Clinical trial NCT03115476
Conditions: Actinic Keratosis Squamous Cell Carcinoma
Sponsor: LEO Pharma
Start date: 2017-06-16; Completion date: 2018-03-12
Enrollment: 563 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
One of the main reasons for treating actinic keratoses (AK) is the wish to lower the risk of progression of AK to squamous cell carcinoma (SCC). This risk is in the order of 1 per 1000 AKs per year, which is in itself a small risk, but since patients can have dozens of AKs and the disease is chronic the cumulative risk for a patient can be substantial.

In this extension protocol of trials LP0084-1193, -1194, -1195 and -1196, LEO will study the incidence of SCCs and other skin neoplasia in vehicle and ingenol disoxate treated patients over a period of 2 years, so that the total follow-up time for each patient will be 3 years and 2 months.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: ingenol disoxate gel 0.018% intervention 2: ingenol disoxate gel 0.037% intervention 3: Vehicle gel
Intervention descriptions: intervention 1: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp. intervention 2: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp. intervention 3: Vehicle to ingenol disoxate gel with no active ingredient

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Trial Protocol LP0084-1369 
 
Incidence of squamous cell carcinoma and other skin neoplasia in subjects 
with actinic keratosis treated with ingenol disoxate gel 0.018% or 0.037%, 
or vehicle 
 
A phase 3 trial to compare the incidence of SCC and other skin neoplasia on skin areas 
treated with ingenol disoxate gel or vehicle gel for actinic keratosis on face and chest or scalp 
 
A multi-centre, randomised, open-label, controlled, parallel group, 24-month trial 
 
 
 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH-GCP 
and the applicable regulatory requirement(s). 
 
LEO Pharma A/S 
Trial ID: 
LP0084-1369 
Date: 
25-Jul-2017 
EudraCT No: 
2017-000228-85 
Version: 
2.0 
 
 


 
 
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1 Clinical Trial Protocol Statement 
1.1 Approval Statement LEO Pharma A/S 
The following persons have approved this clinical trial protocol by using electronic signatures 
as presented on the last page of this document: 
 
PPD 
M.Sc 
Biostatistics Lead, Global Clinical Operations 
 
PPD 
, MD, PhD 
Medical Lead, Medical Science and Safety 
 
1.2 Approval Statement International Coordinating Investigator 
The international coordinating investigator approves the clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by manually 
signing the International Coordinating Investigator Clinical Trial Protocol Approval Form, 
which is a separate document adjoined to this document. 
 
The following person has approved this clinical trial protocol: 
 
PPD 
, MD 
International coordinating investigator 
 
 
1.3 Acknowledgement Statement Investigators 
Each participating investigator must agree to the approved clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by signing a 
Clinical Trial Protocol Acknowledgement Form or a similar document. 


 
 
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Table of Contents 
1 Clinical Trial Protocol Statement ........................................................................................... 2 
1.1 
Approval Statement LEO Pharma A/S .............................................................................. 2 
1.2 
Approval Statement International Coordinating Investigator ........................................... 2 
1.3 
Acknowledgement Statement Investigators ...................................................................... 2 
Table of Contents ........................................................................................................................ 3 
List of Tables ...................................................................................................................................... 7 
List of Figures ............................................................................................................................ 7 
2 Trial Identification ................................................................................................................. 8 
3 Introduction and Rationale .................................................................................................... 8 
3.1 
Actinic Keratosis ............................................................................................................... 8 
3.2 
Experience with Investigational Medicinal Product ......................................................... 9 
3.3 
Trial Rationale ................................................................................................................. 10 
3.4 
Ethical Considerations ..................................................................................................... 10 
4 Trial Objectives .................................................................................................................... 11 
4.1 
Primary Objective ............................................................................................................ 11 
5 Trial Endpoints .................................................................................................................... 11 
5.1 
Primary Endpoint ............................................................................................................. 11 
5.2 
Secondary Endpoints ....................................................................................................... 11 
6 Trial Design ......................................................................................................................... 11 
6.1 
Overall Trial Design ........................................................................................................ 11 
6.2 
Trial Schedule .................................................................................................................. 13 
6.3 
Sample Size ..................................................................................................................... 13 
6.4 
Randomisation ................................................................................................................. 13 
6.5 
Blinding ........................................................................................................................... 13 
7 Trial Population and Withdrawal ......................................................................................... 13 
7.1 
Subject Eligibility ............................................................................................................ 13 
7.2 
Inclusion Criteria ............................................................................................................. 14 
7.3 
Exclusion Criteria ............................................................................................................ 14 
7.4 
Subject Screening Log ..................................................................................................... 14 
7.5 
Subject Identification List ............................................................................................... 14 


 
 
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7.6 
Restrictions during Trial ........................................................................................................ 15 
7.7 
Discontinuation ............................................................................................................... 15 
8 Trial Schedule and Assessments .......................................................................................... 16 
8.1 
Schedule of Trial Procedures ........................................................................................... 16 
8.2 
Subject Eligibility ............................................................................................................ 17 
8.3 
Concomitant Medication and Procedures ........................................................................ 17 
8.4 
Adverse Events ................................................................................................................ 18 
8.4.1 
Adverse EventS of Special Interest and other Skin Neoplasia .................................... 18 
8.5 Scarring ........................................................................................................................... 18 
8.6 End of Trial ............................................................................................................................. 18 
9 Adverse Events .................................................................................................................... 19 
9.1 
Collection of Adverse Events .......................................................................................... 19 
9.1.1 
Local Skin Responses .................................................................................................. 20 
9.2 
Reporting of Adverse Events in the CRF ........................................................................ 20 
9.2.1 
Actions Taken as a Consequence of an Adverse Event ............................................... 20 
9.3 Other Events to be Reported ........................................................................................... 20 
9.3.1 
Pregnancy .................................................................................................................... 20 
9.3.2 
Aggravation of Condition ............................................................................................ 21 
9.3.3 
Adverse Events of Special Interest .............................................................................. 21 
9.4 Additional Reporting Requirements for Serious Adverse Events ................................... 21 
9.4.1 
Investigator Reporting Responsibilities ...................................................................... 21 
9.4.2 
LEO Reporting Responsibilities .................................................................................. 22 
9.5 Follow-up for Final Outcome of Adverse Events ............................................................ 23 
10 Trial Product ........................................................................................................................ 23 
11 Statistical Methods .............................................................................................................. 23 
11.1 Sample Size ..................................................................................................................... 23 
11.2 Trial Analysis Sets ........................................................................................................... 24 
11.3 Statistical Analysis .......................................................................................................... 24 
11.3.1 Disposition of Subjects ................................................................................................ 24 
11.3.2 Demographics and other Baseline Characteristics ...................................................... 24 
11.3.3 Exposure and Treatment Compliance .......................................................................... 25 
11.3.4 Analysis of Primary Endpoint .................................................................................... 25 
11.3.5 Analysis of Secondary Endpoint ................................................................................ 25 
11.3.6 Analysis of Safety........................................................................................................ 26 


 
 
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11.3.6.1 Adverse Events ........................................................................................................ 26 
11.3.7 
Interim Analysis ........................................................................................................... 27 
11.3.8 
General Principles ....................................................................................................... 27 
11.3.9 
Handling of Missing Values ................................................................................................ 28 
12 Trial Committees ................................................................................................................. 28 
12.1 Independent Adjudication Committee ............................................................................. 28 
13 Case Report Forms and Data Handling ............................................................................... 28 
13.1 Case Report Forms (CRFs) ............................................................................................. 28 
13.2 Data Handling .................................................................................................................. 29 
13.3 Source Data ..................................................................................................................... 29 
13.4 Trial Monitoring .............................................................................................................. 30 
14 Handling of an Urgent Safety Measure ............................................................................... 30 
15 Quality Assurance/Audit ...................................................................................................... 31 
16 Completion of Trial ..................................................................................................................... 31 
16.1 Trial Completion Procedures ........................................................................................... 31 
16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site ................................ 31 
16.2 Provision for Subject Care Following Trial Completion ................................................. 32 
16.3 Archiving of Trial Documents ......................................................................................... 32 
17 Ethics and Regulatory Authorities ....................................................................................... 32 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and 
Regulatory Authorities ..................................................................................................... 32 
17.2 Ethical Conduct of the Trial ............................................................................................ 33 
17.3 Subject Information and Informed Consent .................................................................... 33 
17.4 Processing of Personal Data ............................................................................................ 33 
18 Insurance .............................................................................................................................. 34 
19 Use of Information ............................................................................................................... 34 
20 Registration, reporting and publication ............................................................................... 34 
21 Responsibilities .................................................................................................................... 35 
22 List of Abbreviations ........................................................................................................... 36 
23 References ........................................................................................................................... 37 
List of Appendices .................................................................................................................... 38 
Appendix 1: Protocol Summary ............................................................................................... 39 


 
 
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Appendix 2: Definitions of Adverse Events and Serious Adverse Events ............................... 42 
Appendix 3: Classification of Adverse Events ......................................................................... 44 
Appendix 4: Contact list of LEO, protocol authors, vendors, trial committees and coordinating 
investigators ......................................................................................................................... 46 
Appendix 5: Protocol Amendment History .............................................................................. 48 


 
 
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List of Tables 
Table 1 Schedule of Trial Procedures ....................................................................................... 16 
 
Table 2 Overview of AEs to be Collected ................................................................................ 19 
 
 
List of Figures 
Figure 1 Trial Design ................................................................................................................ 12 


 
 
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2 Trial Identification 
This clinical trial (LP0084-1369) is conducted under US IND number 118384. 
EudraCT number: 2017-000228-85 
Clinicaltrials.gov identifier: NCT03115476 
 
3 Introduction and Rationale 
3.1 Actinic Keratosis 
Actinic keratosis (AK) is a common skin condition visible as thickened, cornified, scaly 
lesions and characterised histologically by atypical epithelial proliferation (1). Actinic 
keratoses usually develop on areas that are frequently exposed to the sun (e.g. face, ears, 
scalp, neck, forearms and the back of the hands). 
In population studies performed in the European Union (EU) and the United States (US), 
reported prevalence rates for AK have been approximately 11-25% of the population, while 
estimates are higher in Australian studies (up to 60%) (2). Patients with AK tend to have 
Fitzpatrick type I or II skin that burns with sun exposure and does not tan or tans minimally 
(3). 
There is increasing evidence that AK represents squamous cell carcinoma (SCC) in situ in its 
earliest stages (1, 4, 5). Histological evidence shows that contiguous AK is present in 97% of 
SCC lesions on sun-damaged skin (4). AK is linked epidemiologically to development of SCC 
(6), and both conditions share specific gene expression (7). If left untreated, AK may progress 
to SCC resulting in increased morbidity (4). 
AK usually occurs on large, sun-damaged areas of the skin (field cancerisation). Field 
cancerisation is characterised by the epithelial surface being more susceptible to the 
development of AKs or malignancies than normal skin due to DNA mutations generated in 
epidermis as a result of excessive sun exposure. This is evidenced by the presence of multiple 
subclinical and clinically visible AKs as well as multifocal pre-neoplastic changes with 
genetic mutations (8). Once field cancerisation has developed, new AKs will continue to 
develop. Most treatment therapies are directed against discrete, visible AKs, and there is an 
unmet need for improved therapies for field treatment that will reduce the rate of recurrence 
of AKs. 


