Clinical trial NCT02866695
Conditions: Actinic Keratosis
Keywords: Actinic Keratosis lung transplant kidney transplant
Sponsor: University of California, San Francisco
Start date: 2016-10-06; Completion date: 2018-07-02
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm, open-label interventional study of ingenol mebutate 0.015% in solid organ transplant recipients. The investigators plan to treat 20 subjects, 10 kidney transplant recipients and 10 lung transplant recipients. The investigators have selected these two populations as the represent the spectrum of solid organ transplantation: kidney transplant recipients are the largest transplant population, but have lower levels of immunosuppression and skin cancer risk. Lung transplant recipients have the highest burden of skin cancer and actinic keratoses.

Detailed description:
Actinic keratoses (AK) are patches of dysplastic keratinocytes arising in sun-damaged skin. These lesions are precursors to cutaneous squamous cell carcinoma (SCC), and are treated to prevent progression to SCC. First-line therapy for AK include cryotherapy and curettage, which target clinically visible lesions but do not address the subclinical lesions in the field of ultraviolet radiation damage. Field therapy includes topical chemotherapy, immunotherapy, and photodynamic therapy. Ingenol mebutate is the active compound found in Euphorbia peplus sap, and has been approved for treatment of AK in immunocompetent patients. Ingenol mebutate 0.015% is favored over other topical treatments for treatment of AK on the face due to the brief treatment course, high clearance rate, and resolution without sequelae.

Solid organ transplant recipients (OTR) have a high incidence of AK and high risk of developing SCC, and require frequent field therapy. In addition, OTR generally have a higher burden of AK and require treatment of a larger surface area than the 25 cm2 area labeled for ingenol mebutate 0.015%. The investigators plan to investigate the safety and efficacy of ingenol mebutate 0.015% in OTR, with a treatment area up to 100cm2.

This is a single arm, open-label interventional study of ingenol mebutate 0.015% in solid organ transplant recipients. The investigators plan to treat 20 subjects, 10 kidney transplant recipients and 10 lung transplant recipients. The investigators have selected these two populations as the represent the spectrum of solid organ transplantation: kidney transplant recipients are the largest transplant population, but have lower levels of immunosuppression and skin cancer risk. Lung transplant recipients have the highest burden of skin cancer and actinic keratoses.

Arms: arm 1: All patients will be treated with ingenol mebutate gel 0.015%. There is no placebo or comparator for this study. The investigator will identify the patient's treatment area at Baseline, and provide a detailed application instruction sheet. The first dose will be applied in clinic under the supervision of the investigator.
Interventions: intervention 1: ingenol mebutate gel 0.015%
Intervention descriptions: intervention 1: ingenol mebutate gel 0.015% to be applied on treatment area

Protocol documents:
Prot_SAP_000.pdf: 
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Clinical Research Protocol
Safety and efficacy of ingenol mebutate gel 0.015% for treatment of actinic keratosis on 
the face in solid organ transplant recipients.
Protocol Number:
Version 1.0
Version Date:
December 21, 2015
Investigational Product:
Ingenol Mebutate gel 0.015%
IND Number:
Development Phase:
Not applicable.
Sponsor:
Investigator Initiated Protocol 
Funding Organization:
Leo Pharma
1 Sylvan Way
Parsippany, NJ 07054 USA
Principal Investigator:
Name:
Sarah Arron, MD, PhD
Telephone:
415-353-9684
Fax:
415-353-7838
E-mail:
Sarah.Arron@ucsf.edu   
Approval:
PI or Sponsor Signature (Name and Title) 
Date
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.  


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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing Leo Pharma with complete and timely information, as outlined in the protocol.  
It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures 
required to carry out the study in accordance with accepted GCP principles and to abide 
by the terms of this protocol.
Protocol Number:  Version 1.0
Protocol Title:  Safety and efficacy of ingenol mebutate gel 0.015% for treatment of 
actinic keratosis on the face in solid organ transplant recipients.
Protocol Date:  December 21, 2015
Investigator Signature 
Date
Print Name and Title
Site #
Site Name
Address
Phone Number


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TABLE OF CONTENTS
1
BACKGROUND ..................................................................................................................11
2
STUDY RATIONALE.........................................................................................................11
2.1
Risk / Benefit Assessment............................................................................................11
3
STUDY OBJECTIVES........................................................................................................12
3.1
Primary Objective ........................................................................................................12
3.2
Secondary Objectives...................................................................................................12
4
STUDY DESIGN..................................................................................................................12
4.1
Study Overview............................................................................................................12
5
CRITERIA FOR EVALUATION......................................................................................13
5.1
Primary Efficacy Endpoint...........................................................................................13
5.2
Secondary Efficacy Endpoints.....................................................................................13
5.3
Safety Evaluations........................................................................................................14
6
SUBJECT SELECTION .....................................................................................................14
6.1
Study Population..........................................................................................................14
6.2
Inclusion Criteria..........................................................................................................14
6.3
Exclusion Criteria ........................................................................................................14
7
CONCURRENT MEDICATIONS.....................................................................................15
7.1
Allowed........................................................................................................................15
7.2
Prohibited.....................................................................................................................15
8
STUDY TREATMENTS.....................................................................................................16
8.1
Method of Assigning Subjects to Treatment Groups...................................................16
8.2
Blinding........................................................................................................................16
8.3
Test and Control Formulation......................................................................................16
8.4
Supply of Study Medication at the Site .......................................................................17
8.5
Study Medication Accountability ................................................................................18
8.6
Measures of Treatment Compliance ............................................................................18
9
STUDY PROCEDURES AND GUIDELINES..................................................................18
9.1
Clinical Assessments....................................................................................................18
9.2
Clinical Laboratory Measurements..............................................................................19
10 EVALUATIONS BY VISIT................................................................................................20
10.1 Visit 1 (Screening, Day -14 to 1) .................................................................................20
10.2 Visit 2 (Day 1)..............................................................................................................21
10.3 Visit 3 (Day 4)..............................................................................................................21
10.4 Visit 4 (Day 15)............................................................................................................21
10.5 Visit 5 (Day 29)............................................................................................................22
10.6 Visit 6 (Day 57)............................................................................................................22
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................23
11.1 Adverse Events ............................................................................................................23
11.2 Serious Adverse Experiences (SAE)............................................................................24


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12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ...................................25
12.1 Withdrawal of Subjects................................................................................................25
12.3 Replacement of Subjects..............................................................................................25
13 PROTOCOL VIOLATIONS..............................................................................................26
14 DATA SAFETY MONITORING.......................................................................................26
15 STATISTICAL METHODS AND CONSIDERATIONS................................................26
15.1 Data Sets Analyzed ......................................................................................................26
15.2 Demographic and Baseline Characteristics..................................................................26
15.3 Analysis of Primary Endpoint......................................................................................27
15.4 Analysis of Secondary Endpoints ................................................................................27
15.5 Interim Analysis...........................................................................................................27
15.6 Sample Size and Randomization..................................................................................27
16 DATA COLLECTION, RETENTION AND MONITORING........................................28
16.1 Data Collection Instruments.........................................................................................28
16.2 Data Management Procedures .....................................................................................28
16.3 Data Quality Control and Reporting ............................................................................28
16.4 Archival of Data...........................................................................................................28
16.5 Availability and Retention of Investigational Records................................................29
16.6 Subject Confidentiality ................................................................................................29
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS...................29
17.1 Protocol Amendments..................................................................................................29
17.2 Institutional Review Boards and Independent Ethics Committees..............................29
17.3 Informed Consent Form...............................................................................................30
17.4 Publications..................................................................................................................31
17.5 Investigator Responsibilities........................................................................................31
APPENDIX I. SCHEDULE OF EVENTS ...............................................................................32
APPENDIX II. SUBJECT INSTRUCTIONS FOR USE........................................................33
APPENDIX III. LOCAL SKIN RESPONSE...........................................................................37
APPENDIX IV. VAS PAIN ASSESSMENT............................................................................38
APPENDIX V. SKINDEX-16....................................................................................................39


