To Compare Safety and Efficacy of Perrigo's Drug Compared to an FDA Approved Drug in the Treatment of Actinic Keratosis
Phase: PHASE3
Conditions: Actinic Keratosis
Sponsor: Padagis LLC

 
 
NCT02459795 
 
03-23-2015 

 
 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-Group 
Study to Compare Perrigo New York, Inc.’s  Ingenol Mebutate Topical Gel 0.05% 
to Leo Pharma Inc. Picato® Topical Gel 0.05% (Ingenol Mebutate Topical Gel 
0.05%), and Both Active Treatments to a Vehicle Control in the Treatment of 
Actinic Keratosis on the Trunk and Extremities  
 
 
 
Protocol No.: PRG-NY-15-002 
 
 
 
 
 
 
 
 
Confidential 
 
The confidential information provided in this document is for use by parties directly involved 
in this investigation.  By accepting this document, you agree that the information contained 
herein will not be disclosed to any person not directly involved in this investigation without 
written authorization from Perrigo New York, Inc.  
 
 
 
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Protocol No: PRG-NY-15-002 
 
 
  
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
2     STUDY OBJECTIVES ..............................................................................................................9 
2.1           Endpoints ................................................................................................................... 9 
2.2 
Safety ......................................................................................................................... 9 
3     STUDY DESIGN .................................................................................................................. 10 
3.1           Type/Design of Study ............................................................................................... 10 
3.2           Study Population ...................................................................................................... 11 
4.    SELECTION AND WITHDRAWAL OF STUDY SUBJECTS .......................................................... 11 
          4.1           INCLUSION CRITERIA ......................................................................................... 11 
4.2           Exclusion Criteria...................................................................................................... 13 
4.3            Medications, Supplements, Other Substances and Procedures Prohibited Before    
                 Enrollment and During the Study ............................................................................ 15 
4.4           Precautions .............................................................................................................. 18 
5.     PROCEDURES ................................................................................................................... 19 
         5.1 SUBJECT SCREENING AND ENROLLMENT .................................................................. 19 
5.2           Assignment of Subject Number ............................................................................... 19 
5.3 
Demographics/Medical History ............................................................................... 19 
5.4 
Concomitant Medications ........................................................................................ 19 
5.5 
Physical Examination ............................................................................................... 19 
5.6 
Urine Pregnancy Test ............................................................................................... 19 
5.7 
Dermatological Assessment (Diagnosis) .................................................................. 20 
5.8 
Fitzpatrick Classification Scale ................................................................................. 20 
5.9 
Clinical Actinic Keratosis Lesion Counting & Assessment ........................................ 20 
5.10 
Application Site Reaction Assessment ..................................................................... 22 
5.11 
Study Medication Use, Patient Instructions and Diary ............................................ 23 
5.12 
Visit Specific Procedures .......................................................................................... 24 
 
5.12.1      Visit 1/Day 1 (Baseline) ............................................................................ 24 
 
5.12.2      Visit 2/Day 3(+1 day) ................................................................................ 25 
 
5.12.3      Follow-up Phone Call /Day 15 (± 3 days) .................................................. 25 
 
5.12.4      Visit 3/Day 29 (± 3 days) ........................................................................... 25 
 
5.12.5      Visit 4/Day 57 (± 2days) End of Study /Early Termination Visit ............... 25 
 
5.12.6       Unscheduled ............................................................................................ 25 
5.13 
Summary of Assessments ........................................................................................ 26 
5.14 
Screen Failures ......................................................................................................... 27 
5.15 
Protocol Deviations/Violations ................................................................................ 27 
5.16 
Subject/Treatment Compliance ............................................................................... 28 
5.17 
Discontinuation/Withdrawal of Study Subjects ...................................................... 28 
6.      MATERIALS AND SUPPLIES ............................................................................................... 29 
6.1 
Study Medication ..................................................................................................... 29 
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6.2 
Medication Management ........................................................................................ 29 
6.2.1 
Labeling, Packaging and Distribution ....................................................................... 29 
6.2.2 
Retention Samples ................................................................................................... 30 
6.2.3 
Storage and Test Article Accountability ................................................................... 30 
6.2.4 
Randomization ......................................................................................................... 31 
6.2.5 
Procedure for Breaking the Blind............................................................................. 31 
7.      ADVERSE REACTIONS....................................................................................................... 31 
7.1 
Departure from the Protocol for Individual Subjects .............................................. 31 
7.2 
Definitions ................................................................................................................ 32 
7.3 
Eliciting and Reporting of Adverse Events ............................................................... 33 
 
