performed at visits 
specified in 10.7.1. 
Concomitant medication, treatments and procedures will be recorded at visits specified in 
10.7.1. 
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Skin type of the subjects will be assessed by the investigator and recorded according to the 
following classification: 
Fitzpatrick Skin Types  
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 
Relevant medical history (including first date of AK diagnosis) and concomitant diagnoses 
will be recorded at the screening visit (Visit 1) and will be confirmed at Visit 2. 
The selected treatment area will be identified by the dermatologist and documented on the 
study transparency using a three-point landmark technique. Detailed instructions for the three-
point landmark technique are given in Appendix IV. A biopsy will be taken of one AK lesion 
in the selected treatment area (see 10.7.4 ) for histological confirmation of AK prior to 
randomisation at Day 1 (Visit 2). 
10.7.3 Clinical Assessment 
10.7.3.1 Investigator Assessments 
Identification of the selected treatment area and dermatologic assessments of the selected 
treatment area must be performed by a dermatologist (board-certified or equivalent). The 
same dermatologist should attempt to perform all dermatologic examinations of each individ-
ual subject. 
The (sub)investigator will make the following clinical assessments: 
Identification of the selected treatment area 
At Visit 1 identification of the selected treatment area should be documented on a study 
transparency using a three-point landmark technique (See Appendix IV). At all subsequent 
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visits, the transparency should be used to re-locate the selected treatment area for assessment 
of the treated skin on the face or scalp. 
Clinical Assessment of Neoplasia in the selected treatment area 
At all visits clinical assessment of the selected treatment area for neoplasia will be performed. 
If there is suspicion of SCC, BCC, or other neoplasia, a biopsy will be taken (see 10.7.4 ).  
Local Skin Responses 
Assessment of local skin responses in the selected treatment area using the LSR Grading 
Scale should be performed at visit days as specified in the schedule of trial procedures 
(10.7.1).  
Local skin responses are defined as erythema, flaking/scaling, crusting, swelling, vesicula-
tion/pustulation, and erosion/ulceration. The presence/absence and grade of each LSR will be 
recorded using the LSR Grading Scale shown in Appendix III. This grading scale will also be 
provided as hard copy to the site. Any local skin responses identified within the selected 
treatment area which do not match the criteria in the LSR Grading Scale should be reported as 
AEs. 
AK lesion count 
The number of clinically, visible AK lesions identified in the selected treatment area should 
be recorded at the visit days specified in the schedule of trial procedures (Section 10.7.1). At 
Visit 1, the subject should have 5-9 clinically typical, visible and discrete AK lesions.  
10.7.3.2 Subject assessments 
Not Applicable 
10.7.4 Laboratory Assessments 
10.7.4.1 Central Analysis 
Histological Assessments:  
At Screening (Visit 1) a 3-4 mm punch biopsy will be taken from an AK in the selected area 
to confirm the diagnosis of AK as follows: 
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The biopsy area will be cleaned with an appropriate disinfectant. The skin will be numbed 
using an anaesthetic injection with a vasoconstrictor, e.g. adrenaline. Biopsies will be taken 
using a 3-4-mm disposable punch. If possible, the punch should contain tissue from the 
subcutis. The biopsy specimen will be removed from the punch very gently using forceps. 
Care should be taken not to squeeze the biopsy. The biopsy is transferred immediately into a 
plastic tube of approximately 10 mL containing 8 mL 10% neutral buffered formalin (forma-
lin [40% formaldehyde] diluted 10 times in phosphate buffered saline, pH 7.4). It should be 
assured that the biopsy is submerged completely in the fixative. Specimens will be labelled 
with the study number (LP0041-63), subject (CRF) number and Visit. Haemostasis will be 
secured by pressure with gauze and stitching, if considered necessary. The (stitched) biopsy 
site will be left uncovered or sealed with Steristrip® as required.  
The formalin fixed tissue will be shipped to the central pathology laboratory. The central 
laboratory’s assessment determines whether the inclusion criterion of presence of AK in the 
biopsy is fulfilled. 
Biopsies taken because of suspicion of SCC/BCC or other neoplasia will be processed as 
described above. The formalin fixed tissue will be shipped to a central pathology laboratory. 
The central laboratory will have a maximal turn-around time of 2 weeks to e-mail the 
evaluation back to the investigator for appropriate clinical action. Further details will be 
agreed with the central laboratory as to the number of pathologists to be involved in the final 
diagnosis of an SCC and the procedures to be employed to obtain agreement. 
10.7.4.2 Local Analysis 
A urine pregnancy test will be performed at the trial site at the visits specified in 10.7.1. 
in female subjects of child-bearing potential. 
10.7.5 Adverse Events 
Any untoward medical occurrence in a patient 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)).  
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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
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect
or
•
other medically important conditions*), including SCC and BCC within the selected
treatment area
*) 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 out-
comes listed in the definition above. Examples of such events are allergic broncospasm, 
blood dyscrasias and convulsions. 
Global Pharmacovigilance, LEO Pharma A/S is responsible for the assessment of headquarter 
expectedness according to LEO Pharma A/S procedures. The relevant reference document for 
this clinical trial is current version of the SmPC for ingenol mebutate gel (21) and subsequent 
updates as agreed between the head of Medical Department, and the medical director, Global 
Pharmacovigilance, LEO Pharma A/S. The current version of the SmPC for imiquimod 
(Aldara®) (appendix V) will be used for the assessment of expectedness for imiquimod. 
At all visits, after Visit 1, the subject will be asked a non-leading question by the 
(sub)investigator: “How have you felt since I saw you last?” No specific symptoms will be 
asked for. 
If there are no AEs to record (see Table 2 and Table 3 for reportable AEs), no further 
questions will be asked and “NO” should be stated. In case there are one or more AEs to 
record, “YES” should be stated and the investigator will record the event term, intensity, 
duration, suspected causal relationship to the investigational product and outcome. 
It is important that the investigator also observes the subject for any changes not reported by 
the subject and records these changes where reportable (see Table 2 and Table 3). 
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Only medically qualified personnel must assess AEs. A dermatologist (board-certified or 
equivalent) must do all dermatologic examinations, LSRs and AE evaluation in the selected 
treatment area. 
If the informed consent is obtained before Visit 1, any medical changes until Visit 1 should be 
included in the medical history and not reported as an AE. 
10.7.5.1 Reporting of Adverse Events 
Events reported by the subject or observed by the (sub)investigator and that fall into any of 
the categories below must be recorded on the adverse event page of the CRF: 
Table 2:  
Adverse Event Reporting for Visits until Week 20 
Adverse Event 
Inside treatment area 
Outside treatment area  
including non-cutaneous events 
BCC/SCC 
All BCC/SCCs should be 
recorded in the CRF and 
reported to LEO as SAEs. 
All serious and non-serious BCC/SCCs 
should be recorded in the CRF.  
Serious BCC/SCCs should be reported 
to LEO as SAEs.  
Other AEs 
All AEs and SAEs should be 
recorded in the CRF.  
Serious AEs should be reported 
to LEO as SAEs.  
All AEs and SAEs should be recorded 
in the CRF.  
Serious AEs should be reported to LEO 
as SAEs. 
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Table 3:  
Adverse Event Reporting for Visits after Week 20 
Adverse Event 
Inside treatment area 
Outside treatment area 
including non-cutaneous events 
BCC/SCC 
All BCC/SCCs should be 
recorded in the CRF and 
reported to LEO as SAEs. 
All serious and non-serious BCC/SCCs 
should be recorded in the CRF. 
Only serious BCC/SCCs related to the 
treatment should be reported to LEO as 
SAEs.  
Other AEs 
All AEs and SAEs should be 
recorded in the CRF.  
Serious AEs should be reported 
to LEO as SAEs.  
Only SAEs related to the treatment 
should be recorded in the CRF.  
These should be reported to LEO as 
SAEs. 
Please note: Local Skin Responses which match the criteria in the LSR Grading Scale are to 
be reported as LSRs in the CRF and not as AEs even if they require treatment. Any treatment 
should be recorded on the Concomitant medication page of the CRF together with the most 
important LSR (e.g. swelling should be reported as swelling-LSR).  
Adverse events should be described in the following manner: 
The nature of the event will be described 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 adverse events the anatomical location of the adverse event must be part of the adverse 
event description and may be described as the ‘in the selected treatment area’, ‘within 5 cm of 
the selected treatment area’, ‘more than 5 cm from the selected treatment area’ (with further 
specification for BCC/SCCs) or ‘not applicable’. 
The intensity of the event will be described in terms of mild, moderate or severe according to 
the investigator’s clinical judgement. 
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•
Mild: The adverse event does not interfere in a significant manner with the subject’s
normal functioning level and requires no medical intervention.
•
Moderate: The adverse event interferes with the subject’s normal functioning level and
may or may not require medical intervention.
•
Severe: The adverse event produces significant impairment of the subject’s functioning or
requires medical intervention.
The duration of the event will be reported as the start date and stop date of the event. 
For AEs recorded on Day(s) of starting treatment, it should be specified whether the AE 
started prior to or after first application of trial medication. 
The causal relation of the event to the use of the investigational product will be described in 
terms of probable, possible, not related or not assessable 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 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 investiga-
tional product
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•
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 follow a known pattern of response to the investigational product
Not assessable 
•
The adverse event cannot yet be judged otherwise because present information is insuffi-
cient or contradictory. A final assessment (i.e. probably, possibly or not related) shall be
made as more information becomes available, at the latest when the subject has completed
the trial.
The outcome of the event will 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, however, not yet completely resolved. 
Follow-up on the event is required until final 
outcome is established. 
•
Not recovered/not resolved
Event is still ongoing.  
Follow-up on the event is required until final 
outcome is established. 
•
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. 
•
Fatal
The subject has died as a consequence of the event.  
Date of death is recorded as stop date for the 
adverse event. 
•
Unknown
Unknown to investigator, e.g. subject lost to follow-
up. 
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Upon completion of the last visit, an unscheduled visit may be required for any subject with 
an unresolved, treatment-related AE or LSR, if deemed clinically significant by the investiga-
tor. 
Once a subject has completed the clinical trial, the investigator should follow up for outcome 
on all non-serious adverse events classified as possibly/probably related to the investigational 
product for 6 months or until final outcome is determined, whichever comes first. 
10.7.5.2 Other events to be reported 
Pregnancy 
Pregnancy which occurs during a clinical trial must be reported to LEO Pharma A/S within 
one calendar day of first knowledge using the Pregnancy Follow-up Form supplied by LEO 
Pharma A/S. All pregnancies must be followed up until delivery or termination. 
Overdose 
Any overdose defined as any higher dose than prescribed for the individual subject must be 
reported on the adverse event form of the CRF book. AEs originating due to the overdose 
must be documented on a separate line. 
Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of the initially treated condi-
tion compared to baseline, judged by an overall medical assessment, must be reported as an 
AE. 
10.7.6 Serious adverse events 
10.7.6.1 Reporting of Serious Adverse Events 
Any Serious Adverse Event (SAE), related or unrelated to the investigational product or any 
trial procedure after signature of the Informed Consent Form must be reported to LEO 
Pharma A/S on the (paper) Serious Adverse Event Form – Clinical Trial within one 
calendar day, with the exception that: 
•
After Week 20, non-related serious adverse events outside the treatment area should not
be reported to LEO Pharma A/S (see Table 2 and Table 3)
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An LSR classified as a SAE must be reported on the adverse event form in the CRF and 
reported to LEO Pharma A/S on the paper Serious Adverse Event Form (SAE) – Clinical 
Trial. 