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LIST OF ABBREVIATIONS
AE
adverse event
AK
Actinic keratosis
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CRF
case report form
CRP
C-reactive protein
DMC
Data Monitoring Committee
DSMB
Data Safety Monitoring Board
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intent-to-treat
LOCF
last observation carried forward
LSR
Local skin response
NSAID
nonsteroidal anti-inflammatory drug
OTR
organ transplant recipients
PI
Principal Investigator
PK
pharmacokinetic
SAE
serious adverse experience
SAP
Statistical Analysis Plan
SCC
squamous cell carcinoma
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamate pyruvate transaminase


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PROTOCOL SYNOPSIS
TITLE
Safety and efficacy of ingenol mebutate gel 0.015% for treatment of 
actinic keratosis on the face in solid organ transplant recipients
SPONSOR
Investigator Initiated Protocol 
FUNDING 
ORGANIZATION
Leo Pharma
NUMBER OF SITES
1
RATIONALE
Actinic keratoses (AK) are patches of dysplastic keratinocytes arising 
in sun-damaged skin.  These lesions are precursors to cutaneous 
squamous cell carcinoma (SCC), and are treated to prevent 
progression to SCC. First-line therapy for AK include cryotherapy and 
curettage, which target clinically visible lesions but do not address the 
subclinical lesions in the field of ultraviolet radiation damage.  Field 
therapy includes topical chemotherapy, immunotherapy, and 
photodynamic therapy. Ingenol mebutate is the active compound 
found in Euphorbia peplus sap, and has been approved for treatment 
of actinic keratoses in immunocompetent patients.  Ingenol mebutate 
0.015% is favored over other topical treatments for treatment of 
actinic keratoses on the face due to the brief treatment course, high 
clearance rate, and resolution without sequelae. There are no data on 
safety of this medication in immunosuppressed solid organ transplant 
recipients (OTR).  OTR have a high incidence of AK and high risk of 
developing SCC, and require frequent field therapy. In addition, OTR 
generally have a higher burden of AK and require treatment of a 
larger surface area than the 25 cm2 area labeled for ingenol mebutate 
0.015%. We plan to investigate the safety and efficacy of ingenol 
mebutate 0.015% in OTR, with a treatment area up to 100cm2.
The rationale for an increased dose and surface area for treatment in 
this study is that OTR typically have an extensive burden of AK, 
requiring treatment of larger areas such as those described here.  The 
proposed treatment regimen better reflects the 'real world' need for 
treatment of a larger surface area while evaluating the safety and local 
site reactions associated with this treatment regimen.
STUDY DESIGN
This is a single arm, open-label safety study.
PRIMARY 
OBJECTIVE
To assess the safety of topical ingenol mebutate for treatment of the 
face in solid organ transplant recipients. 


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SECONDARY 
OBJECTIVES
To evaluate the efficacy of ingenol mebutate for reduction of actinic 
keratoses on the face in organ transplant recipients.
To investigate the local skin response to ingenol mebutate in organ 
transplant recipients. 
To investigate the effect of topical treatment with ingenol mebutate on 
patient reported outcomes of pain and quality of life in organ 
transplant recipients.
NUMBER OF 
SUBJECTS
20
SUBJECT 
SELECTION
CRITERIA
Inclusion Criteria:

Adults at least 18 years old.

Subject must be a solid organ transplant recipient at least one year 
from the date of transplantation.

Subjects must be in stable health as confirmed by medical history, 
per investigator judgement.

Subjects must be able to read, sign, and understand the informed 
consent.

Subjects have at least 4 and no more than 20 clinically typical, 
visible actinic keratoses in a treatment area of approximately 
100cm2 on the face.  Treatment areas will include a single cheek 
(nasofacial sulcus to tragus, malar cheekbone to jawline and 
avoiding the lower eyelid and mouth); the forehead (hairline to 
eyebrows, extending laterally to the root of the helix). 

Subject must be willing to forego any other treatments on the face, 
including cryotherapy, tanning bed use and excessive sun 
exposure while in the study.

Subject is willing and able to participate in the study and to 
comply with all study requirements including concomitant 
medication and other treatment restrictions.

If subject is a female of childbearing potential she must have a 
negative urine pregnancy test result prior to study treatment 
initiation and must agree to use an approved method of birth 
control while enrolled in the study.
Exclusion Criteria:

Subjects with an unstable medical condition as deemed by the 
clinical investigator.

Subjects with a history of bone marrow or stem cell 
transplantation.

Subjects with non-melanoma skin cancer in the treatment area.


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
Subjects with any dermatologic disease in the treatment area that 
may be exacerbated by the treatment proposed or that might 
impair the evaluation of AKs.

Women who are pregnant, lactating, or planning to become 
pregnant during the study period.

Subjects who have previously been treated with ingenol mebutate 
in study area within the past 8 weeks.

Subjects who have used any topical prescription medications for 
actinic keratosis on the study area within 8 weeks prior to study 
treatment initiation.

Subjects who have used any topical prescription medications for 
other reason on the study area within 4 weeks prior to study 
treatment initiation. 

Subjects who are currently participating in another clinical study 
or have completed another clinical study with an investigational 
drug or device on the study area within 30 days prior to study 
treatment initiation.

Subjects with known hypersensitivity to Picato gel or any of the 
inactive ingredients: isopropyl alcohol, hydroxyethyl cellulose, 
citric acid monohydrate, sodium citrate, or benzyl alcohol.
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
Ingenol Mebutate, 0.015% topical gel
Subjects will treat a 100 cm2 area of the skin daily for 3 days based on 
the per label dosing for the 0.015% concentration, and assuming a 
deliverable dose weight of 0.25g. Therefore, 4 tubes of the 0.15% 
concentration will be used in the treatment area per day, for 3 
consecutive treatment days, for a total of 12 tubes of the 0.015% 
concentration per patient. This will deliver a dose of 1.5 mcg per cm2 
of treated area each day. Subjects will be instructed to open one tube 
at a time and apply contents to one 25 cm2 skin quadrant, and then 
repeat for each of the remaining three quadrants. The first application 
will be performed in clinic under the guidance of the study 
coordinator.
   
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY
Subjects will be on study for up to 57 days
Screening:  up to 14 days
Treatment:  3 days 
Follow-up:  54 days
The total duration of the study is expected to be 8 months.  6 months 
for subject recruitment and 2 months for final subject follow-up.