 
 
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3.2 Experience with Investigational Medicinal Product 
Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs 
on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp. 
 
The clinical development program for ingenol disoxate gel in AK comprises phase 1, 
seamless phase 1/2 and phase 2 dose (regimen) finding trials, and phase 3 trials. The phase 1 
program addresses various issues potentially relevant to human safety including local 
tolerability, systemic safety and contact sensitization potential. One phase 1 trial investigating 
the biological effects by means of histopathology is ongoing. The phase 2 dose finding 
program is completed. The ongoing phase 3 program includes two confirmatory trials on face 
and chest, and two confirmatory trials on scalp investigating a 3-day treatment period with an 
8-week follow up and an extended 12 month follow-up period. 
 
The safety profile of ingenol disoxate gel is characterised by local skin responses (LSR): 
erythema, flaking/scaling, swelling, crusting, vesiculation/pustulation, and erosion/ulceration. 
In clinical trials, scores are assessed for each of these LSRs (on a scale from 0-4) and 
combined to a composite LSR score (on a scale from 0-24). The LSR profile observed in the 
ingenol disoxate development programme is consistent across anatomical locations. Typically, 
the LSRs peak shortly after last drug application, rapidly decline and resolve within 2 weeks. 
Adverse events (AEs) are predominantly application site reactions in the form of pain, 
pruritus and discomfort of mild or moderate intensity. 
 
In 3 phase 1/2 dose finding trials (LP0084-1013, -1014, and -1015), ingenol disoxate gel, 
0.018%, 0.037% and 0.1% were identified as effective and tolerable doses for once daily 
treatment for 2 consecutive days of AKs on face/chest, scalp, and trunk/extremities, 
respectively. With the intent of developing a dosing regimen with a better efficacy/tolerability 
ratio, these doses were further investigated in an open-label safety trial, Trial LP0084-1148. In 
this trial, dosing regimens of once daily for 3 consecutive days of ingenol disoxate gel 
0.018%, 0.037%, and 0.1% for face/chest, scalp, and trunk/extremities were evaluated and 
were all shown to be well tolerated. 
 
Based on the phase 2 trial results, ingenol disoxate gel, 0.018% once daily for 3 consecutive 
days is being investigated for treatment of the face/chest (Trials LP0084-1193 and -1194), and 
ingenol disoxate gel, 0.037% once daily for 3 consecutive days is being investigated for 
treatment of the scalp (Trials LP0084-1195 and -1196). These 4 phase 3 trials are divided into 
an 8-week short-term part (providing confirmatory efficacy data and short term safety data) 
and a 12 months extended follow up period providing data on recurrence and safety from 


 
 
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Week 8 to Month 14. The present trial is an extension of the 4 ongoing phase 3 trials 
following the subjects for SCC and other neoplasia for additional 24 months. 
 
The safety and preliminary efficacy of ingenol disoxate gel is presented in the Investigator’s 
Brochure. 
 
3.3 Trial Rationale 
One of the main reasons for treating AK is the wish to abate the risk of progression of AK to 
SCC. This risk is in the order of 1 per 1000 AKs per year, which is in itself a small risk, but 
since patients can have dozens of AKs and the disease is chronic the cumulative risk for a 
patient can be substantial. Although it is generally assumed that removal of AKs by surgery or 
topical treatment will reduce the risk of progression, this has never been demonstrated in 
clinical trials. There may be several reasons for this lack of clinical trial evidence of a 
preventive effect of AK treatment on SCC risk: in general, the study of cancer development 
requires large cohorts and long follow-up time; even for a relatively common cancer type as 
SCC of the skin, this is a significant obstacle. Furthermore, the treatment whose effect on 
SCC risk is to be studied, can be actively allocated in the intervention period where also other 
treatment can be prohibited, but it is difficult to keep the exposure clean in a prolonged 
follow-up period. In particular, it is difficult to prohibit other treatments than the experimental 
treatment for AK. Finally, it is difficult to recruit patients for trials dedicated to study the risk 
of SCC of the skin. The latter obstacle is overcome by the design here proposed, where the 
population is initially followed for the treatment effect on AK whereas in the prolonged 
follow-up phase the emphasis shifts to long-term effects on skin neoplasia, in particular SCC. 
 
Patients who enter trials in AK are at increased risk of developing SCC from the outset and 
SCCs will be observed, no matter how effective the treatment. The occurrence of even a few 
cases of SCC after treatment with a topical product may cast a shadow over the new product 
and a large, well-controlled trial would be needed to alleviate this kind of concern. This is 
another reason for implementing this extension protocol. 
 
In this extension protocol, LEO will study the incidence of SCCs and other skin neoplasia in 
vehicle and ingenol disoxate treated patients over a period of 2 years, so that the total follow- 
up time for each patient will be 3 years and 2 months. 
 
3.4 Ethical Considerations 
This extension protocol does not include any experimental treatments or procedures, either 
active or vehicle. Patients will be seen every 6 months by a qualified dermatologist for 


 
 
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assessment of the treatment area specified in the main trial LP0084-1193, -1194, -1195 or - 
1196. 
 
The only restricted medication during this extension protocol is the use of ingenol mebutate 
and ingenol disoxate in and within 5 cm of treatment area, as field treatment or individual 
lesion specific treatment. If it is judged by the investigator that it is in the best interest of the 
patient to receive field treatment in and within 5 cm of treatment area, such a treatment is not 
prohibited. However, investigators will be encouraged to pursue individual lesion specific 
treatment options where clinically relevant and before employing field treatment. If topical 
treatment is indicated, ingenol mebutate and ingenol disoxate are not allowed in and within 5 
cm of the treatment area. Since subjects will not be deprived of active AK treatment options, 
there is no ethical concern related to the treatment of subjects participating in this extension 
protocol. 
 
4 Trial Objectives 
4.1 Primary Objective 
To compare the incidence of SCC after treatment with ingenol disoxate gel and vehicle gel. 
 
5 Trial Endpoints 
5.1 Primary Endpoint 
Time to first SCC in the treatment area 
 
5.2 Secondary Endpoints 
Time to first SCC or other skin neoplasia in the treatment area 
 
Safety Evaluations: Adverse event frequency by MedDRA Preferred Term 
 
6 Trial Design 
6.1 Overall Trial Design 
This is an international, phase 3, multi-centre, randomised, open-label, parallel group, 24- 
month trial in subjects with AK. The subjects who qualify for this trial have previously been 
enrolled in LEO trials LP0084-1193, -1194, -1195, or -1196 (‘main trial’) in which a 
treatment area has been defined. 


 
 
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At Visit 1 (which ideally coincides with visit 11 [Month 14]) subjects will sign the trial- 
specific consent form in the presence of the investigator and the subject’s eligibility will be 
checked. Additional trial visits will take place at Month 6, 12, 18, and 24. 
 
At Visit 2-5 the treatment area will be assessed for any adverse events (AEs). 
 
If a biopsy is taken due to suspicion of SCC or other skin neoplasia in the treatment area (see 
section 8.4.1), it will be sent for central review by an independent adjudication committee 
(IAC) with 3 expert dermatopathologists, see section 12.1. 
 
Cryotherapy is allowed in the treatment area. Investigators are encouraged to pursue these 
treatment options where clinically relevant and before employing other treatments. Until end 
of trial, if topical treatment is indicated, ingenol mebutate and ingenol disoxate are not 
allowed in, and within 5 cm of the treatment area. 
 
Figure 1 Trial Design 
 
 
 


 
 
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6.2 Trial Schedule 
Subjects are expected to participate for up to 24 months. 
 
Planned date of first subject first visit (FSFV): Q2 2017 
Planned date of last subject first visit (LSFV): Q4 2017 
Planned date of last subject last visit (LSLV): Q4 2019 
Estimated number of trial sites and country allocation: Approximately 80 sites in Canada, 
Germany, France, Italy, Spain, the United Kingdom, and USA. 
 
6.3 Sample Size 
No formal sample size calculation has been made. The sample size is determined by the 
number of subjects who complete Visit 11 in the confirmatory phase 3 trials (LP0084-1193, - 
1194, -1195, -1196) and are willing to enter the extension protocol. Two thirds would have 
been treated with ingenol disoxate, one third with vehicle. 
 
6.4 Randomisation 
Not applicable 
 
6.5 Blinding 
The phase 3 trials LP0084-1193, -1194, -1195, or -1196 are vehicle controlled and blinded. 
The blinding will, however, not be maintained during the 2 years of the extension protocol 
except for the blinding of the adjudication committee members, who evaluate the pathology 
slides from skin neoplasias in the treatment area. 
 
7 Trial Population and Withdrawal 
7.1 Subject Eligibility 
The (sub)investigator should only enrol subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial and can be expected to comply with the protocol. 
 
The subject’s eligibility for the clinical trial must be checked according to the inclusion and 
exclusion criteria at Visit 1. 
 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial must be ensured and described in the submission documentation to authorities/ethics 
committees, as applicable. 


 
 
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7.2 Inclusion Criteria 
1. Signed and dated informed consent has been obtained. 
2. The subject has been treated in one of the trials LP0084-1193, -1194, -1195, or -1196 
and has been evaluated at Visit 11 of that trial. 
7.3 Exclusion Criteria 
1. The subject is in need of treatment with ingenol mebutate or ingenol disoxate in the 
selected treatment area*. 
2. The subject is enrolled in any other interventional clinical trial. 
For subjects where there is a gap between Visit 11 in one of the trials LP0084-1193, -1194, - 
1195, or -1196 and participation in the current trial: 
1. The subject has been treated with ingenol mebutate or ingenol disoxate in the selected 
treatment area* after Visit 11 in one of the trials LP0084-1193, -1194, -1195, or -1196 
and until participation in the current trial. 
2. The subject has been enrolled in any other interventional clinical trial after Visit 11 in 
one of the trials LP0084-1193, -1194, -1195, or -1196 and until participation in the 
current trial. 
7.4 Subject Screening Log 
Subjects who have completed Visit 11 of the main trial and given the opportunity to enrol in 
this trial should be registered on the Subject Screening Log. 
 
7.5 Subject Identification List 
The (sub)investigator must maintain a list of all subjects enrolled at the trial site including 
each subject's identity, date of enrolment and corresponding subject ID so that any subject 
may be identified if required for any reason. The list is kept by the investigator and must not 
be copied or retained by LEO or CRO. The subject ID in the present trial and in the main trial 
must be the same. 
 
 
 
 
 
 
 
 
* The selected treatment area that was documented in the main trial (LP0084-1193, -1194, -1195 and -1196). 


 
 
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7.6 Restrictions during Trial 
 
Concomitant treatment in the selected treatment area: 
Cryotherapy and surgical procedures are allowed in the selected treatment area. Investigators 
will be encouraged to pursue these treatment options where clinically relevant and before 
employing other treatments. If topical treatment is indicated, ingenol mebutate and ingenol 
disoxate are not allowed in, and within 5 cm of the treatment area. 
 
Concomitant treatment outside the selected treatment area: 
No restrictions. 
 