Note: Planned hospitalisation or planned prolonged hospitalisation do not fulfil the criteria 
for being an SAE. The elective nature of the event must be clearly documented in the 
subject’s medical record. 
SAEs must be reported on the adverse event form of the CRF book. Additionally reports must 
be made using the paper Serious Adverse Event (SAE) Form – Clinical Trial, supplied by 
LEO Pharma A/S. Apart from the assessment of the intensity, causal relationship to the 
investigational product(s) and/or trial procedures, the action taken and the outcome to date, 
this report must contain a comprehensive narrative description of the course of the event. 
The completed LEO Serious Adverse Event (SAE) Form – Clinical Trial must be faxed or 
scanned and e-mailed Global Pharmacovigilance at LEO Pharma A/S: 
LEO Pharma A/S Head Quarter 
Denmark, Global Pharmacovigilance 
Industriparken 55, DK-2750 Ballerup, Denmark 
Global Pharmacovigilance Fax: +45 72 26 32 87 
E-mail: drug.safety@leo-pharma.com
All other relevant reports of diagnostic procedures, hospital records, autopsy reports etc. must 
be included, as applicable or upon request from Global Pharmacovigilance. 
The IRB(s)/IEC(s), regulatory authorities and concerned investigators will be notified of 
SAEs according to current regulation and local requirements. 
All Suspected, Unexpected Serious Adverse Reactions (SUSARs) are subject to expedited 
reporting to regulatory authorities.  
SAEs must be followed indefinitely 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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10.7.7 Source Data 
Source data: All information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the recon-
struction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). (ICH E6, 1.51). 
Source documents: Original documents, data, and records (e.g., hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or tran-
scriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the phar-
macy, at the laboratories and at medico-technical departments involved in the clinical trial). 
(ICH E6, 1.52). 
Source Data Verification (SDV) is a key function in assuring the sponsor that clinical trial 
information is recorded and handled in a way that allows its accurate reporting, interpretation 
and verification. Monitors will, during the conduct of the clinical trial, perform SDV to 
confirm the accuracy and completeness of CRFs by verifying selected (as specified below) 
data recorded in the CRF against data recorded in source documents to ensure such records 
are consistent.  
To enable SDV, it is essential that what constitutes source data/documents (see definition 
above) for the clinical trial data to be collected in the CRF as well as where such data can be 
found at the trial site is established and agreed with the investigator at each trial site and 
documented prior to initiation of the clinical trial.  
Source data cannot be entered directly into the CRF. 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 may be entered on a worksheet only if the clinical trial requires capture of 
data, which are normally not part of the subject’s medical record. 
For this clinical trial, the following parameters collected in the CRF should be verifiable from 
source documents available at the trial site: 
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•
Date of trial visits and date leaving the clinical trial
•
Relevant medical history and diagnosis, including AK and other skin diseases
•
Nature of contraception used  by the subject and result of pregnancy test(s), when
applicable
•
Data for evaluation of eligibility criteria
•
Abbreviated physical examination
•
Dispensation/administration of trial medication and compliance
•
Concomitant medication (including changes) and diagnoses
•
Subject demographics (e.g. sex, date of birth)
•
Adverse events, (nature, dates)
•
LSRs and AK lesion count
•
Dates and reason for any biopsy
•
Biopsy results
In addition to the above, the following should be added to the subject’s medical record in 
chronological order, i.e. when these are allocated to the subject: 
•
Date(s) of conducting the informed consent process including date of provision of subject
information
•
Date of enrolment
•
CRF book number
•
Study medication kit number(s)
•
The fact that the subject is participating in a clinical trial in AK including treatment with
ingenol mebutate gel, 0.015% or imiquimod cream, 5% for 36 months
10.8 EFFICACY EVALUATION 
Evaluation of efficacy is a secondary objective. 
10.8.1 Secondary Efficacy Response Criteria 
The secondary response criteria are: 
•
Complete clearance after the last treatment cycle (at Week 8 or 16)
•
Partial (at least 75%) clearance after the last treatment cycle (at Week 8 or 16)
•
Complete clearance at 12 months, defined as no AKs at any time in the selected treatment
area at any time from the last treatment cycle at Week 8 or 16 through to Month 12.
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10.9 SAFETY EVALUATION 
The evaluation of the risk of SCC is the primary objective of this trial.  
10.9.1 Primary Response Criterion 
Diagnosis of SCC (defined as invasive SCC i.e. excludes SCC in situ) in the treatment field 
across the 3-year trial period 
10.9.2 Secondary Safety Response Criterion 
Diagnosis of SCC and other neoplasia in the treatment field over a 3-year period. 
10.9.3 Safety Evaluation 
•
Incidence and severity of LSRs
•
Incidence of AEs
•
Incidence of SAEs
10.9.4 Evaluation of (Serious) Adverse Events 
Any (serious) adverse events reported. 
10.9.5 Evaluation of Laboratory Data 
Not applicable 
10.10 STATISTICAL ANALYSIS 
All hypotheses will be tested using two-sided tests with a significance level of 0.05. The null 
hypothesis for all treatment arm comparisons is that there is no difference between the arms 
versus the two-sided alternative that there is a difference between the treatment arms. 
Study results will be summarised into tabulations, listings and figures where appropriate. 
10.10.1 Subject Qualification for Analysis 
All subjects for whom a signed informed consent is obtained and a CRF is started will be 
accounted for in the study report. 
Efficacy analyses will be based on the Full Analysis Set (FAS), which is defined as all 
randomized subjects. Safety analyses will be based on the Safety Analysis Set, which is 
defined as all subjects who receive an initial study treatment and have safety data available. 
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A per protocol (PP) analysis set will be used as safety and efficacy subsets and will be defined 
as subjects in the FAS who complete the trial without major protocol deviations. The compo-
sition of the PP analysis set will be determined and documented in reviews of the study 
database. The safety and efficacy analyses based on the PP analysis set will be performed to 
support the results obtained for the primary and secondary safety and efficacy endpoints. 
10.10.2 Subjects Disposition 
Frequencies of the analysis sets, in total and by treatment arm, will be tabulated. Also reasons 
for premature discontinuations from treatment and from the trial will be presented for the 
FAS. 
10.10.3 Baseline Characteristics 
Descriptive statistics of demographic and other baseline characteristics will be presented for 
the FAS. Demographics will include age, sex, race, ethnic origin and skin types. Other 
baseline characteristics will include height, weight, vital signs, body temperature, other 
diagnoses and concomitant medication. Baseline AK characteristics will include treatment 
location (face or scalp) and baseline lesion count. 
Categorical data will be summarized using the number and percentage of subjects in each 
category and treatment arm. Continuous data will be summarized using the mean, median, 
standard deviation (SD), minimum and maximum values. 
10.10.4 Analysis of Efficacy 
Analysis of Secondary Efficacy Endpoints 
The secondary efficacy endpoints are listed in section 10.8.1.   
The complete and partial clearance rates after the last treatment cycle as well as the complete 
clearance rates at 12 months will be compared between the two treatment arms using a 
Cochran–Mantel-Haenszel stratified by country, anatomical location and history of SCC. The 
ratio of rates will be estimated together with its 95% confidence interval.   
10.10.5 Stratification 
Randomisation will be stratified by country, anatomical location (face or scalp) and history of 
SCC (none or previous SCC). Three countries are identified with a total of 48 investigational 
sites. Roughly 10 subjects will be enrolled at each site. 
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10.10.6 Safety Analysis 
10.10.6.1 Analysis of Primary and Secondary Safety Endpoints 
The primary endpoint and secondary safety endpoint are listed in sections 10.9.1 and 10.9.2 
respectively. Both endpoints will follow the same method of analysis. 
The 3-year cumulative incidence will be calculated for each treatment group using methods of 
survival analysis for estimation of cumulative incidence in the presence of censored time-to-
event data. Annual incidence rates will also be presented for each group. The cumulative inci-
dence rates will be presented for the event of SCC as primary endpoint and for SCC and other 
neoplasia as secondary. No formal statistical test comparing the two arms will be performed. 
For descriptive purposes, as an additional analysis, the difference in cumulative incidence 
rates between the two arms will be estimated and presented together with its 95% confidence 
interval. 
A landmark analysis, conditional on patients’ responses at Week 20, will additionally be 
performed in order to exclude SCC and other neoplasia reported within the first 20 weeks 
which are not assumed to be associated with the study treatment. Patients who experience a 
neoplasia before the 20-week landmark time point are excluded from the time-to-event 
analysis, which is otherwise conducted as above. 
10.10.6.2 Adverse Events 
Reporting of adverse events will be based on the Safety Analysis Set.  
All adverse events recorded will be reported in listings. The investigator’s verbatim term of 
each adverse event will be mapped to SOC and preferred terms using the current version of 
the Medical Dictionary for Regulatory Activities (MedDRA) thesaurus. 
An overall summary of the number (percentage) of subjects with any treatment emergent 
adverse events (TEAEs), SAEs, premature discontinuations from treatment or from the trial 
due to adverse events, treatment related AEs, LSRs, severe AEs (maximum intensity indi-
cated as severe in the CRF) will be presented. The overall and treatment related AE summary 
will also be presented by trial period of the start date of AEs: until Week 20, from Week 20 
until Month 12, Month 12 to 24, Month 24 to 36). 
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The number and percent of subjects with AEs will be tabulated by body system and preferred 
term for the above summaries. Within a specific body system or preferred term, the subject 
will be counted only once if more than one event is reported. Summaries will be presented by 
decreasing frequency. 
Listings will be provided for all subjects with SAEs and study discontinuations due to adverse 
events. 
10.10.6.3 Local Skin Responses 
The incidence and grade of LSRs will be summarised by treatment arm at each assessement 
visit by anatomical location based on the Safety Analysis Set. Local skin response grades will 
be summarised by frequency counts and descriptive statistics by treatment arm and visit for 
each of the six individual LSRs: erythema, flaking/scaling, crusting, swelling, vesicula-
tion/pustulation, and erosion/ulceration. 
A composite (sum) score will be obtained by summing the six individual LSR scores at each 
visit. The composite score and change from baseline will be summarized by treatment arm at 
each visit using descriptive statistics. The visit of occurrence of maximal intensity will be 
tabulated. 
Local skin responses will be converted into MedDRA preferred terms applying the following 
conversions seen in Table 4. These adverse events will be reported separately from adverse 
events recorded on the adverse event form in the CRF. 
Table 4: Conversion of LSRs to MedDRA Preferred Terms 
LSR Term 
LSR Grade 
MedDRA Preferred Term 
Erythema 
1-4
Application site erythema  
Flaking/Scaling
1-4
Application site exfoliation.  
Crusting
1-4 
Application site scab
Swelling
1-4
Application site swelling
Vesiculation/Pustulation 
1
Application site vesicles
2-4
Application site pustules
Erosion/Ulceration 
1-3
Application site erosion 
4
Application site ulcer
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10.10.6.4 Laboratory Safety Examinations 
Not applicable. 
10.10.7 Interim Analysis 
An interim analysis of trial data, obtained when approximately half of the trial period has 
elapsed, will be conducted. Assuming the time schedule shown in section 10.2, this will be 
prepared 3 years after study start. The interim analysis will not impact the conduct of this 
trial. 