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CONCOMMITANT 
MEDICATIONS
Allowed: Bland topical emollients such as Eucerin, Cetaphil. 1% 
topical hydrocortisone cream or ointment allowed after D4 at the 
discretion of the investigator.
Prohibited: Any topical prescription medication on the treatment area 
during the study.
EVALUATIONS
PRIMARY ENDPOINT
The primary outcome will be the safety endpoint of the incidence rate 
of patients who experience:
1) Any adverse event (AE) ascertained by patient report, physician 
evaluation, or laboratory value.  
2) One or more serious adverse events (SAE) as defined by CTCAEv4 
3) Adverse events leading to study drug discontinuation.  
SECONDARY 
ENDPOINTS
Efficacy:
• Reduction in number of actinic keratoses: defined as the percent 
change in actinic keratosis count in the target treatment area on Day 
57, as compared to the baseline lesion count.
• Partial clearance of lesions: defined as the proportion of patients 
with a reduction of 75% of more in the number of clinically visible 
AKs in the target treatment area at Day 57, compared to baseline.
• Complete clearance of lesions: defined as the proportion of patients 
with complete clearance of actinic keratoses in the target treatment 
area.
Local skin response:
• Local skin response (LSR) as measured by visual assessment by the 
investigator using a 4 point scale on six responses for a maximum 
total of 24, according to the LSR scoring scale. 
Patient Reported Outcomes:
• Pain as measured by the 0-10 VAS Numeric Pain Distress Scale (0 = 
no pain, 5 = moderate pain, 10 = unbearable pain).

Patient quality of life as measured by Skindex-16 survey
STATISTICS
Primary Analysis Plan
This is a small descriptive study, with the primary safety endpoint of 
the incidence rate of patients who experience:
1) Any adverse event (AE) ascertained by patient report, physician 
evaluation, or laboratory value, 2) One or more serious adverse events 
(SAE) as defined by CTCAEv4, and 3) Adverse events leading to 
study drug discontinuation.   
The safety analysis will be based on the safety population, which is 
defined as all randomized patients who have received at least one dose 
of study medication and who have had at least one post-baseline 


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safety evaluation.
Adverse events will be explored for trends or heterogeneity between 
the two transplant subgroups; lung and kidney.  If there is evidence 
for a difference between groups, the subgroups will be reported 
separately.
The mean maximum LSR composite score, the VAS score, and the 
Skindex-16 scores and trend in scores over the study visits will be 
reported as descriptive data.  The composite LSR score will be 
compared to historical controls (Lebwohl et al, NEJM 2012).
The efficacy analysis will be based on the intent-to-treat (ITT) 
population. In the ITT population, patients will be counted in the 
treatment group upon informed consent, regardless of receiving any 
dose of study medication. 
For efficacy analysis, all missing values due to patient early 
termination from the study will be imputed using last observation 
carried forward (LOCF) method, as appropriate. For each patient, the 
Baseline values will be defined as those values recorded at Day 1 
prior to dosing or Screening as appropriate. Patients who are lost-to-
follow-up after Baseline will be included to the ITT population 
carrying forward their Baseline values, i.e., these patients will be 
considered as treatment failures. 
Percent reduction in number of actinic keratoses and proportions of 
patients with partial and complete clearance of actinic keratoses will 
be presented descriptively and visualized as histograms.  These scores 
will be compared to historical controls (Lebwohl et al, NEJM 2012).
Rationale for Number 
of Subjects
This is a pilot descriptive sample, not powered for analysis.  The 
sample size of 20 patients is selected to achieve a reportable sample 
size in two subgroups of organ transplant recipients.


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1
BACKGROUND
Ingenol mebutate is the active compound found in Euphorbia peplus sap, and has been 
approved for treatment of actinic keratoses in immunocompetent patients.  Ingenol 
mebutate 0.015% is favored over other topical treatments for treatment of actinic 
keratoses on the face due to the brief treatment course, high clearance rate, and resolution 
without sequelae. There are no data on safety of this medication in immunosuppressed 
solid organ transplant recipients (OTR).  OTR have a high incidence of AK and high risk 
of developing SCC, and require frequent field therapy. 
2
STUDY RATIONALE
Actinic keratoses (AK) are precursors to cutaneous squamous cell carcinoma (SCC), and 
are treated to prevent progression to SCC. First-line therapy for AK include cryotherapy 
and curettage, which target clinically visible lesions but do not address the subclinical 
lesions in the field of ultraviolet radiation damage.  Field therapy includes topical 
chemotherapy, immunotherapy, and photodynamic therapy. Ingenol mebutate is the active 
compound found in Euphorbia peplus sap, and has been approved for treatment of actinic 
keratoses in immunocompetent patients.  Ingenol mebutate 0.015% is favored over other 
topical treatments for treatment of actinic keratoses on the face due to the brief treatment 
course, high clearance rate, and resolution without sequelae. 
There are no data on safety of this medication in immunosuppressed solid organ transplant 
recipients (OTR).  OTR have a high incidence of AK and high risk of developing SCC, 
and require frequent field therapy. In addition, OTR generally have a higher burden of AK 
and require treatment of a larger surface area than the 25 cm2 area labeled for ingenol 
mebutate 0.015%. We plan to investigate the safety and efficacy of ingenol mebutate 
0.015% in OTR, with a treatment area up to 100 cm2.
The rationale for an increased dose and surface area for treatment in this study is that OTR 
typically have an extensive burden of AK, requiring treatment of larger areas such as 
those described here.  The proposed treatment regimen better reflects the 'real world' need 
for treatment of a larger surface area while evaluating the safety and local site reactions 
associated with this treatment regimen.
2.1
Risk / Benefit Assessment
The risks of ingenol mebutate are primarily local site reactions of redness, flaking, 
crusting, swelling, blisters, or erosions. These typically begin at day 1 of treatment. The 
adverse reactions reported in >=2% of patients treated with ingenol mebutate were 
application site pain, pruritus, and infection; periorbital edema, and headache. We will 
monitor the patients at day 4 and counsel them on mitigating site reactions with gentle 
skin care, cold packs, pain control if needed.  Patients will also be counseled to carefully 
avoid the eye and lip area. We expect the infection rate in OTR to be less than the reported 