7.3.1      Expedited Reporting Responsibilities of the Study Center ........................ 34 
 
7.3.2      Submitting an Expedited Safety Report to the IRB .................................... 34 
7.4 
SAE & AEs Requiring Discontinuation of Study Drug, including Pregnancies .......... 35 
 
7.4.1      Pregnancy ................................................................................................... 36 
7.5 
Post Study Adverse Events ....................................................................................... 37 
 
7.5.1      Non-serious Adverse Events ....................................................................... 37 
 
7.5.2      Serious Adverse Events .............................................................................. 37 
8.      STATISTICAL ANALYSIS ..................................................................................................... 37 
8.1 
Statistical Analysis Plan ............................................................................................ 37 
 
8.1.1     Analysis Populations .................................................................................... 37 
 
8.1.2     Planned Analysis .......................................................................................... 38 
 
8.1.3     Sample Size Considerations......................................................................... 38 
 
8.1.4     Efficacy Measures and Analysis ................................................................... 39 
 
8.1.5      Safety and Adverse Events Analysis ........................................................... 40 
8.2 
Comparability of Subjects at Baseline ..................................................................... 40 
9.      CONSENT/ASSENT CONSIDERATIONS AND PROCEDURES .................................................. 40 
9.1 
Subject Confidentiality ............................................................................................. 41 
10.    RECORDS MANAGEMENT ................................................................................................ 41 
10.1 
Data Collection ......................................................................................................... 41 
10.2 
Source Documents ................................................................................................... 42 
10.3 
File Management at the Study Site ......................................................................... 42 
10.4 
Records Retention at the Study Site ........................................................................ 42 
11.    QUALITY CONTROL AND QUALITY ASSURANCE ................................................................. 43 
11.1 
Monitoring ............................................................................................................... 43 
11.2 
Auditing .................................................................................................................... 43 
12.    ETHICS AND RESPONSIBILITY ........................................................................................... 43 
13.    USE OF INFORMATION AND PUBLICATION ....................................................................... 43 
APPENDICES ........................................................................................................................... 46 
Appendix A: Study Personnel Contacts ................................................................................... 46 
Appendix B:  Instructions for the patient ............................................................................... 47 
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STUDY SYNOPSIS 
 
Title: 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-
Group Study to Compare Perrigo New York, Inc.’s  Ingenol Mebutate 
Topical Gel 0.05% to Leo Pharma Inc. Picato® Topical Gel 0.05% (Ingenol 
Mebutate Topical Gel 0.05%), and Both Active Treatments to a Vehicle 
Control in the Treatment of Actinic Keratosis on the Trunk and Extremities  
Study Period: 
57 Days (8 weeks)  
Study Medication: 
1. Ingenol Mebutate Topical Gel 0.05%, Perrigo New York, Inc. 
2. Picato® Topical Gel 0.05% (Ingenol Mebutate Topical Gel 0.05%), Leo 
Pharma Inc.  
3. Vehicle of test product, Perrigo New York, Inc. 
Study Objectives: 
To compare the safety and efficacy profiles of Perrigo New York, Inc.’s  
Ingenol Mebutate Topical Gel 0.05% to Picato® Topical Gel 0.05% (Ingenol 
Mebutate Topical Gel 0.05%) and to demonstrate the superior efficacy of 
the two active formulations over that of the vehicle in the treatment of 
Actinic Keratosis. 
Study Design: 
Subjects in this multi-center, double-blind, randomized, vehicle-controlled, 
parallel-group study will be enrolled into the study only after written 
informed consent/assent has been obtained and after all entry criteria 
have been met.  Male and female subjects at least 18 years of age, with 
Actinic Keratosis will be eligible for enrollment. 
Study Population: 
 healthy males and females, at least 18 years of age with 
4 to 8 clinically typical, visible, discrete nonhyperkeratotic, 
nonhypertrophic Actinic Keratosis lesions within a 25cm2 treatment area 
on the trunk/extremities, who meet the inclusion/exclusion criteria, will be 
enrolled to obtain 
 modified Intent-To-Treat (mITT) and 
 per-
protocol (PP) subjects. 
Dosing: 
Subjects will be randomized 
 to either the test product, 
reference product or vehicle treatment group, respectively, and will apply 
the topical gel 
 once daily for two (2) consecutive days to the 
selected treatment area (one contiguous skin area of approximately 25cm2 
treatment area on the trunk/extremities) avoiding contact with the eyes, 
mouth and other body areas during and after gel application.  
Study Visits: 
Clinical Evaluations will be performed at: 
1. Visit 1/Day 1 (Baseline) 
2. Visit 2/Day 3 (+1 day) (Post-Treatment Interim) 
3. Visit 3/Day 29 (±3 days) (Interim) 
4. Visit 4/Day 57 (±2 days) (End of Study) 
 