10.11 TRIAL COMMITTEES 
A trial committee is not regarded applicable, as all safety issues will be handled by experi-
enced investigators at the sites. 
10.12 QUALITY ASSURANCE/AUDIT 
LEO Pharma A/S has implemented a system of quality assurance, including all elements 
described in this protocol. Within this system company Standard Operating Procedures 
(SOPs) are implemented to ensure that clinical trials are conducted in compliance with 
regulatory requirements and Good Clinical Practice (GCP). Quality control is applied to each 
stage of data handling to ensure that data are accurate, reliable and processed correctly. 
Trial sites, facilities, laboratories and all data (including sources) and documentation must be 
available for GCP audit by LEO Pharma A/S or inspection by competent authorities. 
Any aspect of the clinical trial may be subject to audit by LEO Pharma A/S and/or inspection 
by regulatory authorities (national or foreign) or IEC/IRB. Such audits/inspections may take 
place at the sponsor’s site(s) or at any trial site including, pharmacies etc. 
The monitor will, in case of audit, announce this in advance to the (sub)investigator and, if 
possible, be present at the particular trial site during the audit. 
The site staff should assist in all aspects of audit/inspection. 
10.12.1 Trial Monitoring 
LEO Pharma A/S, as sponsor of this clinical trial, is responsible to the regulatory authorities 
for assuring the proper conduct of the clinical trial with regard to protocol adherence and 
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validity of the data recorded in the CRFs. The company has therefore assigned persons to 
monitor this trial. Their duties are to serve as the principal link between (sub)investigators and 
LEO Pharma A/S and advise the investigator on the collection and maintenance of accurate, 
complete, legible, well organised and easily retrievable data for the clinical trial. In addition, 
they will explain to the investigators any aspect of the (conduct of the) clinical trial, including 
interpretation of the protocol, the purpose of collecting the specified data and reporting 
responsibilities. 
In order to perform their role effectively, monitors and persons involved in quality assurance 
and inspections (see above) will need direct access to primary subject data, e.g. medical 
records, laboratory reports, appointment books etc. Because this affects the subject’s confi-
dentiality, this fact is included on the Subject Information Sheet and Informed Consent Form. 
This clinical trial is organised by LEO Pharma A/S and all enquiries should be made to a 
member of LEO Pharma A/S staff (see section 6.3, LEO Pharma A/S Personnel).  
10.13 CASE REPORT FORM BOOKS AND DATA HANDLING 
10.13.1 Case Report Forms (CRFs) 
In this clinical trial data will be collected by means of Remote Data Capture (RDC). The 
investigator or staff authorised by the investigator will enter subject data into electronic CRFs 
designed by LEO Pharma A/S. A uniquely numbered CRF book will be used for each subject 
enrolled. Data recorded in the electronic CRFs will be accessible to site staff through a secure 
internet connection immediately after entry. The CRFs must be maintained in an up-to-date 
condition at all times by the investigator.  
The investigator, or sub-investigator(s) authorised by the investigator, will electronically sign 
all sections of CRFs used. This signature information (incl. date of signature) will be kept in 
the audit trail and cannot be altered. Only medically qualified (sub)investigators can sign data 
on clinical assessments/safety. Any correction(s) made by the investigator or authorised site 
staff to the CRF after original entry will be documented in the audit trail. Changes to data 
already approved, requires the re-signature of the investigator or authorised staff. The person 
making the change and the date, time and reason for the change will be identified in the audit 
trail.  
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The trial monitor will check the CRFs for accuracy and completeness and perform source data 
verification preferably no later than 12 weeks after each subject visit. For archiving purposes 
each investigator will be supplied with a copy of the CRFs, for all subjects enrolled at the trial 
site, via an electronic medium at completion of the trial. Audit trail information will be 
included. CRFs will be available for inspection by authorised representatives from LEO 
Pharma A/S (e.g. audit by the quality assurance department), from regulatory authorities 
and/or IEC/IRBs. 
10.13.2 Data Handling 
Subject data should be entered into the electronic CRF in a timely manner by authorised site 
staff. Data will be entered by site staff and systematic data validation will be performed 
through the discrepancy management system within the data collection software. Queries for 
discrepant data may be generated automatically by the system upon entry or generated 
manually by the monitor or the study data manager. All queries, whether generated by the 
system or by a user, 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.  
10.14 PROTOCOL AMENDMENTS 
Neither the investigator(s) nor LEO Pharma A/S will change the Clinical Study Protocol 
without written agreement between LEO Pharma A/S and the international co-ordinating 
investigator. Any modification considered substantial requires approval/favourable opinion by 
the appropriate regulatory authority and IEC/IRB. 
Protocol amendments are issued as Consolidated Clinical Study Protocols comprising all 
current amendments. Consolidated Clinical Study Protocols become effective when written 
approval has been provided by the international co-ordinating investigator, the head of 
Medical Department and the head of Biostatistics and Data Management, LEO Pharma A/S, 
and approval/favourable opinion from regulatory authorities and/or IEC/IRB has been 
obtained, as required. 
Alternatively, a protocol addendum may be issued to comply with national/regional specific 
requirements. A protocol addendum becomes effective when written approval has been 
provided by the international co-ordinating investigator, the head of Medical Department and 
the head of Biostatistics and Data Management, LEO Pharma A/S, and the and ap-
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proval/favourable opinion from the relevant regulatory authorities and/or IEC/IRB has been 
obtained, as required. 
10.15 COMPLETION OF TRIAL 
10.15.1 Trial Completion Procedures 
The end of trial is the date of the last subject’s last visit. 
Investigators will be informed when subject recruitment is to cease. 
Trial enrolment will be stopped at a trial site when the total requested number of subjects for 
the clinical trial has been obtained, irrespective of the specific site’s planned inclusion 
number. 
Upon completion of the clinical trial, LEO Pharma A/S will undertake arrangements for 
collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. 
LEO Pharma A/S may stop the clinical trial prematurely after consultation with the interna-
tional co-ordinating investigator, e.g. if the subject recruitment is so slow that the clinical trial 
cannot be completed within a reasonable time frame. Notification of such premature termina-
tion/suspension of the trial will be given to regulatory authorities and IECs/IRBs, as required. 
10.15.2 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. 
10.15.3 Archiving of Trial Documents 
The investigator at each trial site must make arrangements to store the essential trial docu-
ments, (as defined in Essential Documents for the Conduct of a Clinical Trial (ICH E6, 
Guideline for Good Clinical Practice)) including the Investigator Trial File, until LEO Pharma 
A/S informs the investigator that the documents are no longer to be retained. 
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 completion of the trial (e.g. in 
case of inspection from regulatory authorities). 
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The investigator is required to ensure the continued storage of the documents, even if the 
investigator, for example, leaves the clinic/practice or retires before the end of the required 
storage period. 
At present according to ICH Guideline: 
Essential documents should be retained until at least 2 years after last approval of a market-
ing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinua-
tion of clinical development of the investigational product. These documents should be 
retained for a longer period however if required by the applicable regulatory requirements or 
by an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. (ICH E6, 
4.9.5) 
11 USE OF INFORMATION 
This Clinical Study 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 
Pharma A/S and shall not be used by the investigator for purposes other than this clinical trial. 
The investigator agrees that LEO Pharma A/S 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. 
12 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. 
This clinical trial is a multi-centre clinical trial, and publication by an investigator of his/her 
trial results shall not be made before the first multi-centre publication is made public. Such 
multi-centre publication will be prepared in collaboration between LEO Pharma A/S and the 
members of a writing committee, which shall be appointed by LEO Pharma A/S. 
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If there is no multi-centre publication within eighteen (18) months after the clinical trial has 
been completed or terminated at all trial sites and all data has been received, defined as data 
base 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 Pharma A/S a copy of 
all such manuscripts, and LEO Pharma A/S shall have rights to review and comment. Upon 
the request of LEO Pharma A/S 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 Pharma A/S, delay the publica-
tion or presentation to allow LEO Pharma A/S to protect its inventions and other intellectual 
property rights described in any such manuscripts. In case the first multi-centre publication is 
still on-going and has not been made public at the time of notification, LEO Pharma A/S 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 Pharma A/S also subscribes to the joint position of the innovative pharmaceutical 
industry (45) for public disclosure of clinical trial results in a free, publicly accessible 
database, irregardless of outcome. 
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Padilla RS, Sebastian S, Jiang Z, Nindl I, Larson R. Gene expression patterns of normal
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Burge SM, Bristol M, Millard PR, Dawber RP. Pigment changes in human skin after
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Dinehart SM. Treatment of actinic keratoses. J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):
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Efudix (fluorouracil) Summary of Product Characteristics (UK). 2010, Meda Pharmaceu-
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10. Solaraze Gel (diclofenac sodium 3%) Package Insert (FDA-approved). 2008, Phar-
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11. Solaraze Gel (diclofenac sodium 3%) Summary of Product Characteristics (UK). 2010,
Almirall, S.A.
12. Aldara Cream, 5% (imiquimod) Package Insert (FDA-approved). 2009, Graceway
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13. Zyclara Cream, 3.75% (imiquimod) Package Insert (FDA-approved). 2010, Graceway
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14. Aldara Cream, 5% (imiquimod) Summary of Product Characteristics  (EU-approved).
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15. Fu W, Cockerell CJ. The actinic (solar) keratosis:  A 21st century perspective.  Arch
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16. Szeimies RM, Gerritsen M-JP, Gupta G, et al. Imiquimod 5% cream for the treatment of
actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled,
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17. Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, Lee JH, Fox TL.
Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III,
randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol.
2004 May;50(5):714-21.
18. Alomar A, Bichel J, McRae S. Vehicle-controlled, randomized, double-blind study to
assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in
one or two courses of treatment of actinic keratoses on the head. Br J Dermatol. 2007
Jul;157(1):133-41
19. Jorizzo J, Dinehart S, Matheson R, Moore JK, Ling M, Fox TL, McRae S, Fielder S, Lee
JH. Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied
3 days per week in one or two courses of treatment for actinic keratoses on the head. J
Am Acad Dermatol. 2007  Aug;57(2):265-8.
20. Lee PK, Harwell WB, Loven KH, Phillips TJ, Whiting DA, Andres KL, Lee JH. Long-
term clinical outcomes following treatment of actinic keratosis with imiquimod 5%
cream. Dermatol Surg. 2005 Jun;31(6):659-64.
21. Summary of Product Characteristics for Ingenol Mebutate (Picato®).
22. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol Mebutate
Gel for Actinic Keratosis. N Engl J Med 2012;366:1010-9
23. Stockfleth  E, Kerl H. Guidelines for the management of actinic keratoses. Eur J Derma-
tol 2006; 16 (6): 599-606.
24. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol 1994;131:455-464,
25. Esmann S, Jemec GB. Management of actinic keratosis patients: a qualitative study.  J
Dermatolog Treat. 2007;18(1):53-8.
26. Thai KE, Fergin P, Freeman M, Vinciullo C, Fancis D, Spelman L, et al. A prospective
study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol.
2004 Sep;43(9):687-92.
27. Holmes C, Foley P, Freeman M, Chong AH. Solar keratosis: epidemiology, pathogenesis,
presentation, and treatment. Australas J Dermatol. 2007 May;48(2):67-76.
28. Alam M. Actinic keratoses: prevalence, pathogenesis, presentation, and prevention. Adv
Stud Med. 2006;6(8A):S785-90.