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rate of 3% as the majority of OTR are on routine antibiotic prophylaxis; any infections 
will be recorded as adverse events and treated according to standard of care. 
If a patient has a  (1) local skin response score of 3 or greater in any individual category, 
and (2) associated symptoms unrelieved by supportive care such as ice packs and 
nonsteroidal anti-inflammatory drug (NSAID), then 1% topical hydrocortisone cream or 
ointment is allowed after Day 4 at the discretion of the investigator.
Ingenol mebutate has accepted benefits for AK which outweigh the risks. OTR have a 
high burden of AK and frequently require multiple rounds of field treatment to reduce this 
sign of ultraviolet radiation induced skin damage. Other treatments require long-term 
applications or in-office light; ingenol has the benefit of being a short course.  Ingenol 
mebutate is approved for immunocompetent patients, but there is no safety data in OTR.  
Despite this, the medication has been frequently used off-label in OTR and is generally 
believed to be safe due to the absence of systemic absorption.  One recent case reported 
brisk local site reaction without systemic adverse events. 
It is difficult to obtain insurance coverage for ingenol mebutate in OTR without 
demonstrating failure of multiple other treatments for AK. Participants in this study will 
also benefit from access to ingenol mebutate. 
3
STUDY OBJECTIVES
3.1
Primary Objective
The primary objective is to assess the safety of topical ingenol mebutate 0.015 % for 
treatment of the face in solid organ transplant recipients.
3.2
Secondary Objectives
The secondary objectives are (1) to evaluate the efficacy of ingenol mebutate for reduction 
of actinic keratoses on the face in organ transplant recipients; (2) to investigate the local 
skin response to ingenol mebutate in organ transplant recipients; (3) to investigate the 
effect of topical treatment with ingenol mebutate on patient reported outcomes of pain and 
quality of life in organ transplant recipients.
4
STUDY DESIGN
4.1
Study Overview
This is a single arm, open-label interventional study of ingenol mebutate 0.015% in solid 
organ transplant recipients. Twenty subjects are planned; 10 kidney transplant recipients 
and 10 lung transplant recipients. These populations have been selected as they represent 
the spectrum of solid organ transplantation: kidney transplant recipients are the largest 
transplant population, but have lower levels of immunosuppression and skin cancer risk. 
Lung transplant recipients have the highest burden of skin cancer and actinic keratoses.  


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Screening data will be reviewed to determine subject eligibility. Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be enrolled into the study.
The following treatment regimens will be used:

Experimental treatment: Ingenol mebutate 0.015%, topical gel

Placebo or Comparator: None
Total duration of subject participation will be 57 days. Total duration of the study is 
expected to be 8 months.
5
CRITERIA FOR EVALUATION
5.1
Primary Efficacy Endpoint
The primary efficacy endpoint will be the safety endpoint of the incidence rate of patients 
who experience (1) any adverse event ascertained by patient report, physician evaluation, 
or laboratory value; (2) one or more serious adverse events as defined by CTCAEv4; (3) 
adverse events leading to study drug discontinuation.  
The primary efficacy endpoint will be assessed from screening to Day 57 or study 
completion.
5.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are efficacy, local skin response, and patient reported 
outcomes. These endpoints will be assessed from screening to Day 57 or study 
completion.
Efficacy:

Reduction in number of actinic keratoses: defined as the percent change in actinic 
keratosis count in the target treatment area on Day 57, as compared to the baseline 
lesion count.

Partial clearance of lesions: defined as the proportion of patients with a reduction of 
75% of more in the number of clinically visible AKs in the target treatment area at 
Day 57, compared to baseline.

Complete clearance of lesions: defined as the proportion of patients with complete 
clearance of actinic keratoses in the target treatment area.
Local skin response:
Local skin response (LSR) as measured by visual assessment by the investigator using 
a 4 point scale on six responses for a maximum total of 24, according to the LSR 
scoring scale. 
Patient Reported Outcomes:


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
Pain as measured by the 0-10 VAS Numeric Pain Distress Scale (0 = no pain, 5 = 
moderate pain, 10 = unbearable pain).

Patient quality of life as measured by Skindex-16 survey
5.3
Safety Evaluations
Evaluations include: adverse event reporting, clinical laboratory sampling, and physician 
evaluation. Adverse event reporting and physician evaluation will occur at every visit, if 
applicable. Clinical laboratory sampling will occur at Screening, Day 4, Day 29, Day 57, 
and early termination (if applicable). Physical Examination will occur at Screening, Day 
1, Day 29, and early termination (if applicable).
6
SUBJECT SELECTION
6.1
Study Population
Subjects with a solid organ transplant at least one year from the date of transplantation, 
with a diagnosis of AK, who meet the inclusion and exclusion criteria, will be eligible for 
participation in this study.  
6.2
Inclusion Criteria
1.
Adults at least 18 years old.
2.
Subject must be a solid organ transplant recipient at least one year from the date of 
transplantation.
3.
Subjects must be in stable health as confirmed by medical history, per investigator 
judgement.
4.
Subjects must be able to read, sign, and understand the informed consent.
5.
Subjects have at least 4 and no more than 20 clinically typical (non-
hyperkeratotic/hypertrophic), visible actinic keratoses in a treatment area of 
approximately 100cm2 on the face.  Treatment areas will include a single cheek 
(nasofacial sulcus to tragus, malar cheekbone to jawline and avoiding the lower 
eyelid and mouth); the forehead (hairline to eyebrows, extending laterally to the root 
of the helix). 
6.
Subject must be willing to forego any other treatments on the face, including 
cryotherapy, tanning bed use and excessive sun exposure while in the study.
7.
Subject is willing and able to participate in the study and to comply with all study 
requirements including concomitant medication and other treatment restrictions.
8.
If subject is a female of childbearing potential she must have a negative urine 
pregnancy test result prior to study treatment initiation and must agree to use an 
approved method of birth control while enrolled in the study.
6.3
Exclusion Criteria
1.
Subjects with an unstable medical condition as deemed by the clinical investigator.


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2.
Subjects with a history of bone marrow or stem cell transplantation.
3.
Subjects with non-melanoma skin cancer in the treatment area.
4.
Subjects with hyperkeratotic or hypertrophic AKs.
5.
Subjects with any dermatologic disease in the treatment area that may be exacerbated 
by the treatment proposed or that might impair the evaluation of AKs.
6.
Women who are pregnant, lactating, or planning to become pregnant during the study 
period.
7.
Subjects who have previously been treated with ingenol mebutate in study area within 
the past 8 weeks.
8.
Subjects who have used any topical prescription medications for actinic keratosis on 
the study area within 8 weeks prior to study treatment initiation.
9.
Subjects who have used any topical prescription medications for other reason on the 
study area within 4 weeks prior to study treatment initiation. 
10. Subjects who are currently participating in another clinical study or have completed 
another clinical study with an investigational drug or device on the study area within 
30 days prior to study treatment initiation.
11. Subjects with known hypersensitivity to Picato gel or any of the inactive ingredients: 
isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, or 
benzyl alcohol.
7
CONCURRENT MEDICATIONS
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies.
7.1
Allowed Medications and Treatments
Standard therapy for OTR is allowed except for treatments noted in the exclusion criteria 
described above and as noted in the prohibited medications section below.  
If a patient has a  (1) local skin response score of 3 or greater in any individual category, 
and (2) associated symptoms unrelieved by supportive care such as ice packs and 
nonsteroidal anti-inflammatory drug (NSAID), then 1% topical hydrocortisone cream or 
ointment is allowed after Day 4 at the discretion of the investigator.
7.2
Prohibited Medications and Treatments
The following medications are prohibited during the study and administration will be 
considered a protocol violation: any topical prescription medication on the treatment area 
during the study. 