Safety will be assessed by monitoring adverse events at each visit and 
during a Follow-Up Phone Call/Day 15 (±3 days).  
Evaluations: 
At the baseline visit, the principal investigator or sub-investigator will 
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examine the subject to establish the clinical diagnosis of Actinic Keratosis 
(defined as the presence of 4 to 8 clinically typical, visible, discrete, 
nonhyperkeratotic, nonhypertrophic Actinic Keratosis lesions) contained 
within a contiguous 25cm2 area on the trunk or extremities (“treatment 
area”) 
 
The number of Actinic Keratosis lesions in the selected treatment area will 
be counted (and a total provided) and recorded at Visit 1/ Day 1 (Baseline) 
and at Visit 4/Day 57 (should any exist) on source documentation and 
eCRFs.  Additionally, new lesions not present at the baseline visit will also 
be counted and recorded on source documentation and eCRFs at Visit 4 or 
an Unscheduled Visit if applicable.  
 
At Visit 4/Day 57, the principal investigator or sub-Investigator will visually 
inspect the treatment area for any lesions and will confirm complete 
clearance of Actinic Keratosis lesion in the eCRF if lesion count is equal to 
zero at Visit 4/Day 57.  Complete clearance is defined as the absence of 
clinically visible Actinic Keratosis lesions identified at Visit 1 or new lesions 
since Visit 1. 
 
At the baseline visit (prior to initial dosing) and each subsequent visit, 
application site reactions of erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration will be recorded on the 
source document and eCRF. 
Endpoints: 
The primary efficacy endpoint will be the proportion of subjects with 
clinical success defined as complete clearance (absence) of all clinically 
visible Actinic Keratosis lesions identified at the baseline visit and no new 
Actinic Keratosis lesions in the treatment area at Visit 4/Day 57. 
Safety: 
The incidence of all adverse events reported during the study will be 
summarized by treatment group.  Equivalence of the test and reference 
with regard to safety will be evaluated by comparing the nature, severity 
and frequency of their adverse event profiles.  In addition, the test and 
reference treatments’ frequency and distribution of application site 
reactions of erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration will be summarized and 
compared descriptively. 
 
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ABBREVIATIONS 
 
AE 
Adverse Event 
AK 
Actinic Keratosis 
ANOVA 
Analysis of Variance 
ATC 
Anatomic Therapeutic Chemical (classification of drugs) 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
ITT 
Intent to treat population 
IUD 
Intra-Uterine Device 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent To Treat population 
OTC 
Over the counter 
PI 
Principal Investigator 
PP 
Per protocol population 
Rx 
Prescription 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPF 
Sun Protection Factor 
Sub-I  
Sub-Investigator 
 
 
 
 
 
 
 
 
 
 
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3 
STUDY DESIGN 
3.1 Type/Design of Study 
Subjects in this multi-center, double-blind, randomized, vehicle-controlled, parallel-group study 
will be assigned 
 to test product, reference product, or vehicle, respectively.  The 
study medication will be dispensed at Visit 1/Day 1 (Baseline) to subjects meeting all entry 
criteria. The assigned study medication will be applied topically by spreading evenly 
 
 to the designated treatment area (one contiguous skin area of approximately 25cm2) on 
the trunk or extremities once daily for two (2) consecutive days, avoiding contact with the eyes, 
mouth and other body areas during and after gel application.  
 
Subjects will be healthy males and females, at least 18 years of age, with 4 to 8 clinically typical, 
visible and discrete, nonhyperkeratotic, nonhypertrophic Actinic Keratosis lesions within a 
contiguous 25cm2 treatment area on the trunk or extremities.  Visits to the study site are 
scheduled at Day 1, Day 3, Day 29, and Day 57.  There will also be a telephone call at Day 15 to 
follow up on previously reported adverse events and to ask subjects about new adverse events 
or concomitant medications taken.  
 