29. Ibrahim SF, Brown MD. Actinic keratoses: a comprehensive review. J Clin Aesthetic
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30. Vatve M, Ortonne JP, Birch-Machin MA, Gupta G. Management of field change in
actinic keratosis. Br J Dermatol. 2007 Dec; 157 Suppl 2:21-4.
31. Ortonne JP. From actinic keratosis to squamous cell carcinoma.  Br J Dermatol. 2002
Apr;146 Suppl 61:20-3.
32. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to
squamous cell carcinoma. Lancet 1988; i:795–7.
33. Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses
and the controversy over treatment. Arch Dermatol 1991; 127:1029–31.
34. Hartwell JL. Plants used against cancer. A survey.  Lloydia. 1969 Sep;32(3):247-96.
35. Maiden JH. Weeds of New South Wales.  Ag Gazette NSW. 1917;28:56-58.
36. Rizk AM, Hammouda FM, El-Missiry, Radwan HM, Evans FJ. Biologically active
diterpene esters from Euphorbia peplus.  Phytochemistry. 1985;24(7):1605-6.
37. Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, et al. Antitumour
activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and ne-
crotic cell death.  Cancer Res. 2004 Apr 15;64(8):2833-9.
38. Hampson P, Chahal H, Khanim F, Hayden R, Mulder A, Assi LK, et al.  PEP005, a
selective small-molecule activator of protein kinase C, has potent antileukemic activity
mediated via the delta isoform of PKC.  Blood. 2005 Aug 15;106(4):1362-8.
39. Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM. Characterization
of the interaction of ingenol 3-angelate with protein kinase C.  Cancer Res. 2004 May
1;64(9):3243-55.
40. Cozzi SJ, Parsons PG, Ogbourne SM, Pedley J, Boyle GM.  Induction of senescence in
diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of
the mitogen-activated protein kinase pathway.  Cancer Res. 2006 Oct 15;66(20):10083-
91.
41. Hampson P, Kavanagh D, Smith E, Wang K, Lord JM, Rainger G. The anti-tumor agent,
ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by acti-
vation of vascular endothelial cells in the PKCδ dependent manner.  Cancer Immunol
Immunother. 2008 Aug;57(8):1241-51.
42. Serova M, Ghoul A, Benhadji KA, Faivre S, Le Tourneau C, Cvitkovic E, et al. Effects of
protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated
protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells.  Mol Cancer
Ther. 2008 Apr;7(4):915-22.
43. Olsnes AM, Ersvær E, Ryningen A, Paulsen K, Hampson P, Lord JM, et al. The protein
kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and
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increases constitutive chemokine release by primary acute myeloid leukaemia cells.  Br J 
Haematol. 2009 Jun;145(6):761-74. 
44. Challacombe JM, Suhrbier A, Parsons PG, Jones B, Hampson P, Kavanagh D, et al.
Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with
ingenol-3-angelate. J Immunol. 2006 Dec 1;177(11):8123-32.
45. 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_2009_
Up-
dated_Joint_Position_on_the_Disclosure_of_Clinical_Trial_Information_via_Clinical_Tr
ial_Registries_and_Databases.pdf
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14 LIST OF APPENDICES 
Appendix I: 
English translation of the Danish Data Protection Agency’s  
terms and conditions for the processing of clinical trial data  
by medical companies  
Appendix II: 
Declaration of Helsinki [last amended Seoul 2008]  
Appendix III: 
Local Skin Response Grading Scale  
Appendix IV: 
Documentation of the Selected Treatment Area on the Study Transparency  
Appendix V: 
Imiquimod Summary of Product Characteristics  
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Appendix I 
English translation of the Danish Data Protection Agency’s  
terms and conditions for the processing of clinical trial data  
by medical companies 
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English translation of the Danish Data Protection Agency’s terms and conditions for the 
processing of clinical trial data by medical companies*) 
Listed below please find an English version of the general terms and conditions, set by the 
Danish Data Protection Agency, in cases involving authorisation for the processing of 
sensitive data by medical companies conducting continuous clinical trials of medical prod-
ucts. Circumstances may warrant some variation in the terms and conditions in concrete 
cases. 
AUTHORISATION to process personal data 
The Data Protection Agency hereby grants authorisation for processing of personal data for 
the purpose of the Company's continuous clinical trials, cf. section 50(1)(i) of the Danish Act 
on Processing of Personal Data. In this connection, the Data Protection Agency lays down the 
following terms: 
General terms 
Period of validity: The authorisation is valid until further notice. 
1.
LEO Pharma A/S - hereinafter called the "Company" is responsible for compliance with
these present terms.
2.
The data may be used for the sole purpose of performing clinical trials.
3.
The Company shall once a year to the Data Protection Agency submit an overview of
new, commenced trials as well as a corresponding overview of which trials have been
completed in the past year. The overview shall contain as a minimum a title of the trial
and name and address of the clinically responsible investigator.
*)
Source: Letter dated 07-Mar-2003 from the Danish Data Protection Agency (Datatilsynet) to the Danish 
Association of Pharmaceutical Industries (LIF) 
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4.
Processing of personal data must be performed only by the controller or at the instance of
the controller and at his responsibility. It is the responsibility of the controller that com-
pliance of the terms is always observed when data are processed.
5.
Any person processing personal data must be cognizant of these present terms.
6.
The terms must be complied with also where processing is made by a data processor.
7.
Facilities used for storage and processing of the data must be organized and fitted up in
order to prevent unauthorized access.
8.
Data processing must be organized in such a manner that data are protected against
accidental or unlawful destruction, loss or impairment. Furthermore, the necessary con-
trol should be exercised to ensure that no inaccurate or misleading data are processed.
Inaccurate or misleading data or data processed in contravention of the above Act or of
these terms shall be rectified or erased.
9.
Data must not be kept in a form that makes it possible to identify the data subject for a
longer period than is necessary for the implementation of the project.
10. If results from the clinical trial are published this must be done so that it is impossible to
identify individual persons.
11. It is a condition that compliance is made with related terms, if any, laid down in accor-
dance with other legislation.
Electronic data 
12. Identification data must be encrypted or replaced by a code number or the like. Alterna-
tively, all data can be stored encrypted. Encryption keys, code keys etc. must be stored
securely and separate from the personal data.
13. Access to project data can be obtained only through the use of a confidential password. A
password must be replaced at least once a year and when conditions dictate it.
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14. If personal data are transferred over the Internet or other external network, the necessary
security measures must be taken to ensure that the data do not come to the knowledge of
any unauthorized third parties. As a minimum, the data must be encrypted during trans-
mission. Transmission of sensitive personal data requires strong encryption. When using
internal networks, it must be ensured that unauthorized persons are unable to obtain ac-
cess to the data.
15. Removable storage media, safety copies of data etc. must be stored securely and under
lock and so that unauthorized access is prevented.
Manual data 
16. Manual clinical trial materials, including print-outs, failure lists and control lists etc., as
well as other material which may directly or indirectly be linked with specific persons,
must be stored securely under lock and so that unauthorized access is prevented.
Bio-bank and biological material 
17. Samples with biological material and biological material in bio-banks must be stored
securely under lock so that unauthorized access is prevented and in such a manner that it
is ensured that the material is not lost, impaired or accidentally or illegally destroyed.
18. Biological material marked with civil registration number or name must be stored subject
to special safety requirements.
19. The Company shall lay down internal guidelines for storage of biological material
relative to the individual trials, and guidelines for storage of biological material in bio-
banks. The guidelines shall be updated at least once a year.
Information to be provided to the data subject (trial subject) 
20. Where the personal data are to be obtained from the trial subject (through interviews,
questionnaires, clinical or para-clinical examination, treatment, observation etc.), detailed
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data about the project shall be distributed/forwarded to the trial subject. The trial subject 
must be informed of the name of the controller, the purpose of the project and of the fact 
that it is voluntary to participate and that consent may be withdrawn at any time. Where 
the data are to be disclosed to be used for other scientific or statistical purposes, the trial 
subject shall be advised also of the purpose of the disclosure and identity of recipients, if 
applicable.  
The data subject should furthermore be advised that the project is notified to the Data 
Protection Agency in accordance with Act on Processing of Personal Data, and that the 
Agency has laid down specific terms to be complied with for the project for the purpose 
of protecting the data subject's privacy. 
Disclosure of data 
21. Disclosure of data identifying individuals to a third party may take place for other
statistical or scientific purposes only.
22. Disclosure may be made only subject to prior approval of the Data Protection Agency.
The Data Protection Agency may lay down new terms for the disclosure as well as the
recipient’s data processing.
Disclosure of data may, however, take place in accordance with the below-mentioned
authorisation to disclose data.
Right of access to personal data 
23. The subject of the trial i.e. the data subject has no right of access to the data being
processed concerning himself, cf. Section 32(4) of the Act on Processing of Personal
Data. This Act does not prevent the grant of access.
Processing by a data processor 
24. The Data Protection Agency’s conditions shall apply also to processing by a data
processor.
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25. When data are processed by a data processor, a written agreement shall be made between
the controller and the data processor. The agreement shall stipulate that the data processor
acts on behalf of the controller only and that the data must not be used for the data proc-
essor’s own purposes. The controller shall furthermore request sufficient data from the
data processor to ensure that the Data Protection Agency’s terms can and will be com-
plied with.
26. Where the data processor is established in another Member State it shall, furthermore,
appear from the agreement that such other regulations on safety measures with regard to
data processors that may be in force in the Member State in question, shall apply also to
the data processor in question.
Erasure of data  
27. Data in the individual trials shall be erased, made anonymous or destroyed no later than
at the expiry of the storage period stipulated by the GCP-rules.  It must not subsequently
be possible to identify individuals participating in the trial.
28. Alternatively, the data may be transferred for further storage in archive in accordance
with the rules of the archive legislation
29. Erasure of data from electronic media shall take place in such a manner that it is impossi-
ble to recover the data.
Transfer of data to third countries 
30. Transfer of data to third countries, including for the purpose of processing by a data
processor, requires the Data Protection Agency’s prior approval.
Transfer may take place in accordance with the below-mentioned transfer authorisation.
31. Transfer may, however, take place without approval of the Data Protection Agency if the
data subject has given his explicit consent. The data subject can withdraw his consent.
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32. Transfer of data shall take place by courier or registered mail. In case of electronic
transmission the necessary security measures shall be taken to prevent unauthorized ac-
cess. As a minimum, the data must be safely encrypted during the entire transmission.
Transfer of sensitive personal data requires strong encryption.
Changes of the notified data processing  
33. The Data Protection Agency shall prior to implementation be notified of significant
changes to the data processing (in the form of a change to an existing notification). Less
significant changes may be notified to the Data Protection Agency subsequently, however
not later than four (4) weeks after the implementation.
Discontinuance of notified data processing 
34. The Company shall notify the Data Protection Agency immediately if the company
discontinues carrying out the notified data processing.
AUTHORISATION to disclose data 
In connection with its notification the Company has applied for authorisation to disclose data. 
The Company has applied for authorisation to disclose data to relevant national and interna-
tional health and medicines authorities in connection with an application for marketing 
authorization. 
Furthermore, the Company has applied for authorisation to disclose data concerning adverse 
events to national and international health and medicines authorities according to national and 
international law on reporting of adverse events in clinical trials. 
The Data Protection Agency hereby grants authorisation to the disclosure, cf. Section 
10(3) of Act on Processing of Personal Data. 
The authorisation in granted on the following terms: 
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Period of validity: The authorisation is valid until further notice. 