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8
STUDY TREATMENTS
8.1
Method of Assigning Subjects to Treatment Groups
All eligible subjects that have enrolled in the study will be supplied with open-label 
ingenol mebutate 0.015% gel. The investigator or study staff will record the kit number 
dispensed to each subject.
8.2
Blinding
Not applicable. This is an open-label study.
8.2.1
Formulation of Test Product
Not applicable.
8.2.2
Formulation of Control Product
Not applicable.
8.2.3
Packaging and Labeling
Ingenol mebutate 0.015% gel is supplied in cartons containing 4 single use tubes.  
Each carton (kit) of ingenol mebutate 0.015% will be labeled with the required FDA 
warning statement, the protocol number, the name of the investigator, patient number, and 
directions for patient use and storage.  Each tube will be labeled with the expiration date.
8.3
Supply of Study Drug at the Site
Leo Pharma will ship ingenol mebutate 0.015% gel to the investigational site.  The initial 
ingenol mebutate 0.015% shipment will be shipped after site activation (i.e., all required 
regulatory documentation has been received by Leo Pharma and a contract has been 
executed). Subsequent ingenol mebutate 0.015% gel shipments will be made after site 
request for resupply.
8.3.1
Dosage/Dosage Regimen
Ingenol mebutate 0.015% gel will be applied topically once a day, for three continuous 
days. Ingenol mebutate 0.015% gel will be applied to the subject’s forehead, left cheek, 
OR right cheek. Each kit contains 4 tubes of ingenol mebutate 0.015% gel, and subjects 
will apply 1 kit per day to the investigator-determined site.
Subjects should not apply ingenol mebutate 0.015% gel immediately after taking a 
shower, or less than 2 hours before bedtime. Subjects MUST AVOID eyes, lips, and 
mouth while applying ingenol mebutate 0.015% gel.
8.3.2
Dispensing
The investigator or other training study staff will dispense ingenol mebutate 0.015% gel to 
subjects. Subjects will also be given application instructions (Appendix III).


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8.3.3
Administration Instructions 
Ingenol mebutate 0.015% gel will be applied topically once a day, for three continuous 
days.  Each kit contains 4 tubes of ingenol mebutate 0.015% gel, and subjects will apply 1 
kit per day. Subjects should not apply ingenol mebutate 0.015% gel immediately after 
taking a shower, or less than 2 hours before bedtime. Subjects should use a new tube for 
each application. 
Ingenol mebutate 0.015% gel will be applied to the subject’s forehead, left cheek, OR 
right cheek. Subjects should visualize each application site (forehead, left cheek, or right 
cheek) as divided into 4 quadrants. Each kit contains 4 tubes; 1 tube is to be applied to 
each quadrant. The investigator will specify the application site and instructions during 
Screening. 
A detailed subject hand-out containing the following application instructions will also be 
provided at Baseline:
1. Open a new tube of ingenol mebutate 0.015% gel.
2. Squeeze gel from the tube onto a fingertip.
3. Apply gel onto the center of Quadrant 1, spreading the gel evenly over the entire 
skin quadrant.
4. Check off Quadrant 1 on instruction sheet after gel is applied. 
5. Open a 2nd tube of ingenol mebutate 0.015% gel.
6. Squeeze gel from the tube onto a fingertip.
7. Apply gel onto the center of Quadrant 2, spreading the gel evenly over the entire 
skin quadrant.
8. Check off Quadrant 2 on instruction sheet after gel is applied. 
9. Open a 3rd tube of ingenol mebutate 0.015% gel.
10. Squeeze gel from the tube onto a fingertip.
11. Apply gel onto the center of Quadrant 3, spreading the gel evenly over the entire 
skin quadrant.
12. Check off Quadrant 3 on instruction sheet after gel is applied. 
13. Open a 4th tube of ingenol mebutate 0.015% gel.
14. Squeeze gel from the tube onto a fingertip.
15. Apply gel onto the center of Quadrant 4, spreading the gel evenly over the entire 
skin quadrant.
16. Check off Quadrant 4 on instruction sheet after gel is applied. 
17. Allow the treated area to dry for 15 minutes. 
18. Wash hands right away after applying ingenol mebutate 0.015% gel.
19. After use, place tubes into the bag provided, and return to study site at the next 
visit. 


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Subjects are not responsible for medication re-supply, as they will be provided with 
enough tubes at Baseline. Subjects MUST AVOID eyes, lips, and mouth while applying 
ingenol mebutate 0.015% gel.
8.4
Supply of Study Drug at the Site
Kits of ingenol mebutate 0.015% gel will be supplied to each subject at Baseline/Day 1. 
All subjects will be receiving the ingenol mebutate 0.015% gel, as there is no placebo 
control in this protocol.
8.4.1
Storage
Ingenol mebutate 0.015% gel should be stored by the study site in a refrigerator, 2 to 8ºC (36 
to 46ºF). If the temperature of ingenol mebutate 0.015% gel storage in the clinic exceeds or 
falls below this range, this should be reported to Leo Pharma and captured as a deviation. 
Subjects will be instructed to store ingenol mebutate 0.015% gel in original packaging, in a 
refrigerator according to the instructions outlined on the Drug Administration Instructions.
Ingenol mebutate 0.015% gel tubes must be kept away from children at all times.
8.5
Study Drug Accountability
An accurate and current accounting of the dispensing and return of ingenol mebutate 
0.015% gel tubes for each subject will be maintained on an ongoing basis by a member of 
the study site staff.  The number of ingenol mebutate 0.015% gel tubes dispensed and 
returned by the subject will be recorded on the Investigational Drug Accountability 
Record.  
8.6
Measures of Treatment Compliance
Subjects will be asked to keep a patient diary (on the Subject Instructions for Use sheet) 
noting their application of ingenol mebutate 0.015% gel. Subjects will be asked to bring 
their patient diary to Visit 4, to assess compliance.
9
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities.
9.1
Clinical Assessments
9.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at Screening and 
at Study Day 1, 4, 15, 29, 57, and at early termination (if applicable).  Dose, route, unit 
frequency of administration, and indication for administration and dates of medication 
will be captured.


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9.1.2
Demographics 
Demographic information (date of birth, gender, race) will be recorded at Screening.
9.1.3
Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening.
9.1.4
Physical Examination
A complete physical examination will be performed by either the investigator or a 
subinvestigator who is a physician at Screening and at Day 1, 29, and early termination (if 
applicable). New abnormal physical exam findings must be documented and will be 
followed by a physician or other qualified staff at the next scheduled visit.
9.1.5
Actinic Keratoses (AK) count
An AK count will be performed to count the lesions in the treatment area. AK count will 
be performed at Screening, Day 1, Day 29, Day 57, and early termination (if applicable).
9.1.6
Local Skin Response (LSR)
LSR is measured by visual assessment by the investigator using a 4 point scale on 6 
responses for a maximum total of 24. The points are assessed using the LSR scale 
(Appendix III) : The 6 responses are: Erythema, Flaking/Scaling, 
Pustulation/Vesiculation, Crusting, Swelling, and Erosion/Ulceration. The mean 
maximum LSR composite score and trend in score over the study visits will be reported as 
descriptive data and compared to historical controls. LSR assessment will performed at 
every visit.
9.1.7
Visual Analog Scale (VAS) Pain Assessment 
Patients will be asked to rate their pain on a VAS numeric pain distress scale where 0 = no 
pain, 5 = moderate pain, 10 = unbearable pain. The (VAS) Numeric Pain Distress scale 
will be administered on Day 1, Day 4, Day 15, Day 29, Day 57, and early termination (if 
applicable).
9.1.8
Skindex-16
Skindex-16 is used to measure quality of life in patients with skin diseases. The Skindex-
16 will be administered on Day 1, Day 4, Day 15, Day 29, Day 57, and early termination 
(if applicable).
9.1.9
Photography
The investigator or trained study stuff will photograph the subject’s treatment area on Day 
1, Day 4, Day 15, Day 29, Day 57, and early termination (if applicable). Prior to 
photographing the treatment area, study staff will (1) photograph a subject identification 
card including: subject’s initials, subject number, visit day and date; and (2) place a light-
balanced sticker in the treatment area.