At Visit 1/Day 1 (Baseline) written informed consent/assent will be obtained. The subject’s 
demographic profile, medical history, and prior/concomitant medication use will be recorded. A 
urine pregnancy test will be performed for all women of childbearing potential.  A brief physical 
examination (including heart, lung and abdomen evaluations) including vital signs and 
height/weight will be recorded during baseline. 
 
The subject’s history of and current state of Actinic Keratosis will be assessed (diagnosis) and 
their Fitzpatrick skin type will be classified at Visit 1/Day 1 (Baseline). In addition, an application 
site reaction assessment and Actinic Keratosis lesion count will be performed at Visit 1/ Day 1 
(Baseline), Visit 4/Day 57, and if necessary at an Unscheduled Visit.  Subjects who meet all of 
the inclusion and none of the exclusion criteria will be enrolled in the study, dispensed 
 
study medication, and given a daily diary to complete. Instructions on proper treatment 
application and completion of the diaries will be provided to subjects and their Visit 2/ Day 3 
will be scheduled. During the baseline visit, the study staff will demonstrate proper medication 
application to the subject 
 
.  The study staff should instruct the subject to 
apply their second dose of study medication at approximately the same time of day on Day 2. 
Subjects will return to the study site at Visit 2/Day 3 (Post-Treatment).  During this visit, the 
completed subject diary will be collected, a new diary will be given to the subject and the 
Principal Investigator or designated staff will assess the subject’s application site reactions 
provide severity scores as appropriate.   Subjects will return all study medication, and study 
medication accountability will be done. Information on concomitant medication use and 
protocol compliance will be collected and reviewed. Safety will be assessed by the monitoring 
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Protocol No: PRG-NY-15-002 
 
 
  
 
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of the subject’s adverse events (AEs). At this visit, the Follow-Up Telephone Call/Day15, Visit 
3/Day 29 and Visit 4/Day 57 will be scheduled.  
 
A Follow-Up Telephone Call will be made by study staff to the subject at Day 15 to review and 
assess subject compliance (diary completion), record AEs, update concomitant medication use, 
and to remind the subjects of the protocol requirements and next study visit schedule.  
 
At Visit 3/Day 29 (Interim) and Visit 4/Day 57 (End of Study), subjects will be asked if they 
experienced any adverse events, taken any concomitant medications and generally complied 
with protocol requirements.  The diary dispensed at Visit 2 will be collected and reviewed with 
the subject, and a new diary will be dispensed at Visit 3/Day 29.  The diary dispensed at Visit 3 
will be collected and reviewed at Visit 4/Day 57. Safety will be assessed by the monitoring of all 
adverse events (AEs) and clinically significant changes from Visit 1/Day 1 (Baseline) and an 
application site reaction assessment will be conducted at Visit 3/Day 29 and Visit 4/Day 57.   
 
3.2 Study Population 
Healthy male and female subjects, at least 18 years of age, with 4 to 8 clinically typical, visible, 
discrete Actinic Keratosis lesions within a contiguous 25cm2 treatment area on either the trunk 
or extremities who meet all eligibility criteria will be enrolled in this multicenter study.  
 
4. 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS 
4.1 Inclusion Criteria 
Subjects must meet all of the following criteria: 
 
1. Subject must sign an Institutional Review Board (IRB) approved written informed 
consent/assent for this study.  Subjects under the legal age of consent for their respective 
state must sign an IRB approved written informed consent/assent in addition to a parent or 
legally authorized representative.   
2. Subjects must be healthy males or females, at least 18 years of age. 
3. Subjects must be in general good health and free from any clinically significant disease, 
other than Actinic Keratosis that might interfere with the treatment assessment of Actinic 
Keratosis or study evaluations.  
4. Subjects must have a clinical diagnosis of Actinic Keratosis, defined as having 4 to 8 clinically 
typical, visible and discrete, non-hyperkeratotic, non-hypertrophic, Actinic Keratosis lesions 
within a contiguous 25cm2 treatment area on either the trunk or extremities (i.e. to be 
designated as the treatment area).  
5. 
 