7.7 Discontinuation 
Subject may be withdrawn from the trial for any of the following reasons: 
 
Adverse event (please specify) 
Any adverse event (AE) that the (sub)investigator 
considers unacceptable. 
Withdrawal by subject 
Subjects are free to withdraw from the clinical trial at 
any time and for any reason. 
Lost to follow-up 
Death 
Other (please specify) 
Other reasons than stated above which require the 
subject to (be) withdraw(n) should be specified. 
 
 
If adverse event or other is selected, a specification must be supplied. 
Subject must be withdrawn from the trial for any of the following reasons : 
1. If a subject, for any reason, has used ingenol mebutate or ingenol disoxate in or 
within 5 cm of treatment area during this trial 
2. If a subject participates in any other interventional clinical trial. 
 
 
For subjects withdrawn from trial, AEs should be followed up as described in section 9.5. 


 
 
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8 Trial Schedule and Assessments 
8.1 Schedule of Trial Procedures 
 
Table 1 Schedule of Trial Procedures 
 
Visit 
11) 
Visit 2 
Visit 3 
Visit 4 
Visit 5 Unscheduled 
or Early 
Termination 
Day / Month 
Month 62) 
Month 
12 
Month 
18 
Month 
24 
N/A 
Visit window 
N/A 
±16 days2) 
±16 days ±16 days 
±16 
days 
N/A 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X 
Concomitant 
medication and 
procedures3) 
X 
X 
X 
X 
X 
AE(s)4) 
X 
X 
X 
X 
X 
Scarring 
X 
X 
X 
X 
X 
End of Trial 
X 
X5) 
1) Visit 1 ideally coincides with visit 11 (month 14) of the main trial and should be 
performed before or at Visit 2 of the present trial. 
2) Visit 2 is 6 months after visit 11 (month 14) of main trial and the visit window is 
relative to visit 11. 
3) Information regarding medication or treatments which may suppress the immune 
system in subjects or which may alter the course of AK or SCC. Also, any 
medications (topical or systemic) and procedures used for AEs in the treatment 
area. 
4) Within treatment area only (SAEs outside treatment area are only collected if 
deemed related to IMP in main trial or reported elsewhere in the CRF). 
5) Early termination only. 
 
 
All assessments in this trial will be made in the treatment area that was documented in the 
main trial (LP0084-1193, -1194, -1195 and -1196). The study transparency used in the main 
trial should be used to reidentify the treatment area for assessment of the treated skin on the 
face, chest, or scalp for all visits in the present trial. 


 
 
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8.2 Subject Eligibility 
Refer to sections 7.2 and 7.3 
 
8.3 Concomitant Medication and Procedures 
The following should be collected: 
 
Information regarding medication or treatments which may suppress the immune system in 
subjects or which may alter the course of AK or SCC will be collected. 
 
Information will be collected regarding concomitant medications (topical or systemic) and 
procedures used for AEs in the treatment area. 
 
No other information on concomitant medications or procedures will be collected. 
 
Use of concomitant treatment must be recorded in the subject’s medical record and the CRF 
(e.g. treatment/drug name, route of administration, total daily dose, indication and dates of 
start and stop). 
 
If Visit 1 does not not coincide with Visit 11 of trial LP0084-1193, -1194, -1195 and -1196 
concomitant medication and procedures for the period between the two visits must be 
recorded at Visit 1. 


 
 
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8.4 Adverse Events 
Only AEs in the treatment area (including keratoacanthoma [KA], SCC, or other skin 
neoplasia) will be collected. AEs must be assessed and recorded as specified in section 9. 
 
If Visit 1 does not coincide with Visit 11 of the main trial (LP0084-1193, -1194, -1195 and - 
1196) events in the treatment area for the period between the two visits must be recorded at 
Visit 2. 
 
8.4.1 Adverse EventS of Special Interest and other Skin Neoplasia 
All biopsies of KA, SCC or other skin neoplasia in the treatment area should be sent for 
central review in the IAC, Section 12.1. If there are any discrepancies between the local 
histology report and the central pathology review, there should not be any changes in the 
CRF. For the central review, the local pathology laboratory will send the relevant histology 
slides to the investigator who will forward the slides to the CRO for distribution to the 
adjudication committee. Only if the original slides cannot be sent is it acceptable to use new 
slides made from the same tissue block. 
 
A biopsy should be considered in the following clinical situation: 
 
• A new lesion in the treatment area that has bled on more than 2 occasions. 
• Any papular lesion that measures more than 0.5 cm in diameter (0.2 inches). 
• A presumed actinic keratosis that has been treated twice with cryosurgery without 
resolution. 
 
8.5 Scarring 
Presence of scarring (Yes/No) in the treatment area will be recorded at visits indicated in 
Section 8.1. If scarring is present, the investigator should record in the CRF if the scarring is 
hypotrophic, hypertrophic or keloid. If a scarring is recorded it should also be recorded as an 
AE. 
 
8.6 End of Trial 
The End of Trial Form must be completed for all enrolled subjects. This includes last 
attended scheduled visit number and primary reason for withdrawal . 


 
 
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9 Adverse Events 
• AEs and serious adverse events (SAEs) are defined in Appendix 3: Definitions of 
Adverse Events and serious Adverse Events. 
• Classification of AEs in terms of severity, causality and outcome are defined in 
Appendix 4: Classification of Adverse Events. 
9.1 Collection of Adverse Events 
In this extension protocol, where no treatment is being administered, all AEs and SAEs 
occurring in the area treated in the phase 3 trials (treatment area) will be routinely collected 
from completion of Visit 11 in the main trial until the subject’s last visit to the clinic. 
 
SAEs occurring outside the treatment area in the main trial, and considered not related to IMP 
in these trials, will not be systematically collected. For an overview of which AEs should be 
collected, see table below. 
 
Table 2 Overview of AEs to be Collected 
 
AE collection 
Inside treatment area 
Outside treatment area 
AEs 
All 
None 
SAEs 
All 
Related to IMP in main trials 
Referenced elsewhere in the CRF (e.g. death on end of 
trial form, hospitalisation as reason for missing visit) 
 
 
AEs must be assessed by medically qualified personnel. A qualified experienced 
dermatologist must conduct all dermatologic examinations and AE evaluation of the treatment 
area defined in the main trials (LP0084-1193, -1194, -1195, -1196). 
 
At all visits, the subject will be asked a non-leading question by the (sub)investigator about 
AEs, for example: “How have you felt since I saw you last?” No specific symptoms should be 
asked for. It is important that the (sub)investigator also observes the subject for any changes 
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9.1.1 Local Skin Responses 
Local skin responses (LSR) matching the criteria in the LSR grading scale in the pivotal 
phase 3 trials are considered AEs in this extension protocol and should be handled and 
reported as such. 
 
9.2 Reporting of Adverse Events in the CRF 
AEs reported by the subject or observed by the (sub)investigator must be recorded on the AE 
form of the CRF and should be described in the following manner: 
 
The AE term will be in precise English medical terminology (i.e. not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (e.g. 
allergic contact dermatitis). 
 
The duration of the AE must be reported by the start date and stop date of the event. In 
addition, it must be recorded whether the AE started prior to start of IMP. 
 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 4: Classification of Adverse Events. 
 
9.2.1 Actions Taken as a Consequence of an Adverse Event 
Any action taken as a result of the AE must be recorded (none, concomitant medication, 
concurrent procedure). 
 
Withdrawn due to AE: it must be recorded whether the AE leads to withdrawal from the trial. 
 
9.3 Other Events to be Reported 
Overdose, medication error, misuse and abuse will not be reported since no IMP is given in 
this trial. 
 
9.3.1 Pregnancy 
Any pregnancy occurring during the main trials (LP0084-1193, -1194, -1195 and -1196) from 
Visit 1 until Visit 7 has been reported. This extension protocol investigates subjects following 
their participation in one of the four pivotal phase 3 trials without any additional treatment, 
hence pregnancies are not to be reported in the current trial as treatment has been finalised 14 
months prior to enrollment. 


 
 
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9.3.2 Aggravation of Condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to baseline, must be reported as an AE. 
 
9.3.3 Adverse Events of Special Interest 
Due to the sun-damage, the target population is prone to SCC development. Sun-damaged 
skin is also prone to development of keratoacanthoma (KA) as a response to local irritation 
and/or inflammation. To ensure that all information relevant for surveillance is collected, 
SCCs and KAs in the area treated in the pivotal phase 3 trials are considered adverse events of 
special interest (AESI). 
 
For SCCs and KAs in the area treated in the confirmatory phase 3 trials (LP0084-1193, -1194, 
-1195, -1196), the relevant information will be collected in the CRF. In addition, the local 
histology report should be faxed or emailed to Global Pharmacovigilance, once available, 
using the following fax number or email address: 
 
Fax number: +45 7226 3287 
 
Email address: drug.safety@leo-pharma.com 
 
SCCs and KAs in the treatment area (defined in the main phase 3 trials) that meet the criteria 
for being serious should be reported as SAEs (please refer to section 9.4.1 for reporting 
details). 
 
The pathology slides that have been used for the initial diagnosis of the AESI will be sent for 
central pathology review by the procedure outlined in section 8.4 
 
9.4 Additional Reporting Requirements for Serious Adverse Events 
9.4.1 Investigator Reporting Responsibilities 
When reporting SAEs, the paper SAE Form – Clinical Trials, must be used, and submitted to 
LEO within 2 4 hours of first knowledge. This report should contain an assessment of 
available information on seriousness, severity, causal relationship to the IMP, comparator or 
trial procedure, the action taken, the outcome to date, and a narrative description of the course 
of the event. 
 
The completed SAE form must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO using the following fax number or e-mail address: 


 
 
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Fax number: +45 7226 3287 (for Global Pharmacovigilance) 
 
E-mail address: drug.safety@leo-pharma.com (for Global Pharmacovigilance) 
 
It may be relevant for the (sub)investigator to enclose other information with the SAE form, 
such as anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
 
Additionally, Global Pharmacovigilance, LEO may request further information in order to 
fully assess the SAE. The (sub)investigator must forward such information to Global 
Pharmacovigilance, LEO upon request by fax or e-mail (see contact details above). 
 
The investigator must notify the local IRB(s)/IEC(s) of SAEs as required by current 
applicable legislation for the concerned country. 
 
SAEs occurring after the completion of the clinical trial including any protocol required post- 
treatment follow-up period should not be routinely sought or collected. However, such events 
should be reported to Global Pharmacovigilance, LEO (drug.safety@leo-pharma.com) if the 
(sub)investigator becomes aware of them. 
 
9.4.2 LEO Reporting Responsibilities 
Global Pharmacovigilance, LEO is responsible for assessing whether or not an SAE is 
expected. The relevant reference document for this clinical trial is: 
 
For the IMP, the Investigator’s Brochure, LEO 43204, Field Therapy, Edition No. 5 and 
subsequent updates hereof must be used (9). 
 
Global Pharmacovigilance, LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries. 
 
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned countries. 
 
For all non-US countries, all SAEs which are assessed as casually related to the IMP by either 
the investigator or LEO (ICH E2A Guideline), and which are unexpected (Suspected, 
Unexpected Serious Adverse Reactions (SUSARs)), are subject to expedited reporting to 
regulatory authorities and IRB(s)/IEC(s) according to the current applicable legislation in the 
concerned countries. Investigators will be notified of these on an ongoing basis. 