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9.1.10 Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF).
9.2
Clinical Laboratory Measurements 
Clinical laboratory measurements will be performed at Screening, Day 4, Day 29, and 
early termination (if applicable). If a subject’s medical record contains hematology and 
blood chemistry profile results within 14 days of Screening, the existing values may be 
used and Screening laboratory measurements are not required. If a subject’s medical 
record contains hematology and blood chemistry profile results within 5 days of Day 29, 
the existing values may be used and additional laboratory measurements are not required.    
9.2.1
Hematology
Blood will be obtained and sent to each site’s clinical hematology lab for a complete 
blood count (hemoglobin, hematocrit, red blood cell count, white blood cell count, white 
blood cell differential, and platelet count).
9.2.2
Blood Chemistry Profile
Blood will be obtained and sent to the site’s clinical chemistry lab for determination of 
serum sodium, potassium, chloride, bicarbonate, random glucose, BUN, creatinine, 
aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT).
9.2.3
Pregnancy Test
A urine pregnancy test will be obtained from female subjects who are of childbearing age 
prior to their participation in the study, and at Day 1.
9.2.4
Urinalysis
Not applicable.
10 EVALUATIONS BY VISIT
The following is a list of evaluations scheduled to occur at each visit. Screening and Visit 
2 visits can occur on the same day. 
10.1 Visit 1 (Screening, Day -14 to 1)
1.
Review the study with the subject and obtain written informed consent and HIPAA 
authorization.
2.
Assign the subject a unique screening number.
3.
Record demographics data.
4.
Record medical history, including a history of actinic keratosis, diagnosis date, and 
prior actinic keratosis treatments.
5.
Record concomitant medications.
6.
Perform a complete physical examination.


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7.
Perform an actinic keratosis count.
8.
Collect blood for clinical laboratory tests (chemistry and hematology).
9.
Collect urine sample and perform urine pregnancy test (if applicable).
10.
Continue to Visit 2 procedures (can occur on the same day), or schedule subject for 
Visit 2/ Day 1.
10.2 Visit 2 (Day 1)
1.
Record any Adverse Events.
2.
Concomitant medications review.
3.
Perform a complete physical examination.
4.
Perform an actinic keratosis count.
5.
Perform a local skin response assessment.
6.
Subject to perform a VAS pain assessment.
7.
Subject to complete the Skindex-16.
8.
Perform photography in treatment area.
9.
Collect urine sample and perform urine pregnancy test (if applicable).
10.
Dispense a kit of ingenol mebutate 0.015% gel; subject will complete the first 
application under the investigator’s supervision in the clinic.
11.
Dispense subject 2 additional kits for use on Day 2 and Day 3. Subject will also be 
provided with a detailed application instructions hand-out.
12.
Schedule subject for Visit 3/ Day 4.
10.3 Visit 3 (Day 4)
1.
Record any Adverse Events. 
2.
Record changes to concomitant medications.
3.
Review subject diary for compliance. 
4.
Perform a local skin response assessment.
5.
Subject to perform a VAS pain assessment.
6.
Subject to complete the Skindex-16.
7.
Perform photography in treatment area.
8.
Collect blood for clinical laboratory tests (chemistry and hematology).
9.
Schedule subject for Visit 4/ Day 15.
10.4 Visit 4 (Day 15)
1.
Record any Adverse Events.
2.
Record changes to concomitant medications.


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3.
Perform a local skin response assessment.
4.
Subject to perform a VAS pain assessment.
5.
Subject to complete the Skindex-16.
6.
Perform photography in treatment area.
7.
Schedule subject for Visit 5/ Day 29.
10.5 Visit 5 (Day 29)
1.
Record any Adverse Events. 
2.
Record changes to concomitant medications.
3.
Perform complete physical examination.
4.
Perform an actinic keratosis count.
5.
Perform a local skin response assessment.
6.
Subject to perform a VAS pain assessment.
7.
Subject to complete the Skindex-16.
8.
Perform photography in treatment area.
9.
Collect blood for clinical laboratory tests (chemistry and hematology).
10.
Schedule subject for Visit 6/ Day 57.
10.6 Visit 6 (Day 57)
1.
Record any Adverse Events. 
2.
Record changes to concomitant medications.
3.
Perform an actinic keratosis count.
4.
Perform a local skin response assessment.
5.
Subject to perform a VAS pain assessment.
6.
Subject to complete the Skindex-16.
7.
Perform photography in treatment area.
10.7 Early Termination Visit (if required)
1.     Record any Adverse Events. 
2.     Record changes to concomitant medications.
3.     Perform complete physical examination.
4.
Perform an actinic keratosis count.
5.
Perform a local skin response assessment.
6.
Subject to perform a VAS pain assessment.


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7.
Subject to complete the Skindex-16.
8.
Perform photography in treatment area.
9.
Collect blood for clinical laboratory tests (chemistry and hematology).
10.    Collect urine sample and perform urine pregnancy test (if applicable).
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
11.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current U.S. package insert or of greater severity or frequency 
than expected based on the information in the U.S. package insert.
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause.
AE Severity
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious.
Table 1.  AE Severity Grading
Severity (Toxicity Grade)
Description
Mild (1)
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well.
Moderate (2)
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required.
Severe (3)
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible.
Life-threatening (4)
The subject is at risk of death due to the adverse experience as it 


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occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe.
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2.
Table 2.  AE Relationship to Study Drug
Relationship
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis.
Probably
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions.
Possibly
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no relationship to the study 
drug.
11.2 Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:

death

a life-threatening adverse experience

inpatient hospitalization or prolongation of existing hospitalization

a persistent or significant disability/incapacity

a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed. 
11.2.1 Serious Adverse Experience Reporting
The study site will document all SAEs that occur (whether or not related to study drug) 
per UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed.


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In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.  
  