1.
The relevant data may be disclosed to national and international health and medicines
authorities in connection with an application for marketing authorization; to national and
international health and medicines authorities according to national and international law
on reporting of adverse events in clinical trials.
2.
Only data required in the specific situation concerned may be disclosed.
3.
The data may be disclosed to the recipient only in a form that does not identify individual
persons. It must thus not be possible for the recipient on the basis of the received data
alone to identify the persons related to the data.
4.
The Company shall at any time be able to verify to the Data Protection Agency which
transfers of data have been made.
AUTHORISATION to transfer personal data to third countries 
In connection with its notification the Company has applied for authorisation to transfer 
personal data to third countries. The company wishes to transfer data for the purpose of data 
processing to be carried out by named data processors in third countries. 
Furthermore, the Company wishes to transfer data to health and medicines authorities in third 
countries to comply with these countries’ law on reporting of adverse events in clinical trials 
and in connection with applications for a marketing authorization. 
According to Section 50(2) of Act on Processing of Personal Data, transfer of sensitive data to 
third countries can take place with the authorisation of the Data Protection Agency. Accord-
ing to section 50 (5), the Data Protection Agency may lay down more detailed conditions for 
the carrying out of the processing operations for reasons of protection of the privacy of the 
data subject in question. 
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The Data Protection Agency hereby grants authorisation to transfer data to third 
countries, cf. Section 50(2) of Act on Processing of Personal Data. 
The authorisation is granted on the following terms: 
Period of validity: The grant is valid until further notice. 
1.
Data may be transferred for processing by data processors with whom the Company has
an agreement on data processing, and to health and medicines authorities in third coun-
tries in order to comply with the law of these countries on reporting of adverse events in
clinical trials and in connection with an application for marketing authorization.
2.
When data are transferred to and from third countries the necessary safety measurements
must be taken to ensure that the data are not abused and to prevent unauthorized access.
The data shall be delivered personally or sent by courier or registered post. Electronic
transmission of data may take place only if the data are securely encrypted during the
entire transmission. Transfer of sensitive personal data requires strong encryption.
3.
Transfer of data to third countries takes place at the responsibility of the Company. The
Company must therefore in each individual case assess whether the relevant transfer can
take place, especially in consideration of the recipient's data safety. If it is assessed that
the level of protection at the recipient's place is not adequate, transfer is not allowed.
4.
The Company shall be able at any time to verify to the Data Protection Agency to which
third countries data have been transferred and the purpose of this.
The following terms furthermore apply to transfer to data processors in third countries. 
5.
Processing of the data must take place only at the instance of the Company and at the
Company's responsibility.
6.
The Company shall always be in a position to notify the Data Protection Agency of the
data processor’s name and address.
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7.
Prior to any transfer of data a written agreement shall be made with the recipient to the
effect that the Data Protection Agency’s conditions for processing of the data in Denmark
shall be complied with when the data processor processes the data.
8.
As responsible for the processing, the Company shall obtain information sufficient to
ensure that the terms of the Data Protection Agency are complied with.
9.
When the data are no longer to be processed by the data processor they must be erased or
returned to the Company.
The terms of the Data Protection Agency are valid until further notice. The Data Protection 
Agency reserves the right to take up the terms for revisions at a later date, if required. 
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Appendix II 
Declaration of Helsinki [last amended Seoul 2008] 
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Policy 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a
statement of ethical principles for medical research involving human subjects, including
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs
should not be applied without consideration of all other relevant paragraphs.
2.
Although the Declaration is addressed primarily to physicians, the WMA encourages
other participants in medical research involving human subjects to adopt these principles.
3.
It is the duty of the physician to promote and safeguard the health of patients, including
those who are involved in medical research. The physician's knowledge and conscience
are dedicated to the fulfilment of this duty.
4.
The Declaration of Geneva of the WMA binds the physician with the words, "The health
of my patient will be my first consideration," and the International Code of Medical Eth-
ics declares that, "A physician shall act in the patient's best interest when providing medi-
cal care."
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5.
Medical progress is based on research that ultimately must include studies involving
human subjects. Populations that are underrepresented in medical research should be pro-
vided appropriate access to participation in research.
6.
In medical research involving human subjects, the well-being of the individual research
subject must take precedence over all other interests.
7.
The primary purpose of medical research involving human subjects is to understand the
causes, development and effects of diseases and improve preventive, diagnostic and
therapeutic interventions (methods, procedures and treatments). Even the best current
interventions must be evaluated continually through research for their safety, effective-
ness, efficiency, accessibility and quality.
8.
In medical practice and in medical research, most interventions involve risks and
burdens.
9.
Medical research is subject to ethical standards that promote respect for all human
subjects and protect their health and rights. Some research populations are particularly
vulnerable and need special protection. These include those who cannot give or refuse
consent for themselves and those who may be vulnerable to coercion or undue influence.
10. Physicians should consider the ethical, legal and regulatory norms and standards for
research involving human subjects in their own countries as well as applicable interna-
tional norms and standards. No national or international ethical, legal or regulatory re-
quirement should reduce or eliminate any of the protections for research subjects set forth
in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
11. It is the duty of physicians who participate in medical research to protect the life, health,
dignity, integrity, right to self-determination, privacy, and confidentiality of personal in-
formation of research subjects.
12. Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant
sources of information, and adequate laboratory and, as appropriate, animal experimenta-
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tion. The welfare of animals used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that may harm
the environment.
14. The design and performance of each research study involving human subjects must be
clearly described in a research protocol. The protocol should contain a statement of the
ethical considerations involved and should indicate how the principles in this Declaration
have been addressed. The protocol should include information regarding funding, spon-
sors, institutional affiliations, other potential conflicts of interest, incentives for subjects
and provisions for treating and/or compensating subjects who are harmed as a conse-
quence of participation in the research study. The protocol should describe arrangements
for post-study access by study subjects to interventions identified as beneficial in the
study or access to other appropriate care or benefits.
15. The research protocol must be submitted for consideration, comment, guidance and
approval to a research ethics committee before the study begins. This committee must be
independent of the researcher, the sponsor and any other undue influence. It must take
into consideration the laws and regulations of the country or countries in which the re-
search is to be performed as well as applicable international norms and standards but
these must not be allowed to reduce or eliminate any of the protections for research sub-
jects set forth in this Declaration. The committee must have the right to monitor ongoing
studies. The researcher must provide monitoring information to the committee, especially
information about any serious adverse events. No change to the protocol may be made
without consideration and approval by the committee.
16. Medical research involving human subjects must be conducted only by individuals with
the appropriate scientific training and qualifications. Research on patients or healthy vol-
unteers requires the supervision of a competent and appropriately qualified physician or
other health care professional. The responsibility for the protection of research subjects
must always rest with the physician or other health care professional and never the re-
search subjects, even though they have given consent.
17. Medical research involving a disadvantaged or vulnerable population or community is
only justified if the research is responsive to the health needs and priorities of this popula-
tion or community and if there is a reasonable likelihood that this population or commu-
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nity stands to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful
assessment of predictable risks and burdens to the individuals and communities involved
in the research in comparison with foreseeable benefits to them and to other individuals
or communities affected by the condition under investigation.
19. Every clinical trial must be registered in a publicly accessible database before recruitment
of the first subject.
20. Physicians may not participate in a research study involving human subjects unless they
are confident that the risks involved have been adequately assessed and can be satisfacto-
rily managed. Physicians must immediately stop a study when the risks are found to out-
weigh the potential benefits or when there is conclusive proof of positive and beneficial
results.
21. Medical research involving human subjects may only be conducted if the importance of
the objective outweighs the inherent risks and burdens to the research subjects.
22. Participation by competent individuals as subjects in medical research must be voluntary.
Although it may be appropriate to consult family members or community leaders, no
competent individual may be enrolled in a research study unless he or she freely agrees.
23. Every precaution must be taken to protect the privacy of research subjects and the
confidentiality of their personal information and to minimize the impact of the study on
their physical, mental and social integrity.
24. In medical research involving competent human subjects, each potential subject must be
adequately informed of the aims, methods, sources of funding, any possible conflicts of
interest, institutional affiliations of the researcher, the anticipated benefits and potential
risks of the study and the discomfort it may entail, and any other relevant aspects of the
study. The potential subject must be informed of the right to refuse to participate in the
study or to withdraw consent to participate at any time without reprisal. Special attention
should be given to the specific information needs of individual potential subjects as well
as to the methods used to deliver the information. After ensuring that the potential subject
has understood the information, the physician or another appropriately qualified individ-
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ual must then seek the potential subject's freely-given informed consent, preferably in 
writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally
seek consent for the collection, analysis, storage and/or reuse. There may be situations
where consent would be impossible or impractical to obtain for such research or would
pose a threat to the validity of the research. In such situations the research may be done
only after consideration and approval of a research ethics committee.
26. When seeking informed consent for participation in a research study the physician should
be particularly cautious if the potential subject is in a dependent relationship with the
physician or may consent under duress. In such situations the informed consent should be
sought by an appropriately qualified individual who is completely independent of this
relationship.
27. For a potential research subject who is incompetent, the physician must seek informed
consent from the legally authorized representative. These individuals must not be in-
cluded in a research study that has no likelihood of benefit for them unless it is intended
to promote the health of the population represented by the potential subject, the research
cannot instead be performed with competent persons, and the research entails only mini-
mal risk and minimal burden.
28. When a potential research subject who is deemed incompetent is able to give assent to
decisions about participation in research, the physician must seek that assent in addition
to the consent of the legally authorized representative. The potential subject's dissent
should be respected.
29. Research involving subjects who are physically or mentally incapable of giving consent,
for example, unconscious patients, may be done only if the physical or mental condition
that prevents giving informed consent is a necessary characteristic of the research popula-
tion. In such circumstances the physician should seek informed consent from the legally
authorized representative. If no such representative is available and if the research cannot
be delayed, the study may proceed without informed consent provided that the specific
reasons for involving subjects with a condition that renders them unable to give informed
consent have been stated in the research protocol and the study has been approved by a
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research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication
of the results of research. Authors have a duty to make publicly available the results of
their research on human subjects and are accountable for the completeness and accuracy
of their reports. They should adhere to accepted guidelines for ethical reporting. Negative
and inconclusive as well as positive results should be published or otherwise made pub-
licly available. Sources of funding, institutional affiliations and conflicts of interest
should be declared in the publication. Reports of research not in accordance with the
principles of this Declaration should not be accepted for publication.
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH
MEDICAL CARE
31. The physician may combine medical research with medical care only to the extent that
the research is justified by its potential preventive, diagnostic or therapeutic value and if
the physician has good reason to believe that participation in the research study will not
adversely affect the health of the patients who serve as research subjects.
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against
those of the best current proven intervention, except in the following circumstances:
33. The use of placebo, or no treatment, is acceptable in studies where no current proven
intervention exists; or
34. Where for compelling and scientifically sound methodological reasons the use of placebo
is necessary to determine the efficacy or safety of an intervention and the patients who
receive placebo or no treatment will not be subject to any risk of serious or irreversible
harm. Extreme care must be taken to avoid abuse of this option.
35. At the conclusion of the study, patients entered into the study are entitled to be informed
about the outcome of the study and to share any benefits that result from it, for example,
access to interventions identified as beneficial in the study or to other appropriate care or
benefits.
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36. The physician must fully inform the patient which aspects of the care are related to the
research. The refusal of a patient to participate in a study or the patient's decision to with-
draw from the study must never interfere with the patient-physician relationship.