 
 
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For the US, all SAEs which are assessed as casually related to the IMP by LEO (Guidance for 
Industry and Investigators – Safety Reporting Requirements for INDs and BA/BE Studies) 
and which are unexpected (Serious and Unexpected Suspected Adverse Reactions (IND safety 
report)) are subject to expedited reporting to regulatory authorities and IRB(s)/IEC(s) 
according to the current applicable legislation in the concerned countries. Investigators will be 
notified of these on an ongoing basis. 
 
9.5 Follow-up for Final Outcome of Adverse Events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as of possible/probable relationship to the 
investigational product for 2 months or until the final outcome is determined, whichever 
comes first. SAEs must be followed up until a final outcome has been established, i.e. the 
follow-up may continue beyond the end of the clinical trial. 
 
10 Trial Product 
Not applicable 
 
11 Statistical Methods 
Data on skin neoplasia from the 14 months observation time in the confirmatory phase 3 trials 
LP0084-1193, -1194, -1195, and -1196 will be combined with the data from the present trial. 
 
11.1 Sample Size 
No formal sample size calculation has been made. The sample size is determined by the 
number of subjects who complete Visit 11 in the pivotal phase 3 trials (LP0084-1193, -1194, - 
1195, -1196) and are willing to enter the extension protocol. Two thirds have been treated 
with ingenol disoxate, one third with vehicle. 
 
A total of 1200 subjects were planned be enrolled in the pivotal phase 3 trials (LP0084-1193, - 
1194, -1195, and - 1196) and randomised 2:1 to the two treatment groups ingenol disoxate gel 
or vehicle gel. With 800 subjects in the ingenol disoxate treatment group and 400 subjects in 
the vehicle gel group, an adequate precision of the 3-year plus 2 months incidence rate can be 
obtained. Assuming a 3-year plus 2 months rate of 4.0%, the upper 95% confidence limit will 
on average be 5.36% for ingenol disoxate gel and 5.92% for vehicle gel, and assuming a 6.0% 
rate, the upper 95% confidence limit will on average be 7.65% for ingenol disoxate gel and 
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11.2 Trial Analysis Sets 
All subjects enrolled in the trial (i.e. subjects for whom informed consent has been obtained 
and who have been registered in a clinical trial) will be accounted for in the clinical trial 
report. 
 
All randomized subjects from the pivotal phase 3 trials (LP0084-1193, -1194, -1195, -1196) 
are included in the full analysis set (FAS) and will be analysed for incidence of SCC and other 
skin neoplasia. Exclusions from the full analysis set can be considered in special cases as 
described in ICH E9, section 5.2.1., Full Analysis Set. If it is decided to exclude a subject 
from the full analysis set, a justification addressing ICH E9 will be given. 
 
A safety analysis set will be defined by excluding subjects from the full analysis for whom no 
post-baseline safety evaluations are available. 
 
The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial 
analysis sets will be documented in the statistical analysis plan update . 
 
11.3 Statistical Analysis 
11.3.1 Disposition of Subjects 
The reasons for leaving the trial will be presented for the FAS by last visit attended and by 
treatment group in the main trial. This will also be done for the enrolled and eligble subjects 
not included in the FAS. 
 
11.3.2 Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all subjects, by treatment group in the main trial and by country. Presentations of age, sex, 
ethnicity and race and baseline AK count by treatment group will also be given by main trial. 
 
The demographics and other baseline characteristics will be summarised for the 4 main trials 
combined as well as the subset of those who enter the extension trial. 
 
Demographics include age, sex, race, ethnicity and skin type. Other baseline characteristics 
include anatomical location (face, chest, or scalp) of treatment area in the main trials, 
treatment area size, concurrent diagnoses (from medical history and indications for 
concomitant medication), and concomitant medication. Baseline AK characteristics will 
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AKs (anywhere) and previous treatment of AKs in the treatment area as reported in the main 
trial. 
 
11.3.3 Exposure and Treatment Compliance 
11.3.4 Analysis of Primary Endpoint 
The null hypothesis is that there is no difference in time to first SCC between ingenol disoxate 
gel and vehicle gel. The hypothesis will be tested against the two-sided alternative that there 
is a difference between the two treatment groups. 
 
Primary endpoint is time to first SCC in the treatment area from Visit 2 in trials LP0084-1193, 
-1194, -1195 and -1196. 
 
Only the SCC confirmed by the IAC will be used in the primary endpoint analysis. 
 
The annual and the 3-year and 2 months cumulative incidence of first event of SCC will be 
calculated for each treatment group (active and vehicle) in main trial using methods of 
survival analysis in the presence of censoring. The cumulative incidence rates will be 
presented by treatment group for the event of first SCC as primary endpoint. A proportional 
hazards model will be fitted if the model assumptions are valid. Log-rank test comparing the 
two treatment groups 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 will additionally be 
performed in order to exclude SCC and other neoplasia reported within the first 8 weeks 
which are not assumed to be associated with the trial treatment. This corresponds to left- 
truncation of the trial period at 8 weeks, the analysis will otherwise be conducted as above. 
Patients who experience a SCC before the 8-week landmark time point are excluded from the 
landmark analysis. 
 
11.3.5 Analysis of Secondary Endpoint 
For the secondary endpoint, the null hypothesis is that there is no difference in time to first 
SCC or other skin neoplasia between ingenol disoxate gel and vehicle gel. The hypothesis will 
be tested against the two-sided alternative that there is a difference between the two treatment 
groups. 
 
Secondary endpoint is time to first SCC or other skin neoplasia in the treatment area from 
Visit 2 in trials LP0084-1193, -1194, -1195 and -1196. 


 
 
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Only the SCC or other skin neoplasia confirmed by the IAC will be used in the secondary 
endpoint analysis. 
 
Analysis of the secondary endpoint will be performed as outlined above for the primary 
endpoint. 
 
11.3.6 Analysis of Safety 
The analysis of safety will be based on the safety analysis set. 
 
11.3.6.1 Adverse Events 
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred terms and primary 
system organ class (SOC). 
 
AEs from the 24-month trial period, will be summarised and included in the subject data 
listings by its start date. All adverse events will be considered treatment-emergent and will be 
included in the tabulations described in the following. In each of the tabulations, AEs are 
defined by MedDRA preferred terms within primary SOC. 
 
An overall summary of the number (percentage) of subjects with any AEs, SAEs, premature 
discontinuations from the trial due to AEs, treatment-related AEs and severe AEs will be 
presented overall and by treatment group in main trial. 
 
The number of subjects experiencing each type of AEs will be tabulated by treatment group in 
main trial regardless of the number of times each AE is reported by each subject. The 
percentage of subjects with any AEs will be compared between treatment groups by a chi- 
square test or Fisher’s exact test (if expected cell count < 5). 
 
Severity 
The severity for each type of AE will be tabulated by treatment group in main trial. Where 
there are several recordings of severity for a given type of AE, severity will be taken as the 
most severe recording for that AE. 
 
Causal relationship 
The causal relationship to IMP for each type of AE will be tabulated by treatment group. 
Where there are several recordings of causal relationship to the IMP for a given type of AE, 
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since that is when the (sub)investigator will be in possession of most information and so best 
able to judge causal relationship. 
 
Related AEs are defined as AEs for which the (sub)investigator has not described the causal 
relationship to IMP as ‘not related’. The number of subjects experiencing each type of related 
AE will be tabulated regardless of the number of times each related AE is reported by each 
subject. The percentage of subjects with related AEs will be compared between treatment 
groups by a chi-square test or Fisher’s exact test (if expected cell count < 5). 
 
Most common adverse events 
The most common AEs (≥2% of subjects in the active treatment group in the main trial) will 
be presented by treatment group. 
 
Serious adverse events and withdrawal 
SAEs will be evaluated separately and a narrative for each will be given. AEs leading to 
withdrawal from trial will be listed. 
 
Adverse events of special interest 
AESI will be presented by treatment group in the main trial. For the AESI the number of 
events with agreement and disagreement between data from the AE form in the CRF and data 
from the central review will be presented by treatment group. A narrative for each AESI will 
be given. 
 
11.3.7 Interim Analysis 
No interim analyses are planned. 
 
11.3.8 General Principles 
All significance tests will be two-sided using the 5% significance level . All confidence 
intervals will be presented with 95% degree of confidence. 
 
An observed-cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
 
Categorical data will be summarised using the number and percentage of subjects in each 
category. Continuous data will be summarised using the mean, median, standard deviation 
(SD), minimum and maximum values. 


 
 
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Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment/the statistical analysis plan update and/or in 
the clinical trial report dependent on the type of deviation. 
 
11.3.9 Handling of Missing Values 
Missing values for time to occurrence of SCC or other neoplasia will be handled as censored 
observations. 
 
12 Trial Committees 
12.1 Independent Adjudication Committee 
In LEO ingenol trials, squamous cell carcinoma (SCC) and keratoacanthoma (KA) inside the 
treatment area have been defined as an AESI. KA may be difficult for some pathologists to 
distinguish from SCC and may be underreported due to the fear of misdiagnosing the 
malignant SCC. As many AK patients are prone to SCC as well as KA due to the heavy sun 
damage, it is of great importance that possible tumours that occur after treatment with ingenol 
disoxate are diagnosed correctly. An independent adjudication committee (IAC) has therefore 
been assembled to provide consistent evaluation of the incidence of KA in the patient 
population as opposed to the incidence of SCC. The IAC comprises 3 medical doctors, who 
are experts in dermatopathology. 
 
All biopsies of AESIs and other skin neoplasia in the treatment area at any time during the 
trial will be sent to the IAC for central review, as described in sections 8.4 and 9.3.3. 
 
See Appendix 4: Contact list of LEO, protocol authors, vendors, trial committees and 
coordinating investigators for contact details on all trial committee members. 
 
13 Case Report Forms and Data Handling 
13.1 Case Report Forms (CRFs) 
Data will be collected by means of Electronic Data Capture (EDC). The investigator or staff 
authorised by the investigator will enter subject data into electronic CRFs. Data recorded in 
the electronic CRFs will be accessible to the trial site and LEO personnel immediately after 
entry. The CRFs must be maintained in an up-to-date state by the trial site at all times. 
 
The investigator must verify the correctness of the data entered by the site by electronically 
date and sign all CRFs used. This signature information will be kept in the audit trail and 
cannot be altered. Any correction(s) made by the (sub)investigator or authorised site staff to 


 
 
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the CRF after original entry will be documented in the audit trail. Changes to data already 
approved will require the re-signature by the investigator. The person making the change to 
the data, and the date, time and reason for the change will be identified in the audit trail. 
 
For archiving purposes, each investigator will be supplied with a copy of the CRFs for all 
subjects enrolled at the trial site. This is done after completion of the trial and before access to 
the eCRF is revoked. Audit trail information will be included. CRFs must be available for 
inspection by authorised representatives from LEO, from regulatory authorities and/or 
IEC/IRBs. 
 
13.2 Data Handling 
Subject data should be entered into the CRF as soon as possible after each visit in accordance 
with the requirements described in the Clinical Trial Agreement. Queries for discrepant data 
will be generated automatically by the system upon entry or manually by the monitor or the 
data manager. All queries will be raised electronically within the EDC system. This systematic 
validation will ensure that a clean and consistent database is provided for the statistical 
analysis. 
 