     
 
 
 
.   
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4.2 Exclusion Criteria  
Subjects may not be enrolled if any of the following criteria exist: 
 
1. Subjects who are pregnant, nursing, or planning a pregnancy within the study period. 
2. Subjects who are immunocompromised or HIV positive or who have any immune-system 
disorders including auto-immune diseases. 
3. Subjects who have or had an active herpes infection 
 prior to the Visit1/Day 1 
(Baseline) (i.e., including presence of herpes labialis).  
4. Subjects who have any evidence of systemic cancer, squamous cell carcinoma, basal cell 
carcinoma, or any other cancer in the treatment area.  
5. 
 
. 
6. Presence of any confounding skin conditions in the treatment area that may be made worse 
by treatment with Ingenol Mebutate gel 0.05% 
 
7. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
  
 
  
  
  
  
  
  
11. Subjects who have had or are scheduling elective surgery within 1 month (30 days) before 
or after the study period. 
12. Use 
prior to Visit 1/Day 1 (Baseline) or planned use during the 
study of: 
  
 
  
    
 
 
  
  
  
 
  
 
  
,   
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13. Subjects who are undergoing treatment or received treatment with the following 
 
 of Visit 1/Day 1 (Baseline) and 
 of the selected treatment area 
or planned anytime during the study. 
  
 
  
 
  
   
  
    
 
  
14. Use of Ingenol Mebutate gel 0.05% 
 of Visit 1/Day 1. Previous use 
 of Ingenol Mebutate gel 0.05% is allowed if a different treatment 
area was successfully treated.) 
15. History of unresponsiveness, hypersensitivity or allergy to ingenol mebutate therapy and/or 
any ingredient in the study medication. 
16. Subjects who used PUVA (psoralen plus ultraviolet A therapy), or UVB therapy in the  
treatment area 
 prior to Visit 1/Day 1 (Baseline) or are planning 
to receive treatment with PUVA therapy, UVB therapy, nonprescription UV light sources  
anywhere on the body during the study.  
17. Subjects who have taken systemic chemotherapy medications 
 
prior to Visit 1/Day 1 (Baseline) or planned use anytime during the study.  
18. 
 
 
19. 
 
 
 
 
 
 
 
 
20.  
 
 
 
21. Start 
 of dose of hormonal treatment (oral, implanted, topical contraceptives and 
androgens) 
 or planned start or change throughout the 
study.  Use of such therapy must remain constant during the study. 
22. Subject consumes excessive alcohol, abuses drugs, or has a condition that could 
compromise the subject’s ability to comply with study requirements. 
23. Participation in any clinical study involving an investigational product, agent or device (that 
might influence the intended effects or mask the side effects of study medication) in the 30 
days prior to Visit 1/Day 1 (Baseline) or throughout the study. 
24. Previous enrollment in this study or current enrollment in this study at another participating 
site. 
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25. Employee (or employee’s family member) of the research center or private practice, or 
subjects who have a conflict of interest. 
26. Subjects who in the opinion of the investigator, are unlikely to be able to follow the 
restrictions of the protocol and complete the study. 
 
4.3 Medications, Supplements, Other Substances and Procedures Prohibited Before 
Enrollment and During the Study 
 
The medications prohibited prior to enrollment, and required washout period, are listed in 
Table 4.3.1 with the subject exclusion criteria. 
 
Table 4.3.1 Medications, Supplements, and Other Substances Prohibited for Study Entry 
 
Prohibited Medications, Supplements, and Other 
Treatment 
Exclusion Criteria 
Number 
Washout Period Prior to 
Randomization 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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Subjects must not take the treatments listed in TABLE 4.3.2 during study participation.   
 
Table 4.3.2 Medications (Prescription and Over-the-Counter), Supplements, and Other 
Treatments Prohibited During the Study 
 
Prohibited Medications, Over-The-counter (OTC) 
medications, and Treatments 
Location 
Exclusion Period 
Restrictions 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
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4.4 Precautions 
The following precautions are to be taken during this study: 
1. Subjects should wash their hands with mild soap and water before and after applying 
study medication and should take care not to transfer the study medication to other 
body areas, including the eye. 
 
  
2. Subjects should allow the treated area to dry 
. 
3. 
 
 
 
4. 
 
 
 
 
 
 
.   
5. The study medication should not be applied to unhealed skin, open skin wounds, cuts, 
abrasions, infections, exfoliative dermatitis, eczematous or sunburned skin. 
6. 
 
. 
7. 
 
 
8. Subjects should avoid contact of the study medication with the eyes and with skin 
outside the selected treatment area defined by the study physician. In case of accidental 
exposure, the eyes should be rinsed with plenty of water and get medical care as soon 
as possible.  
9. 
 