37. In the treatment of a patient, where proven interventions do not exist or have been
ineffective, the physician, after seeking expert advice, with informed consent from the
patient or a legally authorized representative, may use an unproven intervention if in the
physician's judgement it offers hope of saving life, re-establishing health or alleviating
suffering. Where possible, this intervention should be made the object of research, de-
signed to evaluate its safety and efficacy. In all cases, new information should be re-
corded and, where appropriate, made publicly available.
22.10.2008 
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Appendix III 
Local Skin Response Grading Scale 
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Documentation of the Selected Treatment Area on the Study 
Transparency 
Appendix IV, Page 114 of 140
Appendix IV 
Documentation of the Selected Treatment Area on the Study Transparency 
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Identifying and Documenting the Selected Treatment Area  
All subjects qualifying for this trial are to have 5 to 9 clinically typical, visible and discrete 
AK lesions within a contiguous 25 cm2 treatment area on the face or scalp. 
This area of skin will be referred to as the "selected treatment area" and will be documented 
using a "3-point landmark technique" on the study transparency.  
Instructions for the 3-point landmark technique study transparency are described below.  
Transparencies (pre-marked 1 cm2 grid) and markers will be provided to the study sites. 
Three point landmark technique for the study transparency 
1. Complete information (e.g. CRF number) on the transparency using a fine-tipped indelible
marker.
2. Place the transparency over the selected treatment area.
3. Map and label at least 3 anatomical landmarks on the transparency which are in the
vicinity of the selected treatment area.  These landmarks should not change during the
study (e.g. ear, eyebrow, scars, moles, birthmarks, bony landmarks, etc.)
4. Mark the outline of the selected treatment area (contiguous 25 cm2), containing the lesions
on the provided 1 cm2 grid transparency. Ensure that the selected treatment area contains
25 unit areas, each unit area being 1 cm2 in size.
5. Use the transparency to locate the selected treatment area for subsequent study visits.
When re-aligning the transparency, use the documented anatomical landmarks to dupli-
cate transparency placement.
6. At the start of treatment visit in a treatment cycle (Day 1 or Week 8 if retreatment is
required), mark the location/corners of the selected treatment area on the skin using the
fine-tipped indelible marker so that the subject can identify where the trial medication is
to be applied for the second and third applications.
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Appendix V 
Imiquimod Summary of Product Characteristics 
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Uploaded from http://www.medicines.org.uk/EMC/medicine/8/SPC/Aldara+5++Cream/ - 28-
AUG-2012 
Summary of Product Characteristics last updated on the eMC: 24/06/2010  
SPC Aldara 5% Cream  
Table of Contents 
• 1. NAME OF THE MEDICINAL PRODUCT
• 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
• 3. PHARMACEUTICAL FORM
• 4. CLINICAL PARTICULARS
• 4.1 Therapeutic indications
• 4.2 Posology and method of administration
• 4.3 Contraindications
• 4.4 Special warnings and precautions for use
• 4.5 Interaction with other medicinal products and other forms of interaction
• 4.6 Pregnancy and lactation
• 4.7 Effects on ability to drive and use machines
• 4.8 Undesirable effects
• 4.9 Overdose
• 5. PHARMACOLOGICAL PROPERTIES
• 5.1 Pharmacodynamic properties
• 5.2 Pharmacokinetic properties
• 5.3 Preclinical safety data
• 6. PHARMACEUTICAL PARTICULARS
• 6.1 List of excipients
• 6.2 Incompatibilities
• 6.3 Shelf life
• 6.4 Special precautions for storage
• 6.5 Nature and contents of container
• 6.6 Special precautions for disposal and other handling
• 7. MARKETING AUTHORISATION HOLDER
• 8. MARKETING AUTHORISATION NUMBER(S)
• 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
• 10. DATE OF REVISION OF THE TEXT
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1. NAME OF THE MEDICINAL PRODUCT
ALDARA 5% cream
Go to top of the page  
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each sachet contains 12.5 mg of imiquimod in 250 mg cream (5 %).
100 mg of cream contains 5 mg of imiquimod.
Excipients:
Methyl hydroxybenzoate (E218)
Propyl hydroxybenzoate (E216)
Cetyl alcohol
Stearyl alcohol
For a full list of excipients, see section 6.1.
Go to top of the page  
3. PHARMACEUTICAL FORM
Cream.
White to slightly yellow cream.
Go to top of the page  
4. CLINICAL PARTICULARS
Go to top of the page  
4.1 Therapeutic indications 
Imiquimod cream is indicated for the topical treatment of :  
• External genital and perianal warts (condylomata acuminata) in adults.
• Small superficial basal cell carcinomas (sBCCs) in adults.
• Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AKs) on
the face or scalp in immunocompetent adult patients when size or number of
lesions limit the efficacy and/or acceptability of cryotherapy and other topical
treatment options are contraindicated or less appropriate.
Go to top of the page  
4.2 Posology and method of administration 
Posology 
The application frequency and duration of treatment with imiquimod cream is 
different for each indication.  
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External genital warts in adults: 
Imiquimod cream should be applied 3 times per week (example: Monday, 
Wednesday, and Friday; or Tuesday, Thursday, and Saturday) prior to normal 
sleeping hours, and should remain on the skin for 6 to 10 hours. Imiquimod 
cream treatment should continue until the clearance of visible genital orperianal 
warts or for a maximum of 16 weeks per episode of warts.  
For quantity to be applied see 4.2 Method of administration.  
Superficial basal cell carcinoma in adults: 
Apply imiquimod cream for 6 weeks, 5 times per week (example: Monday to 
Friday) prior to normal sleeping hours, and leave on the skin for approximately 8 
hours.  
For quantity to be applied see 4.2 Method of administration.  
Actinic keratosis in adults 
Treatment should be initiated and monitored by a physician. Imiquimod cream 
should be applied 3 times per week (example: Monday, Wednesday and Friday) 
for four weeks prior to normal sleeping hours, and left on the skin for approx-
imately 8 hours. Sufficient cream should be applied to cover the treatment area. 
After a 4-week treatment-free period, clearance of AKs should be assessed. If 
any lesions persist, treatment should be repeated for another four weeks.  
The maximum recommended dose is one sachet. The maximum recommended 
treatment duration is 8 weeks.  
An interruption of dosing should be considered if intense local inflammatory 
reactions occur (see section 4.4) or if infection is observed at the treatment site. 
In this latter case, appropriate other measures should be taken. Each treatment 
period should not be extended beyond 4 weeks due to missed doses or rest 
periods.  
If the treated lesion(s) show an incomplete response at the follow-up examination 
at 4-8 weeks after the second treatment period, a different therapy should be 
used (see section 4.4)  
Information applicable to all indications: 
If a dose is missed, the patient should apply the cream as soon as he/she 
remember and then he/she should continue with the regular schedule. However 
the cream should not be applied more than once a day.  
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Paediatric patients 
Use in the paediatric patient population is not recommended. There are no data 
available on the use of imiquimod in children and adolescents in the approved 
indications.  
Aldara should not be used in children with molluscum contagiosum due to lack of 
efficacy in this indication (see section 5.1).  
Method of administration 
External genital warts: 
Imiquimod cream should be applied in a thin layer and rubbed on the clean wart 
area until the cream vanishes. Only apply to affected areas and avoid any 
application on internal surfaces. Imiquimod cream should be applied prior to 
normal sleeping hours. During the 6 to 10 hour treatment period, showering or 
bathing should be avoided. After this period it is essential that imiquimod cream 
is removed with mild soap and water. Application of an excess of cream or 
prolonged contact with the skin may result in a severe application site reaction 
(see sections 4.4, 4.8 and 4.9). A single-use sachet is sufficient to cover a wart 
area of 20 cm2 (approx. 3 inches2). Sachets should not be re-used once opened. 
Hands should be washed carefully before and after application of cream.  
Uncircumcised males treating warts under the foreskin should retract the foreskin 
and wash the area daily (see section 4.4).  
Superficial basal cell carcinoma: 
Before applying imiquimod cream, patients should wash the treatment area with 
mild soap and water and dry thoroughly. Sufficient cream should be applied to 
cover the treatment area, including one centimetre of skin surrounding the 
tumour. The cream should be rubbed into the treatment area until the cream 
vanishes. The cream should be applied prior to normal sleeping hours and 
remain on the skin for approximately 8 hours. During this period, showering and 
bathing should be avoided. After this period it is essential that imiquimod cream 
is removed with mild soap and water.  
Sachets should not be re-used once opened. Hands should be washed carefully 
before and after application of cream.  
Response of the treated tumour to imiquimod cream should be assessed 12 
weeks after the end of treatment. If the treated tumour shows an incomplete 
response, a different therapy should be used (see section 4.4).  
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A rest period of several days may be taken (see section 4.4) if the local skin 
reaction to imiquimod cream causes excessive discomfort to the patient, or if 
infection is observed at the treatment site. In this latter case, appropriate other 
measures should be taken.  
Actinic keratosis: 
Before applying imiquimod cream, patients should wash the treatment area with 
mild soap and water and dry thoroughly. Sufficient cream should be applied to 
cover the treatment area. The cream should be rubbed into the treatment area 
until the cream vanishes. The cream should be applied prior to normal sleeping 
hours and remain on the skin for approximately 8 hours. During this period, 
showering and bathing should be avoided. After this period it is essential that 
imiquimod cream is removed with mild soap and water. Sachets should not be re-
used once opened. Hands should be washed carefully before and after applica-
tion of cream.  
Go to top of the page  
4.3 Contraindications 
Hypersensitivity to the active substance or to any of the excipients.  
Go to top of the page  
4.4 Special warnings and precautions for use 
External genital warts, superficial basal cell carcinoma and actinic keratosis: 
Avoid contact with the eyes, lips and nostrils.  
Imiquimod has the potential to exacerbate inflammatory conditions of the skin.  
Imiquimod cream should be used with caution in patients with autoimmune 
conditions (refer to section 4.5). Consideration should be given to balancing the 
benefit of imiquimod treatment for these patients with the risk associated with a 
possible worsening of their autoimmune condition.  
Imiquimod cream should be used with caution in organ transplant patients (refer 
to section 4.5). Consideration should be given to balancing the benefit of imiqui-
mod treatment for these patients with the risk associated with the possibility of 
organ rejection or graft-versus-host disease.  
Imiquimod cream therapy is not recommended until the skin has healed after any 
previous drug or surgical treatment. Application to broken skin could result in 
increased systemic absorption of imiquimod leadling to a greater risk of adverse 
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events (refer to section 4.8 and 4.9)  
The use of an occlusive dressing is not recommended with imiquimod cream 
therapy.  
The excipients methylhydroxybenzoate (E218), propylhydroxybenzoate (E216), 
cetyl alcohol and stearyl alcohol may cause allergic reactions.  
Rarely, intense local inflammatory reactions including skin weeping or erosion 
can occur after only a few applications of imiquimod cream. Local inflammatory 
reactions may be accompanied, or even preceded, by flu-like systemic signs and 
symptoms including malaise, pyrexia, nausea, myalgias and rigors. An interrup-
tion of dosing should be considered.  
Imiquimod should be used with caution in patients with reduced haematologic 
reserve (refer to section 4.8d).  