13.3 Source Data 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be one source defined at any time for 
any data elements. 
 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. 
 
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
• Date(s) of conducting the informed consent process (date of enrolment) including 
date of provision of subject information 
• A statement from the investigator to verify that each of the eligibility criteria are 
met for each subject 
• Subject ID 
• The fact that the subject is participating in a clinical trial. 


 
 
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• Other relevant medical information 
The trial monitor will check the CRFs for accuracy and completeness by verifying data 
recorded in the CRF against source data to ensure such records are consistent. 
13.4 Trial Monitoring 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol 
and GCP are adhered to, that all issues have been recorded to perform source data 
verification, and to monitor drug accountability. 
 
The monitoring visit intervals will depend on the trial site’s recruitment rate, the compliance 
of the trial site with the protocol and GCP. 
 
In order to perform their role effectively, monitors and persons involved in quality assurance 
and inspections will need d irect access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the monitor with signed and dated printouts. In addition, relevant 
site staff should be available for discussions at monitoring visits and between monitoring 
visits (e.g. by telephone). 
 
14 Handling of an Urgent Safety Measure 
An Urgent Safety Measure is a measure taken to implement an action/protocol deviation 
under an emergency. This is defined within the EU Directive as “…the occurrence of any new 
event relating to the conduct of the trial or the development of the investigational medicinal 
product where that new event is likely to affect the safety of the subjects, the sponsor and the 
investigator shall take appropriate urgent safety measures to protect the subjects against any 
immediate hazard.” (Article 10(b) of Directive 2001/20/EC). 
 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order to protect clinical trial 
subjects from any immediate hazard to their health and safety, the investigator can do so 
without prior approval from LEO, regulatory authority(ies) or IRB(s)/IEC(s). 
 
The investigator must immediately inform LEO - by contacting the CPM or medical expert - 
of this change in the clinical trial procedure or of the temporary halt providing full details of 
the information and the decision making process leading to the implementation of the urgent 
safety measure. 


 
 
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LEO must act immediately upon receipt of the urgent safety measure notification in 
accordance with the internal procedures and national requirements. 
 
15 Quality Assurance/Audit 
The clinical trial will be subject to audits conducted by LEO or inspections from domestic or 
foreign regulatory authorities or from IRBs/IECs. Audits and inspections may take place 
during or after the trial. The investigator and the site staff as well as LEO staff have an 
obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant 
to the clinical trial. This includes permission to examine, verify and reproduce any records 
and reports that are important to the evaluation of the trial. 
 
If the trial site is contacted for an inspection by competent authorities, LEO must be notified 
immediately. 
 
16 Completion of Trial 
16.1 Trial Completion Procedures 
End of trial is defined as the date of the last subject’s last visit in each participating country 
and overall (all countries). 
 
Investigators will be informed when subject recruitment is to cease (if applicable) 
 
16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site 
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the trial, part 
of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained. 
 
If a trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. As specified by applicable regulatory 
requirements, the investigator or LEO must promptly inform IRB/IECs and provide a detailed 
written explanation. Relevant competent authorities must be informed. 
 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
 
Due to the design of this trial, there are no statistical criteria for trial termination. 


 
 
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16.2 Provision for Subject Care Following Trial Completion 
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. 
 
16.3 Archiving of Trial Documents 
The investigator at each trial site must make arrangements to store the essential trial 
documents including the Investigator Trial File (ICH E6, Guideline for Good Clinical 
Practice) until LEO informs the investigator that the documents are no longer to be retained or 
longer if required by local regulations. 
 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (e.g. 
in case of an inspection from regulatory authorities). 
 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the clinic/practice or retires before the end of the required storage period. 
 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
 
17 Ethics and Regulatory Authorities 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) and Regulatory Authorities 
Written approval or favourable opinion must be obtained from relevant IRB/IECs prior to the 
enrolment of subjects. 
 
Any amendments to the approved clinical trial must be approved by/receive favourable 
opinion from relevant IRBs/IECs and regulatory authorities as required prior to the 
implementation. 
 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial as 
required. 


 
 
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17.2 Ethical Conduct of the Trial 
This clinical trial must be conducted in accordance with the principles of the revision current 
at the start of the trial of the World Medical Association (WMA), Declaration of Helsinki, 
Ethical Principles for Medical Research Involving Human Subjects. 
 
17.3 Subject Information and Informed Consent 
All subjects shall receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
 
The subject’s signed and dated informed consent to participate in the clinical trial must be 
obtained prior to any clinical trial related procedure being carried out in accordance with ICH 
GCP (4.8) and all applicable laws and regulations. 
 
17.4 Processing of Personal Data 
This protocol specifies the personal data on trial subjects (e.g. age, gender, health condition, 
height, medical history, test results, etc.) which shall be collected as part of the trial and 
processed during and after trial completion. 
 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator and LEO. 
 
Processing of personal data on behalf of LEO requires a written agreement between LEO and 
the relevant party which covers collection, processing and transfer of personal data in the 
clinical trial. In certain cases an agreement on transfer of personal data may also be required. 
 
Investigators and LEO must ensure that collection, processing and transfer of personal data 
are in compliance with national legislation on data protection and privacy. 
 
The investigator/institution may be considered as data controller when they wish to use 
personal data collected in the clinical trial for their own purpose such as publication of 
clinical trial results. 
 
Subjects [(or their legally acceptable representative)] must be asked to consent to the 
collection, processing and transfer of their personal data to [EU and non-EU countries] for the 
purpose of conducting the clinical trial, research and development of new or existing 


 
 
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products/services, improving existing products/services, applying for marketing 
authorisations for products/services, marketing of products/services and other related 
activities. 
 
LEO has obtained the necessary authorisations for the processing of personal data collected in 
the trial. 
 
18 Insurance 
LEO has taken out relevant insurances covering the subjects in the present clinical trial in 
accordance with applicable laws and regulations. 
 
19 Use of Information 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the IMP(s) is confidential information of LEO and shall not be used by 
the investigator for purposes other than this clinical trial. 
 
The investigator agrees that LEO may use any and all information, data and results from this 
clinical trial in connection with the development of the IMP(s) and, therefore, may disclose 
and/or transfer information, data and/or results to other investigators, regulatory authorities 
and/or commercial partners. 
 
20 Registration, reporting and publication 
Basic information of this clinical trial will be registered in the global data registry, 
www.clinicaltrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
 
Results of this trial will be posted on the corporate website of LEO in accordance with LEO’s 
Position on Public Access to Clinical Trial Information, latest 12 months after trial 
completion. Results may also become reported in ClinicalTrials.gov, 
www.clinicaltrialsregister.eu and national data registries in accordance with applicable law 
and regulations after trial completion or premature termination. In the case of a multi-centre 
trial the first publication will be a joint multi-centre publication. Multi-centre publications 
will be prepared in collaboration between LEO and the members of a writing group, which 
shall be appointed by LEO. 
 
Publication by an investigator of his/her trial results shall not be made public before the first 
multi-centre publication. 


 
 
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If no multi-centre publication has been submitted for publication within eighteen months after 
the clinical trial has been completed or terminated at all trial sites and all data have been 
received, defined as database lock of the clinical trial, the investigator shall have the right to 
publish the results from the clinical trial generated by the investigator, subject to the following 
notice requirements. 
 
Prior to submitting or presenting a manuscript relating to the clinical trial to a publisher, 
reviewer or other outside person, the investigator shall provide to LEO a copy of all such 
manuscripts, and LEO shall have rights to review and comment. Upon the request of LEO, the 
investigator shall remove any confidential information (other than results generated by the 
investigator) prior to submitting or presenting the manuscripts. The investigator shall, upon 
the request of LEO, delay the publication or presentation to allow LEO to protect its 
inventions and other intellectual property rights described in any such manuscripts. In case the 
first multi-centre publication is still ongoing and has not been made public at the time of 
notification, LEO and the writing group 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 still be followed. 
 
LEO complies with recommendations from the International Committee of Medical Journal 
Editors and with the positions of the International Federation of Pharmaceutical 
Manufacturers & Associations (IFPMA), European Federation of Pharmaceutical Industries 
and Associations (EFPIA), Japan Pharmaceutical Manufacturers Association (JPMA) and 
Pharmaceutical Research and Manufacturers of America (PhRMA) on disclosure of 
information about clinical trials, trial results and authorship (10). 
 
21 Responsibilities 
The international coordinating investigator (ICI) is responsible for the approval of the 
(Consolidated) Clinical Trial Protocol, Clinical Trial Protocol Amendment(s) and the Clinical 
Trial Report on behalf of all clinical trial investigators and as agreed to in an International 
Coordinating Investigator Agreement. 
 
The national coordinating investigator(s) are responsible for national issues relating to the 
clinical trial as agreed to in a National Coordinating Investigator Agreement. 
 
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. 


 
 
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22 List of Abbreviations 
 
AESI 
Adverse Events of Special Interest 
AE 
Adverse Event 
CMO 
Contract Manufacturing Organisation 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
EDC 
Electronic Data Capture 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GPV 
Global Pharmacovigilance 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IAC 
Independent Adjudication Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
KA 
Keratoacanthoma 
LSR 
Local Skin Response 
MedDRA 
Medical Dictionary for Regulatory Activities 
Main trial 
LEO trials LP0084-1193, -1194, -1195, or -1196 
NLCRA 
National Lead Clinical Research Associate 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
SCC 
Squamous cell carcinoma 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
WMA 
World Medical Association 


 
 
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23 References 
1. Einspahr JG, Stratton SP, Bowden GT, et al. Chemoprevention of human skin cancer. 
Crit Rev Oncol Hematol. 2002;41:269-285. 
2. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol 1994;131:455- 
464. 
3. Alam M. Actinic keratoses: prevalence, pathogenesis, presentation, and prevention. 
Adv Stud Med. 2006;6(8A):S785-90. 
4. Fu W, Cockerell CJ. The actinic (solar) keratosis: A 21st century perspective. Arch 
Dermatol. 2003 Jan; 139(1): 66-70. 
5. Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol. 2002 
Apr;146 Suppl 61:20-3. 
6. Cohen JL. Actinic keratosis treatment as a key component of preventive strategies for 
nonmelanoma skin cancer. J Clin Aesthetic Dermatol. 2010 Jun; 3(6): 39-44 
7. Padilla RS, Sebastian S, Jiang Z, Nindl I, Larson R. Gene expression patterns of 
normal human skin, actinic keratosis, and squamous cell carcinoma: a spectrum of 
disease pro-gression, Arch Dermatol. 2010 Mar; 146(3): 288-293. 
8. 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. 
9. Investigator's Brochure, LEO 43204, Field Therapy, Edition No.5, Ballerup, Denmark: 
LEO Pharma A/S, 16-Sep-2016. 
10. Joint Position on the Publication of Clinical Trial Results in the Scientific Literature, 
available from: 
http://www.ifpma.org/fileadmin/content/Ethics/Clinical_Trials/June2010_Joint_Positi 
on_CT_Data_Publication-scientific_literature.pdf 


 
 
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List of Appendices 
Appendix 1: Protocol Summary 
 