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS
12.1 Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, or the 
investigator feels that it is not in the subject’s best interest to continue.  The following is a 
list of possible reasons for study treatment discontinuation:
Subject withdrawal of consent 
Subject is not compliant with study procedures
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment
Protocol violation requiring discontinuation of study treatment
Lost to follow-up
Positive pregnancy test (females)
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.  
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures.
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents Refer to Section 10 for early termination procedures.
12.3
Withdrawal of Subjects from the Study
A subject may be withdrawn from the study at any time if the subject or the investigator 
feels that it is not in the subject’s best interest to continue.  
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to Visit 6) should have an early discontinuation 
visit. Refer to Section 10 for early termination procedures.  Subjects who withdraw after 


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Visit 2 but prior to Visit 6 should be encouraged to come in for a final visit (and the 
procedures to be followed would include those for their next scheduled visit).  
12.4
Replacement of Subjects
Subjects who withdraw from the study treatment will not be replaced.  
Subjects who withdraw from the study will not be replaced.  
13 PROTOCOL VIOLATIONS
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following:
Failure to meet inclusion/exclusion criteria
Failure to apply ingenol mebutate 0.015% gel per protocol.
Use of a prohibited concomitant medication
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by the 
Investigator. A copy of the form will be filed in the site’s regulatory binder.
14 DATA SAFETY MONITORING
Due to the scope of this study, there will be no formal Data Safety Monitoring Board 
(DSMB) or Data Monitoring Committee (DMC). This is an open-label, single-center 
study for an FDA-approved medication, and the investigator will have access to all study 
data. 
15 STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.  
15.1 Data Sets Analyzed
All eligible patients who are enrolled in the study and receive at least one dose of the 
study drug (the Safety Population) and who have had at least one post-baseline safety 
evaluation will be included in the safety analysis.
15.2 Demographic and Baseline Characteristics
The following demographic variables at screening will be summarized: race, gender, age, 
height and weight.  


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15.3 Analysis of Primary Endpoint
This is a small descriptive study, with the primary safety endpoint of the incidence rate of 
patients who experience:
1) Any adverse event (AE) ascertained by patient report, physician evaluation, or 
laboratory value, 2) One or more serious adverse events (SAE) as defined by CTCAEv4, 
and 3) Adverse events leading to study drug discontinuation.   
Adverse events will be explored for trends or heterogeneity between the two transplant 
subgroups; thoracic and abdominal.  If there is evidence for a difference between groups, 
the subgroups will be reported separately.
15.4 Analysis of Secondary Endpoints
Safety and tolerability data will be summarized by each secondary endpoint.  
The mean maximum LSR composite score, the VAS score, and the Skindex-16 scores and 
trend in scores over the study visits will be reported as descriptive data.  The composite 
LSR score will be compared to historical controls (Lebwohl et al, NEJM 2012).
The efficacy analysis will be based on the intent-to-treat (ITT) population. In the ITT 
population, patients will be counted in the treatment group upon informed consent, and 
receipt of at least one dose of study medication. 
For efficacy analysis, all missing values due to patient early termination from the study 
will be imputed using last observation carried forward (LOCF) method, as appropriate. 
For each patient, the Baseline values will be defined as those values recorded at Day 1 
prior to dosing or Screening as appropriate. Patients who are lost-to-follow-up after 
Baseline will be included to the ITT population carrying forward their Baseline values, 
i.e., these patients will be considered as treatment failures. 
Percent reduction in number of actinic keratoses and proportions of patients with partial 
and complete clearance of actinic keratoses will be presented descriptively and visualized 
as histograms.  These scores will be compared to historical controls (Lebwohl et al, NEJM 
2012).
15.5 Interim Analysis
Not applicable.
15.6 Sample Size and Randomization
This is a pilot descriptive sample, not powered for analysis.  The sample size of 20 
patients is selected to achieve a reportable sample size in two subgroups of organ 
transplant recipients.


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16 DATA COLLECTION, RETENTION AND MONITORING
16.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.  
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific paper Case Report Form (CRF) when the 
information corresponding to that visit is available.  Subjects will not be identified by 
name in the study database or on any study documents to be collected, but will be 
identified by a site number, subject number and initials.
If a correction is made on a CRF, the study staff member will line through the incorrect 
data, write in the correct data and initial and date the change.
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study.
16.2 Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials.
16.3 Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. 
Query reports (Data Clarification Requests) pertaining to data omissions and 
discrepancies will be forwarded to the Investigators and study monitors for resolution.  
The study database will be updated in accordance with the resolved queries.  All changes 
to the study database will be documented.
16.4 Archival of Data
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.  
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures.


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16.5 Availability and Retention of Investigational Records
The Investigator must make study data accessible to authorized representatives of Leo 
Pharma , IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request.  A file 
for each subject must be maintained that includes the signed Informed Consent, HIPAA 
Authorization and Assent Form and copies of all source documentation related to that 
subject.  The Investigator must ensure the reliability and availability of source documents 
from which the information on the CRF was derived.
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.  There may be other circumstances for which Leo Pharma is 
required to maintain study records and, therefore, should be contacted prior to removing 
study records for any reason.
16.6 Subject Confidentiality
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation.  
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement.
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC).
17.1 Protocol Amendments
Any amendment to the protocol will be written by the investigator..  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days.
17.2 Institutional Review Boards and Independent Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 


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procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, U.S. package insert, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the study 
protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to Leo Pharma prior to the shipment of study supplies to 
the site.  This approval must refer to the study by exact protocol title and number and 
should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.  
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed.
17.3 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations.
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to Leo Pharma for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to Leo 
Pharma and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to Leo Pharma for the study file.
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form will be given to the subject or legal representative of 
the subject and the original will be maintained with the subject’s records.


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17.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
investigator, Leo Pharma, and participating institution.  The publication or presentation of 
any study results shall comply with all applicable privacy laws, including, but not limited 
to, the Health Insurance Portability and Accountability Act of 1996. 
17.5
Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol, except when to protect the safety, 
rights or welfare of subjects.
2.
Personally conduct or supervise the study (or investigation).
3.
Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.
5.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with Leo Pharma.
6.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.
7.
Promptly report to the IRB and Leo Pharma all changes in the research activity and 
all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports).
8.
Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.
9.
Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.


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APPENDIX 1. SCHEDULE OF STUDY VISITS
Study Visit 
Activities
Screening 
(-14 to 1)
Day 1
Day 4
Day 15
Day 29
Day 57
Early 
Termination
Assess study 
eligibility
X
Informed Consent/ 
HIPAA
X
Medical History/ 
Demographics/ 
Previous therapies 
and Procedures
X
Physical exam
X
X
X
X
CBC Auto Differential
X
X
X
X
CMP (Chem20)
X
X
X
X
AK Count
X
X
X
X
X
Local skin response 
Assessment
X
X
X
X
X
X
VAS Pain 
Assessment
X
X
X
X
X
X
Skindex-16
X
X
X
X
X
X
Photography
X
X
X
X
X
X
Con 
meds/procedures
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
Ingenol mebutate 
dispensing
X
Ingenol mebutate 
accountability
X
X
Urine pregnancy
X
X
X


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APPENDIX II. SUBJECT INSTRUCTIONS FOR USE
Instructions for Use
Ingenol Mebutate gel, 0.015%
Be sure that you read, understand, and follow these Instructions for Use before you use 
ingenol mebutate gel, 0.015% for the first time.
Treatment Diary
Day 1:  Did you apply all 4 tubes to the treatment area?
            
 Quadrant 1    
 Quadrant 2   
 Quadrant 3   
 Quadrant 4   
            
 No, please specify reason: _________________________________________
Day 2: Did you apply all 4 tubes to the treatment area?
           
 Quadrant 1    
 Quadrant 2   
 Quadrant 3   
 Quadrant 4   
           
 No, please specify reason: _________________________________________
Day 3: Did you apply all 4 tubes to the treatment area?
           