External genital warts: 
There is limited experience in the use of imiquimod cream in the treatment of 
men with foreskin-associated warts. The safety database in uncircumcised men 
treated with imiquimod cream three times weekly and carrying out a daily foreskin 
hygiene routine is less than 100 patients. In other studies, in which a daily 
foreskin hygiene routine was not followed, there were two cases of severe 
phimosis and one case of stricture leading to circumcision. Treatment in this 
patient population is therefore recommended only in men who are able or willing 
to follow the daily foreskin hygiene routine. Early signs of stricture may include 
local skin reactions (e.g. erosion, ulceration, oedema, induration), or increasing 
difficulty in retracting the foreskin. If these symptoms occur, the treatment should 
be stopped immediately. Based on current knowledge, treating urethral, intra-
vaginal, cervical, rectal or intra-anal warts is not recommended. Imiquimod cream 
therapy should not be initiated in tissues where open sores or wounds exist until 
after the area has healed.  
Local skin reactions such as erythema, erosion, excoriation, flaking and oedema 
are common. Other local reactions such as induration, ulceration, scabbing, and 
vesicles have also been reported. Should an intolerable skin reaction occur, the 
cream should be removed by washing the area with mild soap and water. 
Treatment with imiquimod cream can be resumed after the skin reaction has 
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moderated.  
The risk of severe local skin reactions may be increased when imiquimod is used 
at higher than recommended doses (see section 4.2). However, in rare cases 
severe local reactions that have required treatment and/or caused temporary 
incapacitation have been observed in patients who have used imiquimod accord-
ing to the instructions. Where such reactions have occurred at the urethral 
meatus, some women have experienced difficulty in urinating, sometimes 
requiring emergency catheterisation and treatment of the affected area.  
No clinical experience exists with imiquimod cream immediately following 
treatment with other cutaneously applied drugs for treatment of external genital or 
perianal warts. Imiquimod cream should be washed from the skin before sexual 
activity. Imiquimod cream may weaken condoms and diaphragms, therefore 
concurrent use with imiquimod cream is not recommended. Alternative forms of 
contraception should be considered.  
In immunocompromised patients, repeat treatment with imiquimod cream is not 
recommended.  
While limited data have shown an increased rate of wart reduction in HIV positive 
patients, imiquimod cream has not been shown to be as effective in terms of wart 
clearance in this patient group.  
Superficial basal cell carcinoma: 
Imiquimod has not been evaluated for the treatment of basal cell carcinoma 
within 1 cm of the eyelids, nose, lips or hairline.  
During therapy and until healed, affected skin is likely to appear noticeably 
different from normal skin. Local skin reactions are common but these reactions 
generally decrease in intensity during therapy or resolve after cessation of 
imiquimod cream therapy. There is an association between the complete clear-
ance rate and the intensity of local skin reactions (e.g. erythema). These local 
skin reactions may be related to the stimulation of local immune response. If 
required by the patient's discomfort or the severity of the local skin reaction, a 
rest period of several days may be taken. Treatment with imiquimod cream can 
be resumed after the skin reaction has moderated.  
The clinical outcome of therapy can be determined after regeneration of the 
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treated skin, approximately 12 weeks after the end of treatment.  
No clinical experience exists with the use of imiquimod cream in immunocom-
promised patients.  
No clinical experience exists in patients with recurrent and previously treated 
BCCs, therefore use for previously treated tumours is not recommended.  
Data from an open label clinical trial suggest that large tumours (>7.25 cm2) are 
less likely to respond to imiquimod therapy.  
The skin surface area treated should be protected from solar exposure.  
Actinic keratosis 
Lesions clinically atypical for AK or suspicious for malignancy should be biopsied 
to determine appropriate treatment.  
Imiquimod has not been evaluated for the treatment of actinic keratoses on the 
eyelids, the inside of the nostrils or ears, or the lip area inside the vermilion 
border.  
There are very limited data available on the use of imiquimod for the treatment of 
actinic keratoses in anatomical locations other than the face and scalp. The 
available data on actinic keratosis on the forearms and hands do not support 
efficacy in this indication and therefore such use is not recommended.  
Imiquimod is not recommended for the treatment of AK lesions with marked 
hyperkeratosis or hypertrophy as seen in cutaneous horns.  
During therapy and until healed, affected skin is likely to appear noticeably 
different from normal skin. Local skin reactions are common but these reactions 
generally decrease in intensity during therapy or resolve after cessation of 
imiquimod cream therapy. There is an association between the complete clear-
ance rate and the intensity of local skin reactions (e.g. erythema). These local 
skin reactions may be related to the stimulation of local immune response. If 
required by the patient's discomfort or the intensity of the local skin reaction, a 
rest period of several days may be taken. Treatment with imiquimod cream can 
be resumed after the skin reaction has moderated.  
Each treatment period should not be extended beyond 4 weeks due to missed 
doses or rest periods.  
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The clinical outcome of therapy can be determined after regeneration of the 
treated skin, approximately 4-8 weeks after the end of treatment.  
No clinical experience exists with the use of imiquimod cream in immunocom-
promised patients.  
No data are available on re-treating actinic keratoses that have cleared after one 
or two courses of treatment and subsequently recur, and any such use is there-
fore not recommended.  
Data from an open-label clinical trial suggest that subjects with more than 8 AK 
lesions showed a decreased rate of complete clearance compared to patients 
with less than 8 lesions.  
The skin surface area treated should be protected from solar exposure.  
Go to top of the page  
4.5 Interaction with other medicinal products and other forms of interaction 
No interaction studies have been performed. This includes studies with immuno-
suppressive drugs. Interactions with systemic drugs would be limited by the 
minimal percutaneous absorption of imiquimod cream.  
Due to its immunostimulating properties, imiquimod cream should be used with 
caution in patients who are receiving immunosuppressive medication (see 
Section 4.4).  
Go to top of the page  
4.6 Pregnancy and lactation 
For imiquimod no clinical data on exposed pregnancies are available. Animal 
studies do not indicate direct or indirect harmful effects with respect to pregnan-
cy, embryonal/foetal development, parturition or postnatal development (see 5.3). 
Caution should be exercised when prescribing to pregnant women.  
As no quantifiable levels (>5 ng/ml) of imiquimod are detected in the serum after 
single and multiple topical doses, no specific advice can be given on whether to 
use or not in lactating mothers.  
Go to top of the page  
4.7 Effects on ability to drive and use machines 
No studies on the effects on the ability to drive and use machines have been 
performed. From the undesirable effects noted in section 4.8, it is unlikely that 
treatment will have any effect on the ability to drive and use machines.  
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Go to top of the page  
4.8 Undesirable effects 
a) General Description:
External genital warts: 
In the pivotal trials with 3 times a week dosing, the most frequently reported 
adverse drug reactions judged to be probably or possibly related to imiquimod 
cream treatment were application site reactions at the wart treatment site (33.7% 
of imiquimod treated patients). Some systemic adverse reactions, including 
headache (3.7%), influenza-like symptoms (1.1%), and myalgia (1.5%) were also 
reported.  
Patient reported adverse reactions from 2292 patients treated with imiquimod 
cream in placebo controlled and open clinical studies are presented below. 
These adverse events are considered at least possibly causally related to 
treatment with imiquimod.  
Superficial basal cell carcinoma: 
In trials with 5 times per week dosing 58% of patients experienced at least one 
adverse event. The most frequently reported adverse events from the trials 
judged probably or possibly related to imiquimod cream are application site 
disorders, with a frequency of 28.1%. Some systemic adverse reactions, includ-
ing back pain (1.1%) and influenza-like symptoms (0.5%) were reported by 
imiquimod cream patients.  
Patient reported adverse reactions from 185 patients treated with imiquimod 
cream in placebo controlled phase III clinical studies for superficial basal cell 
carcinoma are presented below. These adverse events are considered at least 
possibly causally related to treatment with imiquimod.  
Actinic keratosis 
In the pivotal trials with 3 times per week dosing for up to 2 courses each of 4 
weeks, 56% of imiquimod patients reported at least one adverse event. The most 
frequently reported adverse event from these trials judged probably or possibly 
related to imiquimod cream was application site reactions (22% of imiquimod 
treated patients). Some systemic adverse reactions, including myalgia (2%) were 
reported by imiquimod treated patients.  
Patient reported adverse reactions from 252 patients treated with imiquimod 
cream in vehicle controlled phase III clinical studies for actinic keratosis are 
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Imiquim
prese
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b) Ta
Frequ
and U
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External g
warts  
(3x/ wk,16
N = 2292
Common
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 at least po
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V, Page 12
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common 
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27 of 140
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10) 
are 
tosis 
8 
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nutrition disorders: 
Anorexia
Uncommon
Common
Psychiatric disor-
ders: 
Insomnia  
Uncommon 
Depression
Uncommon
Uncommon
Irritability 
Uncommon 
Nervous system 
disorders: 
Headache
Common
Common
Paraesthesia 
Uncommon 
Dizziness 
Uncommon 
Migraine 
Uncommon 
Somnolence 
Uncommon 
Eye disorders 
Conjunctival irritation 
Uncommon 
Eyelid oedema 
Uncommon 
Ear and labyrinth 
disorders: 
Tinnitus 
Uncommon 
Vascular disorders: 
Flushing 
Uncommon 
Respiratory, thoracic 
and mediastinal 
disorders: 
Pharyngitis 
Uncommon 
Rhinitis 
Uncommon 
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Nasal congestion 
Uncommon 
Pharyngo laryngeal 
pain 
Uncommon 
Gastrointestinal 
disorders: 
Nausea
Common 
Uncommon 
Common
Abdominal pain 
Uncommon 
Diarrhoea
Uncommon
Uncommon
Vomiting 
Uncommon 
Rectal disorder 
Uncommon 
Rectal tenesmus 
Uncommon 
Dry mouth 
Uncommon 
Skin and subcutane-
ous tissue disorders: 
Pruritus 
Uncommon 
Dermatitis
Uncommon 
Uncommon
Folliculitis 
Uncommon 
Rash erythematous 
Uncommon 
Eczema 
Uncommon 
Rash 
Uncommon 
Sweating increased 
Uncommon 
Urticaria 
Uncommon 
Actinic keratosis 
Uncommon 
Erythema 
Uncommon 
Face oedema 
Uncommon 
Skin ulcer 
Uncommon 
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Musculoskeletal and 
connective tissue 
disorders: 
Myalgia
Common
Common
Arthralgia
Uncommon
Common
Back pain 
Uncommon 
Common 
Pain in extremity 
Uncommon 
Renal and urinary 
disorders: 
Dysuria 
Uncommon 
Reproductive system 
and breast disorders: 
Genital pain male 
Uncommon 
Penile disorder 
Uncommon 
Dyspareunia 
Uncommon 
Erectile dysfunction 
Uncommon 
Uterovaginal prolapse Uncommon 
Vaginal pain 
Uncommon 
Vaginitis atrophic 
Uncommon 
Vulval disorder 
Uncommon 
General disorders 
and administration 
site conditions: 
Application site 
pruritus 
Very common 
Very common 
Very common 
Application site pain 
Very common 
Common 
Common 
Application site 
burning 
Common
Common
Common
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Application site 
irritation 
Common
Common
Common
Application site 
erythema 
Common 
Common 
Application site 
reaction 
Common 
Application site 
bleeding 
Common 
Uncommon 
Application site 
papules 
Common 
Uncommon 
Application site 
paraesthesia 
Common 
Uncommon 
Application site rash 
Common 
Fatigue
Common
Common
Pyrexia
Uncommon
Uncommon
Influenza-like illness 
Uncommon 
Uncommon 
Pain 
Uncommon 
Asthenia
Uncommon
Uncommon
Malaise 
Uncommon 
Rigors
Uncommon
Uncommon
Application site 
dermatitis 
Uncommon 
Application site 
discharge 
Uncommon 
Uncommon 
Application site 
hyperaesthesia 
Uncommon 
Application site 
inflammation 
Uncommon 
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Application site 
oedema 
Uncommon 
Uncommon 
Application site 
scabbing 
Uncommon 
Uncommon 
Application site scar 
Uncommon 
Application site skin 
breakdown 
Uncommon 
Application site 
swelling 
Uncommon 
Uncommon 
Application site ulcer 
Uncommon 
Application site 
vesicles 
Uncommon 
Uncommon 
Application site 
warmth 
Uncommon 
Lethargy 
Uncommon 
Discomfort 
Uncommon 
Inflammation 
Uncommon 
c) Frequently occurring adverse events:
External genital warts: 
Investigators of placebo controlled trials were required to evaluate protocol 
mandated clinical signs (skin reactions). These protocol mandated clinical sign 
assessments indicate that local skin reactions including erythema (61%), erosion 
(30%), excoriation/flaking/scaling (23%) and oedema (14%) were common in 
these placebo controlled clinical trials with imiquimod cream applied three times 
weekly (see section 4.4). Local skin reactions, such as erythema, are probably an 
extension of the pharmacologic effects of imiquimod cream.  