Appendix 2: Definitions of Adverse Events and Serious Adverse Events 
Appendix 3: Classification of Adverse Events 
Appendix 4: Contact list of LEO, protocol authors, vendors, trial committees and coordinating 
investigators 
 
Appendix 5: Protocol Amendment History 


 
 
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Appendix 1: Protocol Summary 
 
Name of finished/ 
IMP 
NA 
Name of active 
substance 
NA 
Title of trial/ 
trial ID/ 
EudraCT no. 
Incidence of squamous cell carcinoma and other skin neoplasia in 
subjects with actinic keratosis treated with ingenol disoxate gel 0.018% 
or 0.037%, or vehicle / 
LP0084-1369 / 
EudraCT number: 2017-000228-85 
Coordinating 
investigator(s) 
PPD 
, MD 
Sponsor’s name/ 
address 
LEO Pharma A/S 
Industriparken 55 
DK-Ballerup 
Estimated 
number of trial 
sites and 
distribution 
Approximately 80 sites in Canada, Germany, France, Italy, Spain, the 
United Kingdom, and USA 
Trial period 
Planned First Subject First Visit (FSFV): Q2 2017 
Planned Last Subject Last Visit (LSLV): Q4 2019 
Main objective(s) 
To compare the incidence of SCC after treatment with ingenol disoxate 
gel and vehicle gel 
Methodology 
A phase 3 trial to compare the incidence of SCC and other skin neoplasia 
on skin areas treated with ingenol disoxate gel or vehicle gel for multiple 
actinic keratosis on face and chest or scalp. The trials is a multi-centre, 
randomised, open-label, controlled, parallel group, 24-month trial 
Number of 
subjects to be 
enrolled 
No formal sample size calculation has been made. The sample size is 
determined by the number of subjects who complete Visit 11 in the 
pivotal phase 3 trials (LP0084-1193, -1194, -1195, -1196) and are willing 
to enter the extension protocol. 
Main criteria for 
inclusion 
1. Signed and dated informed consent has been obtained. 
2. The subject has been treated in one of the trials LP0084-1193, - 
1194, -1195, or -1196 and has been evaluated at Visit 11 of that 
trial. 
Main criteria for 
exclusion 
1. The subject is in need of treatment with ingenol mebutate or 
ingenol disoxate in the selected treatment area* . 
2. The subject is enrolled in any other interventional clinical trial. 


 
 
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For subjects where there is a gap between Visit 11 in one of the trials 
LP0084-1193, -1194, -1195, or -1196 and participation in the current 
trial: 
1. The subject has been treated with ingenol mebutate or ingenol 
disoxate in the selected treatment area* after Visit 11 in one of the 
trials LP0084-1193, -1194, -1195, or -1196 and until participation 
in the current trial. 
2. The subject has been enrolled in any other interventional clinical 
trial after Visit 11 in one of the trials LP0084-1193, -1194, -1195, or - 
1196 and until participation in the current trial. 
* The selected treatment area that was documented in the main trial (LP0084- 
1193, -1194, -1195 and -1196). 
IMP(s) 
NA 
Investigational 
reference 
product(s) 
NA 
Duration of 
treatment 
NA 
Main assessments Adverse events in the treatment area that was documented in the main 
trials (LP0084-1193, -1194, -1195 and -1196). 
Primary endpoint 
Time to first squamous cell carcinoma (SCC) in the treatment area 
Secondary 
endpoint(s) 
Time to first squamous cell carcinoma (SCC) or other skin neoplasia in 
the treatment area 
Statistical 
methods 
Data on skin neoplasia from the 14 months observation time in the main 
trials will be combined with the data from the present trial 
Primary endpoint: The annual and the 3-year and 2 months cumulative 
incidence of first event of SCC will be calculated for each treatment 
group (active and vehicle) using methods of survival analysis in the 
presence of censoring. The incidence rates will be presented for the 
event of first SCC as primary endpoint . A proportion hazards model will 
be fitted if the model assumptions are valid. Log-rank test comparing the 
two arms will be performed. For descriptive purposes, as an additional 
analysis, the difference in cumulative incidence rates between the two 


 
 
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arms will be estimated and presented together with its 95% confidence 
interval. A landmark analysis will additionally be performed in order to 
exclude SCC and other neoplasia reported within the first 8 weeks which 
are not assumed to be associated with the study treatment. This 
corresponds to left-truncation of the trial period at 8 weeks, which is 
otherwise conducted as above. Patients who experience a neoplasia 
before the 8-week landmark time point are excluded from the landmark 
analysis. 


 
 
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Appendix 2: Definitions of Adverse Events and Serious Adverse Events 
Adverse Event Definition 
An AE is defined as 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 AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH Harmonized Tripartite Guideline for Good Clinical Practice, 
E6 (R1)). 
 
This definition includes: 
 
• accidental injuries, events related to trial procedures, reasons for any unfavourable 
and unplanned change in medication (drug and/or dose), clinically significant 
worsening of pre-existing conditions, or reasons for admission to hospital or 
surgical procedures unless these were planned before enrolment. It also includes 
AEs commonly observed and AEs anticipated based on the pharmacological effect 
of the IMP. In addition, any laboratory abnormality assessed as clinically 
significant by the (sub)investigator must be recorded as an AE. 
Serious Adverse Event Definition 
 
An SAE is any untoward medical occurrence that 
 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation. 
Planned hospitalisation or planned prolonged hospitalisation do not fulfill the 
criteria for being an SAE but should be documented in the subject’s medical 
record. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
or 


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


 
 
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Appendix 3: Classification of Adverse Events 
Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the (sub)investigator’s clinical judgement. 
 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
 
Causality 
 
The causal relation of the AE to the use of the IMP should be described in terms of probable, 
possible or not related according to the following: 
 
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
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 IMP. 
Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
Follows a reasonable temporal sequence from the administration of the IMP. 
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 IMP. 
Not related 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 


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


 
 
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PPD 
 
Appendix 4: Contact list of LEO, protocol authors, vendors, trial 
committees and coordinating investigators 
Contact details for the clinical project manager (CPM), national lead CRA (NLCRA), 
medical expert and safety scientist/safety physician are provided to participating trial sites in a 
separate sponsor contact list. 
 
Sponsor 
LEO Pharma A/S (referred to as ‘LEO’ in this clinical trial protocol) is the sponsor of the 
clinical trial: 
 
LEO Pharma A/S 
Industriparken 55 
P
 
DK-2750 Ballerup 
Denmark 
Protocol authors 
PPD 
, M.D. International Coordinating Investigator 
 
PPD 
, Trial Statistician, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, 
Danmark 
 
PPD 
, M.D. Medical Expert, LEO Pharma A/S, Industriparken 55, DK-2750 
Ballerup, Danmark 
 
PPD 
, MSc Pharm., Safety Scientist, LEO Pharma A/S, Industriparken 55, 
DK-2750 Ballerup, Danmark 
 
PPD 
, M.S., CPM, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Danmark 
 
CRO(s)/vendors 
 
PPD 
, PPD 
, PPD 
, PPD 
, USA will maintain the study 
portal and eLearning for study personnel 
 
PPD 
, PPD 
, PPD 
, PPD 
, USA will manage and 
provide the clinical database. 
PPD , PPD , PPD 
, PPD 
, 
, Ireland, will provide 
lab kit and logistic support for AESI review. 


 
 
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Independent Adjudication Committee: 
Prof. PPD 
Department of Pathology and Laboratory Medicine, Geffen-UCLA 
School of Medicine, 1250 16th Street, Santa Monica, CA 90404 USA 
 
Prof. PPD 
, Department of Dermatology and Venereology, Medical University of 
Graz, Auenbruggerplatz, 8, A-8036 Graz, AUSTRIA 
 
Dr. PPD 
 
Catolicos 2, 28040 Madrid, SPAIN 
Fundacion Jimenez Diaz, Avda. Reyes 
 
Coordinating investigators 
International Coordinating Investigator: PPD 
, M.D. 


 
 
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Appendix 5: Protocol Amendment History 
 
 
Amendment 1 (27-Jul-2017) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
 
Overall rationale for the amendment 
The reason for the amendment is to change the definition of the FAS to include all 
randomised subjects from the pivotal phase 3 trials. The amendment also addresses requests 
for changes from the Health Authorities in Europe and US after their review of the protocol. 
 
Note: In the table below, text added to the protocol is written in bold and deleted text has a 
line through it. 
 
Section 
number and 
name 
Description of change 
Brief rationale 
1.1.Approval 
Statement LEO 
Pharma A/S 
PPD 
, PhD PPD 
M.Sc 
New biostatistician 
2 Trial 
identidication 
Clinicaltrials.gov identifier: 
NCT03115476 
Include CT.gov identifier 
6.1 Trial Design (see section 8.4.1) 
Clarification 
6.3 Sample Size 
The sample size is determined by the 
number of subjects who complete Visit 11 
in the confirmatory phase 3 trials (LP0084- 
1193, -1194, -1195, -1196) and are willing 
to enter the extension protocol and is 
 expected to be around 1080. 
Aligned with Section 11.1 
7.4 Subject 
Screening and 
Enrolment Log 
Subject Screening and Enrolment Log 
Correction of title of log 
8.1 Schedule of 
Trial Procedures 
4) Within treatment area only (SAEs 
outside treatment are only collected if 
deemed related to IMP in main trial or 
Clarification 


 
 
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Table 1 
reported elsewhere in the CRF). 
5) Early termination only. 
8.3 
Concomitant 
Medication and 
Procedures 
The sentence: “If visit 1 (…)must be 
recorded at Visit 1.” has been moved to the 
end of the section. 
The following should be collected: 
In addition, Information will be collected 
regarding concomitant medications (topical 
or systemic) and procedures used for AEs 
in the treatment area. 
Clarification 
8.4 Adverse 
Events 
If Visit 1 does not coincide with Visit 11 of 
the main trial trial(LP0084-1193, -1194, - 
1195 and -1196) events in the treatment 
area for the period between the two visits 
must be recorded at Visit 28.4.1 
8.4.1 Adverse Events of Special Interest 
and other Skin Neoplasia 
• A new lesion in the treatment area that 
has bled on more than 2 occasions. 
• Any papular lesion that measures more 
than 0.5 cm in diameter (0.2 inches). 
• A presumed actinic keratosis that has 
been treated twice with cryosurgery 
without resolution. 
Editorial change 
Delete repeated word and 
insert Heading 3 
Addition of clinical 
guidelines for when 
investigators should 
consider biopsy of a 
‘suspicious’ lesion 
9.1 Collection 
of Adverse 
Events 
SAEs occurring outside the treatment 
area in the main trial, and considered 
not related to IMP in these trials, will 
not be systematically collected. For an 
overview of which AEs should be 
collected, see table below. 
Clarification of which AEs 
will be collected 


 
 