 Quadrant 1    
 Quadrant 2   
 Quadrant 3   
 Quadrant 4   
           
 No, please specify reason: _________________________________________
IMPORTANT:

Always use ingenol mebutate gel exactly as your study doctor tells you. Check with your 
study doctor if you are not sure.

Only use ingenol mebutate gel to treat actinic keratosis on your assigned study treatment 
area.

Assigned study treatment area: ________________________________________

Apply ingenol mebutate gel to the skin area to be treated 1 time each day for 3 days in a 
row. Day 1 will be applied at your study visit, days 2 and 3 will be applied at home.

Wash your hands well with soap and water after applying it. After applying ingenol 
mebutate gel, be careful to keep ingenol mebutate gel on treated area from coming into 


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contact with your eyes. Irritation may happen if you get ingenol mebutate gel in your 
eyes.

Use a new kit (4 tubes) for each day of treatment. Avoid touching the treatment area or 
doing activities that cause a lot of sweating for 6 hours after applying ingenol mebutate 
gel. After 6 hours you may wash the treatment area with a mild soap and water.
DO NOT:

apply right after taking a shower or less than 2 hours before bedtime.

get ingenol mebutate gel in, around, or near your eyes. Do not touch your eyes while 
you are applying ingenol mebutate gel (if you accidentally get ingenol mebutate gel in 
your eyes, flush them with large amounts of water and get medical care as soon as 
possible). 

get ingenol mebutate gel in, around, or near your lips and mouth.
Applying Ingenol Mebutate gel
Step 1. Open a new kit (containing 4 tubes) each time you use ingenol mebutate gel. 
Step 2. Select the first tube. Remove cap from tube just before use. (See Figure A).
Figure A
Step 3. Squeeze the gel from the tube onto a fingertip. (See Figure B). 
Figure B
Step 4. Visually divide your (treatment area – cheek or forehead) into 4 quadrants. (See 
Figure C).


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Figure C
Step 5. Apply gel onto the center of Quadrant 1, spreading the gel evenly over the entire 
skin quadrant. 
Step 6: Select the second tube. 
Step 7: Remove cap from the tube, and squeeze the gel from the tube onto a fingertip.
Step 8: Apply gel onto the center of Quadrant 2, spreading the gel evenly over the entire 
skin quadrant.
Step 9: Select the third tube.
Step 10: Remove cap from the tube, and squeeze the gel from the tube onto a fingertip.
Step 11: Apply gel onto the center of Quadrant 3, spreading the gel evenly over the entire 
skin quadrant.
Step 12: Select the fourth tube.
Step 13: Remove cap from the tube, and squeeze the gel from the tube onto a fingertip.
Step 14: Apply gel onto the center of Quadrant 4, spreading the gel evenly over the entire 
skin quadrant.
Step 15: DO NOT get in, around or near your eyes, lips, and mouth. Allow the gel to dry 
for 15 minutes.
Step 16: Wash your hands right away after applying the gel. (See Figure D). 
Figure D
Step 17: After use, place tubes into the bag provided, and return to study site at your next 
visit.
Repeat the above steps for each day of treatment.


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How should I store the Ingenol Mebutate gel?

Store the gel in a refrigerator at 36oF to 46oF (2oC to 8oC). Do not freeze.

The gel has an expiration date (exp) marked on the end of the tube. Do not use the gel 
after this date.

After use, place tubes into the bag provided, and return to study site at your next visit.


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APPENDIX III. LOCAL SKIN RESPONSE ASSESSMENT
Grade
0
1
2
3
4
Erythema
Not 
present
Slightly 
pink 
<50%
Pink or 
light red 
>50%
Red, 
restricted to 
treatment 
area
Red 
extending 
outside 
treatment 
area
Flaking/Scaling
Not 
present
Isolated 
scale, 
specific to 
lesions
Scale <50%
Scale >50%
Scaling 
extending 
outside 
treatment 
area
Crusting
Not 
present
Isolated 
crusting, 
specific to 
lesions
Crusting 
<50%
Crusting 
>50%
Crusting 
extending 
outside 
treatment 
area
Swelling
Not 
present
Slight, 
lesion 
specific 
edema
Palpable 
edema 
extending 
beyond 
individual 
lesions
Confluent 
and/or 
visible 
edema
Marked 
swelling 
extending 
outside 
treatment 
area
Vesiculation/Pustulation
Not 
present
Vesicles 
only
Transudate 
or pustules, 
with or 
without 
vesicles, 
<50%
Transudate 
or pustules, 
with or 
without 
vesicles, 
>50%
Transudate 
or pustules, 
with or 
without 
vesicles, 
extending 
outside 
treatment 
area
Erosion/Ulceration
Not 
present
Lesion 
specific 
erosion
Erosion 
extending 
beyond 
individual 
lesions
Erosion 
>50%
Black 
eschar or 
ulceration


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APPENDIX IV. VAS PAIN ASSESSMENT
How would you rate your pain over the last 24 HOURS?


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APPENDIX V. SKINDEX-16
Have you answered every item?  Yes    No 
   During the past week, how often 
   have you been bothered by:
 
  Never                                            Always
  Bothered                                    Bothered
                                                       
  ______________________________ 
 
    1.
Your skin condition itching      .    .    .    .    .    .    .    .     .
  0     1     2      3     4      5     6
    2.
Your skin condition burning or stinging     .    .     .    .    .
  0     1     2      3     4      5     6
    3.
Your skin condition hurting    .     .    .    .    .    .     .    .    .
  0     1     2      3     4      5     6
    4.
Your skin condition being irritated    .    .    .    .     .    .    .
  0     1     2      3     4      5     6
    5.
The persistence / reoccurrence of your skin condition   .    0     1     2      3     4      5     6
    6.
Worry about your skin condition   (For example: that it 
will spread, get worse, scar, be unpredictable, etc)    .    .    
.    .    .
 
  0     1     2      3     4      5     6
    7.
The appearance of your skin condition   .    .    .    .    .    .
  0     1     2      3     4      5     6
    8.
Frustration about your skin condition      .    .    .    .    .    .
  0     1     2      3     4      5     6
    9.
Embarrassment about your skin condition   .    .    .    .    .
  0     1     2      3     4      5     6
  10.
Being annoyed about your skin condition    .    .    .    .    .
  0     1     2      3     4      5     6
  11.
Feeling depressed about your skin condition   .    .    .    .
  0     1     2      3     4      5     6
  12.
The effects of your skin condition on your interactions 
with others   (For example: interactions with family, 
friends, close relationships, etc)     .    .    .     .    .    .    .    
.    .    .    .
 
  0     1     2      3     4      5     6
  13.
The effects of your skin condition on your desire
 to be with people   .    .    .    .    .    .     .    .    .    .    .    .
 
  0     1     2      3     4      5     6
  14.
Your skin condition making it hard to show affection .    .
  0     1     2      3     4      5     6
  15.
The effects of your skin condition on your daily 
activities.
  0     1     2      3     4      5     6
  16.
Your skin condition making it hard to work or do what 
you enjoy   .    .    .    .    .    .    .    .    .    .    .    .    .    .    .
 
  0     1     2      3     4      5     6