Remote site skin reactions, mainly erythema (44%), were also reported in the 
placebo controlled trials. These reactions were at non-wart sites which may have 
been in contact with imiquimod cream. Most skin reactions were mild to moderate 
in severity and resolved within 2 weeks of treatment discontinuation. However, in 
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some cases these reactions have been severe, requiring treatment and/or 
causing incapacitation. In very rare cases, severe reactions at the urethral 
meatus have resulted in dysuria in women (see section 4.4).  
Superficial basal cell carcinoma: 
Investigators of the placebo controlled clinical trials were required to evaluate 
protocol mandated clinical signs (skin reactions). These protocol mandated 
clinical sign assessments indicate that severe erythema (31%) severe erosions 
(13%) and severe scabbing and crusting (19%) were very common in these trials 
with imiquimod cream applied 5 times weekly. Local skin reactions, such as 
erythema, are probably an extension of the pharmacologic effect of imiquimod 
cream.  
Skin infections during treatment with imiquimod have been observed. While 
serious sequelae have not resulted, the possibility of infection in broken skin 
should always be considered.  
Actinic keratosis 
In clinical trials of imiquimod cream 3 times weekly for 4 or 8 weeks the most 
frequently occurring application site reactions were itching at the target site (14%) 
and burning at the target site (5%). Severe erythema (24%) and severe scabbing 
and crusting (20%) were very common. Local skin reactions, such as erythema, 
are probably an extension of the pharmacologic effect of imiquimod cream. See 
4.2 and 4.4 for information on rest periods.  
Skin infections during treatment with imiquimod have been observed. While 
serious sequelae have not resulted, the possibility of infection in broken skin 
should always be considered.  
d) Adverse events applicable to all indications:
Reports have been received of localised hypopigmentation and hyperpigmenta-
tion following imiquimod cream use. Follow-up information suggests that these 
skin colour changes may be permanent in some patients. In a follow-up of 162 
patients five years after treatment for sBCC a mild hypopigmentation was 
observed in 37% of the patients and a moderate hypopigmentation was observed 
in 6% of the patients. 56% of the patients have been free of hypopigmentation; 
hyperpigmentation has not been reported.  
Clinical studies investigating the use of imiquimod for the treatment of actinic 
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Imiquim
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V, Page 13
the treatm
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5. PHARMACOLOGICAL PROPERTIES
Go to top of the page  
5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Chemotherapeutics for topical use, antivirals : ATC 
Code : D06BB10.  
Imiquimod is an immune response modifier. Saturable binding studies suggest a 
membrane receptor for imiquimod exists on responding immune cells. Imiquimod 
has no direct antiviral activity. In animal models imiquimod is effective against 
viral infections and acts as an antitumour agent principally by induction of alpha 
interferon and other cytokines. The induction of alpha interferon and other 
cytokines following imiquimod cream application to genital wart tissue has also 
been demonstrated in clinical studies.  
Increases in systemic levels of alpha interferon and other cytokines following 
topical application of imiquimod were demonstrated in a pharmacokinetic study.  
External genital warts: 
Clinical Efficacy  
The results of 3 phase III pivotal efficacy studies showed that treatment with 
imiquimod for sixteen weeks was significantly more effective than treatment with 
vehicle as measured by total clearance of treated warts.  
In 119 imiquimod-treated female patients, the combined total clearance rate was 
60% as compared to 20% in 105 vehicle-treated patients (95% CI for rate 
difference: 20% to 61% , p<0.001). In those imiquimod patients who achieved 
total clearance of their warts, the median time to clearance was 8 weeks.  
In 157 imiquimod-treated male patients, the combined total clearance rate was 
23% as compared to 5% in 161 vehicle-treated patients (95%CI for rate differ-
ence: 3% to 36% , p<0.001). In those imiquimod patients who achieved total 
clearance of their warts, the median time to clearance was 12 weeks.  
Superficial basal cell carcinoma: 
Clinical efficacy:  
The efficacy of imiquimod 5 times per week for 6 weeks was studied in two 
double-blind vehicle controlled clinical trials. Target tumours were histologically 
confirmed single primary superficial basal cell carcinomas with a minimum size of 
0.5 cm2 and a maximum diameter of 2 cm. Tumours located within 1 cm of the 
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eyes, nose, mouth, ears or hairline were excluded. In a pooled analysis of these 
two studies, histological clearance was noted in 82% (152/185) of patients. When 
clinical assessment was also included, clearance judged by this composite 
endpoint was noted in 75% (139/185) of patients. These results were statistically 
significant (p<0.001) by comparison with the vehicle group, 3% (6/179) and 2% 
(3/179) respectively. There was a significant association between the intensity of 
local skin reactions (e.g. erythema) seen during the treatment period and com-
plete clearance of the basal cell carcinoma.  
Five -year data from a long-term open-label uncontrolled study indicate that an 
estimated 77.9% [95% CI (71.9%, 83.8%)] of all the subjects who initially re-
ceived treatment became clinically clear and remained clear at 60 months.  
Actinic keratosis: 
Clinical efficacy:  
The efficacy of imiquimod applied 3 times per week for one or two courses of 4 
weeks, separated by a 4 week treatment-free period, was studied in two double-
blind vehicle controlled clinical trials. Patients had clinically typical, visible, 
discrete, nonhyperkeratotic, nonhypertrophic AK lesions on the balding scalp or 
face within a contiguous 25 cm2 treatment area. 4-8 AK lesions were treated. The 
complete clearance rate (imiquimod minus placebo) for the combined trials was 
46.1% (CI 39.0%, 53.1%).  
One-year data from two combined observational studies indicate a recurrence 
rate of 27% (35/128 patients) in those patients who became clinically clear after 
one or two courses of treatment. The recurrence rate for individual lesions was 
5.6% (41/737). Corresponding recurrence rates for vehicle were 47% (8/17 
patients) and 7.5% (6/80 lesions). The rate of progression to squamous cell 
carcinoma (SCC) was reported in 1.6% (2/128 patients).  
There are no data on recurrence and progression rates beyond 1 year.  
Paediatric patients:  
The approved indications genital warts, actinic keratosis and superficial basal cell 
carcinoma are conditions not generally seen within the paediatric population and 
were not studied.  
Aldara Cream has been evaluated in four randomised, vehicle controlled, double-
blind trials in children aged 2 to 15 years with molluscum contagiosum (imiqui-
mod n = 576, vehicle n = 313) . These trials failed to demonstrate efficacy of 
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Go to top of the page  
5.3 Preclinical safety data 
Non-clinical data revealed no special hazard for humans based on conventional 
studies of safety pharmacology, mutagenicity and teratogenicity.  
In a four-month rat dermal toxicity study, significantly decreased body weight and 
increased spleen weight were observed at 0.5 and 2.5 mg/kg; similar effects 
were not seen in a four month mouse dermal study. Local dermal irritation, 
especially at higher doses, was observed in both species.  
A two-year mouse carcinogenicity study by dermal administration on three days a 
week did not induce tumours at the application site. However, the incidences of 
hepatocellular tumours among treated animals were greater than those for 
controls. The mechanism for this is not known, but as imiquimod has low system-
ic absorption from human skin, and is not mutagenic, any risk to humans from 
systemic exposure is likely to be low. Furthermore, tumours were not seen at any 
site in a 2-year oral carcinogenicity study in rats.  
Imiquimod cream was evaluated in a photocarcinogenicity bioassay in albino 
hairless mice exposed to simulated solar ultraviolet radiation (UVR). Animals 
were administered imiquimod cream three times per week and were irradiated 5 
days per week for 40 weeks. Mice were maintained for an additional 12 weeks for 
a total of 52 weeks. Tumours occurred earlier and in greater number in the group 
of mice administered the vehicle cream in comparison with the low UVR control 
group. The significance for man is unknown. Topical administration of imiquimod 
cream resulted in no tumour enhancement at any dose, in comparison with the 
vehicle cream group.  
Go to top of the page  
6. PHARMACEUTICAL PARTICULARS
Go to top of the page  
6.1 List of excipients 
isostearic acid  
benzyl alcohol  
cetyl alcohol  
stearyl alcohol  
white soft paraffin  
polysorbate 60  
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sorbitan stearate  
glycerol  
methyl hydroxybenzoate (E218)  
propyl hydroxybenzoate (E216)  
xanthan gum  
purified water.  
Go to top of the page  
6.2 Incompatibilities 
Not applicable.  
Go to top of the page  
6.3 Shelf life 
2 years.  
Go to top of the page  
6.4 Special precautions for storage 
Do not store above 25°C.  
Sachets should not be re-used once opened.  
Go to top of the page  
6.5 Nature and contents of container 
Boxes of 12 or 24 single-use polyester/aluminium foil sachets, containing 250 mg 
of cream.  
Not all pack sizes may be marketed.  
Go to top of the page  
6.6 Special precautions for disposal and other handling 
No special requirements.  
Go to top of the page  
7. MARKETING AUTHORISATION HOLDER
Meda AB
Pipers väg 2A
170 73 Solna
Sweden
Go to top of the page  
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/98/080/001-002
Go to top of the page  
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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 18/09/1998
Date of last renewal: 03/09/2008
Go to top of the page  
10. DATE OF REVISION OF THE TEXT
April 2010
Meda Pharmaceuticals  
Sky Way House, Parsonage Road, Takeley, Bishop's Stortford, 
CM22 6PU  
Telephone: 0845 460 0000  
Fax: 0845 460 0002  
Medical Information Direct Line: +44 (0)1748 828 810  
Medical Information e-mail: me-
da@professionalinformation.co.uk  
Medical Information Fax: +44 (0)1748 828 801  
Out of Hours contact: +44 (0)1748 828 810  
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ELECTRONIC SIGNATURES 
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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)
 
 
 
LP0041-63  Clinical Study Protocol 13-Mar-2013 - English
Head of Biostatistics Approval
15-Mar-2013 14:55 GMT+01
Head of Department, Medical
Approval
15-Mar-2013 17:50 GMT+01
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