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Table 2 Overview of AEs to be Collected 
note: the new table is not inserted here but 
can be found in Section 9.1 
9.4.1 
Investigator 
Reporting 
Responsibilities 
 Any SAE must be reported to LEO on 
When reporting SAEs, the (paper) SAE 
Form – Clinical Trials, must be used, and 
submitted to LEO within 24 hours of 
first knowledge 
Clarification 
11.1 Sample 
size 
 The total number of subjects in the trials is 
 around 1200, and assuming 10% drop outs 
 after 14 months, the number of subjects 
 being offered the extension protocol will 
 be around 1080. 
A total of 1200 subjects were planned be 
enrolled in the pivotal phase 3 trials 
(LP0084-1193, -1194, -1195, and - 1196) 
and randomised 2:1 to the two 
treatment groups ingenol disoxate gel or 
vehicle gel. With 800 subjects in the 
ingenol disoxate treatment group and 
400 subjects in the vehicle gel group, an 
adequate precision of the 3-year plus 2 
months incidence rate can be obtained. 
Assuming a 3-year plus 2 months rate of 
4.0%, the upper 95% confidence limit 
will on average be 5.36% for ingenol 
disoxate gel and 5.92% for vehicle gel, 
and assuming a 6.0% rate, the upper 
95% confidence limit will on average be 
7.65% for ingenol disoxate gel and 
8.33% for vehicle gel. 
Rationale added 


 
 
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11.2 Trial 
Analysis Sets 
All enrolled and eligble randomized 
subjects from the pivotal phase 3 trials 
(LP0084-1193, -1194, -1195, -1196) are 
included in the full analysis set (FAS) and 
will be analysed for incidence of SCC and 
other skin neoplasia. 
Change definition of FAS 
Analysis of 
Primary 
Endpoint 
The null hypothesis is that there is no 
difference in time to first SCC between 
ingenol disoxate gel and vehicle gel. The 
hypothesis will be tested against the two- 
sided alternative that there is a 
difference between the two treatment 
groups. 
The annual and the 3-year and 2 months 
cumulative incidence of first event of SCC 
will be calculated for each treatment group 
(active and vehicle) in main trial using 
methods of survival analysis in the 
presence of censoring. 
Specification of the null 
hypothesis for the primary 
endpoint 
Analysis of 
Secondary 
Endpoint 
For the secondary endpoint, the null 
hypothesis is that there is no difference 
in time to first SCC or other skin 
neoplasia between ingenol disoxate gel 
and vehicle gel. The hypothesis will be 
tested against the two-sided alternative 
that there is a difference between the 
two treatment groups. 
Specification of the null 
hypothesis for the secondary 
endpoint 
14 Handling of 
Urgent Safety 
Measure 
LEO must act immediately upon receipt of 
the urgent safety measure notification in 
accordance with the internal procedures 
and national requirements. 
Request from MHRA 


 
 
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23 References 
Reference list revised 
There was a disconnect 
between the footnotes and 
the references listed in 
section 23 
List of 
Appendices 
Appendix 5: Protocol amendment 
history 
 

SAP_001.pdf: 
 
 
 
 
 
Statistical Analysis Plan Update 
 
 
Incidence of squamous cell carcinoma and other skin neoplasia in subjects 
with actinic keratosis treated with ingenol disoxate gel 0.018% or 0.037% 
or vehicle 
 
Phase 3 
 
A multi-centre, randomised, open-label, controlled, parallel group, 24-month trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEO Pharma A/S 
Trial ID: 
LP0084-1369 
Date: 
27-May-2018 
Version: 
1.0 
 
 
 
 
TMF-000038911 - Version 3.0 


 
 
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1 Statistical Analysis Plan Approval 
1.1 Approval Statement 
On behalf of LEO, the Biostatistics Lead and the Medical Lead, are authorised to approve the 
Statistical Analysis Plan. 
 
The QC statistician has by approving this document confirmed that the statistical information 
has been subject to statistical quality control. 
 
The following persons have approved this Statistical Analysis Plan using electronic signatures 
as presented on the last page of this document. 
 
PPD 
 
Biostatistics Lead, Global Clinical Operations 
 
 
 
PPD 
 
Medical Lead, Medical Science and Safety 
 
 
 
PPD 
 
QC Statistician, Biostatistics 


 
 
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2 Statistical Analysis Plan Statements 
2.1 Compliance with Good Clinical Practice 
This Statistical Analysis Plan is designed to comply with the standards issued by the 
International Conference on Harmonisation (ICH) (E3: Structure and Content of Clinical 
Study Reports, E6: Good Clinical Practice, and E9: Statistical Principles for Clinical Trials). 


 
 
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Table of Contents 
1 Statistical Analysis Plan Approval ......................................................................................... 2 
1.1 Approval Statement ........................................................................................................... 2 
2 Statistical Analysis Plan Statements ...................................................................................... 3 
2.1 Compliance with Good Clinical Practice .......................................................................... 3 
Table of Contents ........................................................................................................................ 4 
3 List of Abbreviations ............................................................................................................. 5 
3.1 List of Abbreviations ......................................................................................................... 5 
4 Statistical Analysis Plan Authors ........................................................................................... 5 
5 Introduction ........................................................................................................................... 5 
6 Trial Analysis Sets ................................................................................................................. 6 
6.1 Subjects enrolled in to LP0084-1369 ................................................................................ 6 
6.2 Full Analysis Set ................................................................................................................ 6 
6.3 Safety Analysis Set ............................................................................................................ 7 
6.4 Follow-up Analysis Set...................................................................................................... 7 
7 Statistical Analysis ................................................................................................................. 7 
7.1 Baseline Considerations .................................................................................................... 7 
7.1.1 
Demographics ................................................................................................................ 7 
7.2 Analysis of Efficacy .......................................................................................................... 7 
7.2.1 
Primary Efficacy Criterion ............................................................................................ 8 
7.2.2 
Secondary Efficacy Criteria ........................................................................................... 8 
7.3 Analysis of Safety ............................................................................................................. 9 
7.3.1 
Adverse Events .............................................................................................................. 9 
7.3.2 
Scarring ......................................................................................................................... 9 
7.3.3 
Concomitant medication ................................................................................................ 9 
7.4 General Principles ........................................................................................................... 10 
7.4.1 
Handling of Drop-outs and Missing Values ...................................................................... 10 
7.4.2 
Treatment Labels ......................................................................................................... 10 
Appendix I ................................................................................................................................ 11 


 
 
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3 List of Abbreviations 
3.1 List of Abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AK 
Actinic Keratosis 
CTP 
Clinical Trial Protocol 
FAS 
Full Analysis Set 
FUAS 
Follow-up Analysis Set 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Regulatory Activities 
SAE 
Serious Adverse Event 
SCC 
Squamous Cell Carcinoma 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
 
 
4 Statistical Analysis Plan Authors 
PPD 
, PhD, Statistician, Consultant to Biostatistics, LEO Pharma A/S, DK-2750, 
Ballerup, Denmark, tel: +45 PPD 
, e-mail: PPD 
@leo-pharma.com 
 
PPD 
, MSc Pharm, Senior Clinical Project Manager, Trial Execution, LEO Pharma 
A/S, DK-2750, Ballerup, Denmark, tel: +45 PPD 
, e-mail: PPD 
@leo-pharma.com 
 
PPD 
, MSc, Medical Writer, Consultant to Medical Communication, LEO Pharma A/S, 
DK-2750, Ballerup, Denmark, tel: +45 PPD 
, e-mail: PPD 
@leo-pharma.com 
 
PPD 
, MD, PhD, Associate Research Fellow, Medical Sciences and Safety, LEO 
Pharma A/S, DK-2750, Ballerup, Denmark, tel: +45 PPD 
, e-mail: PPD @leo- 
pharma.com 
 
5 Introduction 
The statistical analysis will be performed as outlined in the Clinical Trial Protocol including 
amendments. This Statistical Analysis Plan contains a more technical and detailed elaboration 
of some points in the statistical analysis described in the Clinical Trial Protocol. Minor 


 
 
Trial ID: LP0084-1369 
Date: 27-May-2018 
Version: 1.0 
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deviations from the planned data presentation and analysis are accounted for. Furthermore, the 
analysis sets, which are to be used for the statistical analysis, are presented. 
 
The original protocol was dated 23-Feb-2017 and a protocol amendment was issued 25-Jul- 
2017. Section 6.3 of the protocol was updated to include how sample size was determined for 
1369. Section 11.1 was updated to include a precision estimate of the 3-year plus 2 month 
event rate of squamous cell carcinoma (SCC) where the 95% upper confidence limits are 
presented. Section 11.2 was updated to change the definition of the full analysis set from all 
enrolled and eligible subjects in 1369 to all randomized subjects from the pivotal phase 3 
trials (LP0084-1193, -1194, -1195, -1196). Sections 11.3.4 and 11.3.5 were updated to include 
text specifying their respective null hypotheses. The remaining changes were either 
administrative or matters that needed further clarification. The change to section 11.2 has an 
impact on the data selection for the primary and secondary analyses, but does not change the 
manner in which the analyses are conducted. LEO Pharma decided to stop the trial 
prematurely and hence less data than expected were collected and analyzed. 
 
6 Trial Analysis Sets 
The analysis sets are determined based on the criteria defined in the Clinical Trial Protocol, 
which was changed from the original protocol dated 23-Feb-2017 to an amended version 
dated 25-Jul-2017. The analysis sets are defined as in the 4 main trials, and therefore a 
classification meeting will not take place for this trial. 
 
6.1 Subjects enrolled in to LP0084-1369 
A total of 562 subjects consented to and were enrolled into the extension trial LP0084-1369. 
 
6.2 Full Analysis Set 
A total of 1243 subjects were randomized in the 4 main trials. A total of 9 subjects withdrew 
consent prior to first application of investigational medicinal product (IMP). IMP was handed 
out to all 9 subjects but they returned the IMP unused. For all 9 subjects the decision to 
withdraw could therefore not have been biased by knowledge of the assigned treatment. The 9 
subjects were excluded from the full analysis set (FAS) in alignment with ICH E9. 
 
The remaining 1234 randomized subjects applied IMP and were included in the FAS. 


 
 
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6.3 Safety Analysis Set 
All 1234 subjects in the FAS applied at least one dose of IMP and had presence or confirmed 
absence of adverse events (AEs) and thereby had post-baseline safety evaluations available. 
All 1234 subjects in the FAS are included in the safety analysis set. 
 
6.4 Follow-up Analysis Set 
The follow-up analysis set (FUAS) was defined as subjects in the FAS who were still in one 
of the main trials at visit 7 (week 8) and/or for whom evaluations after visit 7 (week 8) were 
available. The FUAS consists of 1172 subjects. 
 
A difference between actual and planned treatment was only observed for 1 subject in FAS. 
The planned treatment was vehicle but the subject was treated with Ingenol Disoxate. The 
subject was included in FUAS but did not experience an event of SCC or other skin neoplasia. 
 
7 Statistical Analysis 
7.1 Baseline Considerations 
7.1.1 Demographics 
Demographics will be tabulated for the FAS as well as for subjects enrolled in LP0084-1369. 
Data will be presented by treatment location (face/chest or scalp) and treatment group within 
treatment location as well as overall by treatment group (ingenol disoxate versus vehicle). The 
protocol states that demographics will be presented by treatment group in the main trials and 
by country. However, from the analysis of the main trials it was found that treatment location 
is an important factor and therefore it was decided to present data by treatment group and 
location instead of by country. The demographic data, including age, from the time of 
randomization will be used. The analyses of demographics will be based on the planned 
treatment. 
 
7.2 Analysis of Efficacy 
The primary endpoint is time to first SCC in the treatment area. The event of an SCC is 
defined as AEs coded to the preferred term “Squamous cell carcinoma of skin” (MedDRA v. 
18.1). The secondary time-to-event endpoint is time to first SCC or other skin neoplasia in the 
treatment area. The event of an SCC or other skin neoplasia is defined as AEs coded to 
preferred terms that are included in the standardised MedDRA query (SMQ) “Skin 


 
 
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malignancies” (MedDRA v. 18.1). The analyses of efficacy endpoints will be based on the 
planned treatment. 
 
7.2.1 Primary Efficacy Criterion 
The primary endpoint will be analysed as described in the clinical trial protocol (CTP). 
 
The proportional hazards model will include planned treatment as explanatory variable, and 
have the proportional hazards assumptions checked by assessing whether or not the survival 
functions cross each other. The hazard ratio and corresponding 95% Wald confidence limits 
will be estimated within the proportional hazards model with planned treatment group as 
explanatory variable. A likelihood ratio test within the proportional hazards model will be 
applied for comparison of treatment groups. The results will be presented by treatment 
location (face/chest or scalp) and treatment group within treatment location as well as overall 
by treatment group (ingenol disoxate versus vehicle). The analysis will be based on the FAS. 
 
The cumulative incidence rate will be calculated as the number of subjects with one or more 
events divided by the total observation period across all subjects in the FAS. The lower and 
upper limits of the 95% confidence interval will be calculated using the following SAS code: 
 
Lower=((cinv(0.025,#subjects*2)/2)/total_obs_period) 
Upper = ((cinv(0.975,2*(#subjects+1))/2)/total_obs_period) 
The cumulative incidence rate and corresponding 95% confidence interval will also be 
presented by treatment location (face/chest or scalp) and treatment group within treatment 
location as well as overall by treatment group (ingenol disoxate versus vehicle). 
 
For the landmark analysis described in the CTP time=0 will be defined as the date of visit 7 
(week 8). This analysis will be based on the follow-up analysis set (FUAS) excluding subjects 
who experience an event prior to visit 7. Subjects in FUAS who do not have a visit 7, will 
have the date of their visit 7 imputed as the date of their visit 6 (week 4) plus 28 days. 
 
7.2.2 Secondary Efficacy Criteria 
The secondary endpoint will be analysed as described in the CTP and above for the primary 
endpoint. 


 
 
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7.3 Analysis of Safety 
7.3.1 Adverse Events 
AEs will be analysed as described in the CTP. AE tables will show the number of subjects and 
events. When counting the number of events multiple occurrences of the same preferred term 
within a subject will be counted as multiple events. Due to the premature stop of the trial no 
statistical testing will be performed for AEs. The CTP specified that serious adverse events 
(SAEs) occurring outside the treatment areas and considered not related to IMP in the main 
trials, should not be collected. Sporadically reported SAEs outside treatment area will 
therefore be removed from the ADaM datasets, but will appear in the SDTM datasets and the 
listing. 
 
AEs that were ongoing at the end of the main trials were re-entered in the LP0084-1369 
database for subjects enrolled in LP0084-1369, and these events were marked in the SDTM 
domain SUPPAE as such. A total of 69 AEs were re-entered in the LP0084-1369 database. 
The corresponding AEs in the main trials were identified by merging by subject, reported term 
and start date. In the 4 cases where the AEs in the main trials could not be identified by 
merging a manual review was performed to identify the corresponding AEs in the main trials. 
In cases of duplicate AEs only the AEs recorded in LP0084-1369 were included in the ADaM 
dataset. The analyses of AEs will be based on the actual treatment. 
 
7.3.2 Scarring 
Scarring will be presented in shift tables for the safety analysis set as well as for the set of 
subjects enrolled into trial LP0084-1369. All data on scarring collected in the 4 main trials 
and in trial LP0084-1369 will be included in the shift tables. The analyses of scarring will be 
based on the actual treatment. 
 
7.3.3 Concomitant medication 
Concomitant medication will be tabulated by ATC4 code and WHO dictionary derived term 
for subjects enrolled into trial LP0084-1369. Only concomitant medications registered in trial 
LP0084-1369 will be included. The analyses of concomitant medication will be based on the 
actual treatment. 


 
 
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7.4 General Principles 
7.4.1 Handling of Drop-outs and Missing Values 
Relatively few subjects in the FAS are expected to experience an event of SCC or other skin 
neoplasia, and therefore the amount of censoring in the analyses of the primary and secondary 
endpoints is expected to be substantial. All subjects who completed the 4 main trials without a 
prior event of SCC or other skin neoplasia and choose not to participate in the extension trial 
will be censored at the time they complete the main trial. All discontinued subjects without a 
prior event of SCC or other skin neoplasia will be censored at the time of discontinuation 
from the trial. The survival analyses performed will be evaluated in the presence of censoring. 
 
7.4.2 Treatment Labels 
In general, the results will be presented by treatment location (face/chest or scalp) and 
treatment group within treatment location as well as overall by treatment group (ingenol 
disoxate versus vehicle). The following treatment labels will be used: 0.018%, 0.037%, 
Ingenol disoxate and Vehicle. 


 
 
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Tables 
Appendix I 
 
• Analysis of time to first SCC in the treatment area from Visit 2 in trials LP0084-1193, - 
1194, -1195 and -1196: full analysis set 
• Analysis of time to first SCC or other skin neoplasia in the treatment area from Visit 2 in 
trials LP0084-1193, -1194, -1195 and -1196: full analysis set 
• Analysis of time to first SCC in the treatment area from Visit 7 in trials LP0084-1193, - 
1194, -1195 and -1196: full analysis set 
• Analysis of time to first SCC or other skin neoplasia in the treatment area from Visit 7 in 
trials LP0084-1193, -1194, -1195 and -1196: full analysis set 
 
• Incidence of SCC in the treatment area from Visit 2 in trials LP0084-1193, -1194, -1195 
and -1196: full analysis set 
• Incidence of SCC or other skin neoplasia in the treatment area from Visit 2 in trials 
LP0084-1193, -1194, -1195 and -1196: full analysis set 
• Incidence of SCC in the treatment area from Visit 7 in trials LP0084-1193, -1194, -1195 
and -1196: full analysis set 
• Incidence of SCC or other skin neoplasia in the treatment area from Visit 7 in trials 
LP0084-1193, -1194, -1195 and -1196: full analysis set 
 
• Demographics: full analysis set 
• Demographics: subjects enrolled in LP0084-1369 
 
• Disposition: full analysis set 
• Disposition: subjects enrolled in LP0084-1369 
 
• Concomitant medication in LP0084-1369: subjects enrolled in LP0084-1369 
 
• Scarring, shift table by visit (observed cases): safety analysis set 
• Scarring, shift table by visit (observed cases): subjects enrolled in LP0084-1369 
 
• Adverse events summary for LP0084-1369: subjects enrolled in LP0084-1369 
• Adverse events summary (week 8 - months 14 in main trials and LP0084-1369): follow- 
up analysis set 


 
 
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• Adverse events by SOC and preferred term in LP0084-1369: subjects enrolled in LP0084- 
1369 
• Adverse events by SOC and preferred term (week 8 - months 14 in main trials and 
LP0084-1369): follow-up analysis set 
 
• Frequent adverse events (>= 2% in the active treatment group) by SOC and preferred term 
in LP0084-1369: subjects enrolled in LP0084-1369 
• Frequent adverse events (>= 2% in the active treatment group) by SOC and preferred term 
(week 8 - months 14 in main trials and LP0084-1369): follow-up analysis set 
 
• Adverse events by severity, SOC and preferred term in LP0084-1369: subjects enrolled in 
LP0084-1369 
• Adverse events by severity, SOC and preferred term (week 8 - months 14 in main trials 
and LP0084-1369): follow-up analysis set 
 
• Related adverse events by SOC and preferred term in LP0084-1369: subjects enrolled in 
LP0084-1369 
• Related adverse events by SOC and preferred term (week 8 - months 14 in main trials and 
LP0084-1369): follow-up analysis set 
 
• Related adverse events by severity, SOC and preferred term in LP0084-1369: subjects 
enrolled in LP0084-1369 
• Related adverse events by severity, SOC and preferred term (week 8 - months 14 in main 
trials and LP0084-1369): follow-up analysis set 
 
• Serious adverse events by SOC and preferred term in LP0084-1369: subjects enrolled in 
LP0084-1369 
• Serious adverse events by SOC and preferred term (week 8 - months 14 in main trials and 
LP0084-1369): follow-up analysis set 
• Serious adverse events by causal relationship, SOC and preferred term in LP0084-1369: 
subjects enrolled in LP0084-1369 
• Serious adverse events by causal relationship, SOC and preferred term (week 8 - months 
14 in main trials and LP0084-1369): follow-up analysis set 


 
 
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• SCC or other skin neoplasia inside treatment area by lowest level term in LP0084-1369: 
subjects enrolled in LP0084-1369 
• SCC or other skin neoplasia inside treatment area by lowest level term (week 8 - months 
14 in main trials and LP0084-1369): follow-up analysis set 
 
• SCC or other skin neoplasia (consolidated terms) inside treatment area by preferred term 
in LP0084-1369: subjects enrolled in LP0084-1369 
• SCC or other skin neoplasia (consolidated terms) inside treatment area by preferred term 
(week 8 - months 14 in main trials and LP0084-1369): follow-up analysis set 
 
• Non-serious adverse events by SOC and preferred term in LP0084-1369: subjects enrolled 
in LP0084-1369 
• Non-serious adverse events by SOC and preferred term (week 8 - months 14 in main trials 
and LP0084-1369): follow-up analysis set 
 
• Adverse events leading to withdrawal by SOC and preferred term in LP0084-1369: 
subjects enrolled in LP0084-1369 
• Adverse events leading to withdrawal by SOC and preferred term (week 8 - months 14 in 
main trials and LP0084-1369): follow-up analysis set 
 
 
Figures 
 
• Kaplan-Meier curve for SCC (face/chest): full analysis set 
• Kaplan-Meier curve for SCC (landmark analysis, face/chest): follow-up analysis set 
• Kaplan-Meier curve for SCC (scalp): full analysis set 
• Kaplan-Meier curve for SCC (landmark analysis, scalp): follow-up analysis set 
• Kaplan-Meier curve for SCC: full analysis set 
• Kaplan-Meier curve for SCC (landmark analysis): follow-up analysis set 
• Kaplan-Meier curve for SCC or other skin neoplasia (face/chest): full analysis set 
• Kaplan-Meier curve for SCC or other skin neoplasia (landmark analysis, face/chest): 
follow-up analysis set 
• Kaplan-Meier curve for SCC or other skin neoplasia (scalp): full analysis set 
• Kaplan-Meier curve for SCC or other skin neoplasia (landmark analysis, scalp): full 
analysis set 


 
 
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• Kaplan-Meier curve for SCC or other skin neoplasia: full analysis set 
• Kaplan-Meier curve for SCC or other skin neoplasia (landmark analysis): follow-up 
analysis set 
• Onset of each SCC for face/chest (left panel) and scalp (right panel): follow-up analysis 
set 
• Onset of each SCC or other skin neoplasia for face/chest (left panel) and scalp (right 
panel): follow-up analysis set 
 
 
Listings 
 
• Serious adverse events (week 8 - months 14 in main trials and LP0084-1369): follow-up 
analysis set