. 
10. 
 
 
. 
11. Subjects should limit sun exposure, including sunlamps (non-prescription UV light 
sources), and avoid tanning beds/booths/parlors. 
12. Subjects should consult the investigator with any questions regarding concomitant 
medications. 
13.  
 
 
14. 
 
. 
 
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5. PROCEDURES 
5.1 Subject Screening and Enrollment 
The study personnel will review the IRB approved informed consent form and assent form, if 
applicable, with each subject and give the subject an opportunity to have all questions 
answered before proceeding.  The consent/assent form must be signed by each subject and 
witnessed before the subject is enrolled into the study.  A copy of the signed consent/assent 
will be given to every subject and the original will be maintained with the subject’s records.   
Subjects under the legal age of consent must sign an IRB approved written informed 
consent/assent in addition to a parent or legally authorized representative.   
Subjects that require a wash-out 
 from their initial informed 
consent/assent signing must be re-consented before any further study procedures can begin.  
 
5.2 Assignment of Subject Number 
Once the subject has consented, met eligibility criteria and is considered enrolled in the study, 
study staff will assign a subject number to the subject. The subject number will correspond to a 
computer-generated randomization schedule assigning the number to one of the three study 
treatment groups.  The subject numbers will be assigned sequentially in the order in which 
subjects are enrolled at each center. 
 
5.3 Demographics/Medical History 
A demographic profile and complete medical history will be recorded prior to starting study 
medication.  The medical history will include a complete review of all current diseases and their 
respective treatments. 
 
5.4 Concomitant Medications 
Concurrent medications and any medications taken 
 prior to signing informed 
consent/assent will be recorded as prior/concomitant medications (using their generic name, if 
known) with the corresponding indication.  The medications to be recorded will include 
prescription (Rx) and over-the-counter (OTC) medications and dietary supplements.  All 
medications taken on either a regular or “prn” basis, including vitamins, aspirin and 
acetaminophen, should be recorded on this page prior to commencing the use of the study 
medication. 
 
5.5 Physical Examination 
The investigator, sub-investigator or appropriately delegated and qualified designee will 
perform a brief physical examination 
 prior to 
the subject starting study medication.  
 
 
 
5.6 
Urine Pregnancy Test 
Females of childbearing potential (excluding women who are surgically sterilized or post-
menopausal for at least 2 years), in addition to having a negative urine pregnancy test, must be 
willing to use an acceptable form of birth control during the study. 
 
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any shape, 
 to be treated with the study 
medication gel as the designated treatment area on the trunk or extremities.  This selected 
treatment area should have 4 to 8 visible clinically discrete Actinic Keratosis lesions.  
Additionally, the PI or designated staff will document the location of each lesion, the 
designated treatment area, and the size (in cm2) of the treatment area at Visit 1/Day 1 
(Baseline) will be marked in the subject’s source documentation 
 
 
 
 
 
 
  
 
 
 
  
 
To the greatest extent possible, the same investigator who made Visit 1/Day 1 (Baseline) 
assessments will perform evaluations at Visit 4/Day 57. At Visit 1/Day 1 (Baseline), Visit 4/ Day 
57, and Unscheduled Visit, if applicable, the number of Actinic Keratosis lesions within the 
treatment area will be counted and recorded in the source documentation and eCRFs. 
Additionally, at Visit 4/Day 57, and Unscheduled Visit, if applicable, new Actinic Keratosis 
lesions as compared to Visit 1/Day 1 (Baseline) will be counted and recorded in the source 
documentation and eCRFs.  
 
 
 
  
 
Complete clearance (Actinic Keratosis lesion count in the selected treatment area) at Visit 
4/Day 57 will be assessed. Complete clearance is defined as absence of clinically visible Actinic 
Keratosis lesions (including presence of new lesions) in the selected treatment area at Visit 
4/Day 57. The investigator or sub-investigator will confirm the number of lesions in the selected 
treatment area (including new lesions) and clinical response success if lesion count is equal to 
zero at Visit 4/Day 57. 
 
 
.  
 
Lesion counting must be conducted by qualified investigators or designated staff listed on the 
Form FDA 1572 who have been delegated these tasks by the PI. 
 
 
  
 
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5.10 Application Site Reaction Assessment 
To the greatest extent possible, the same investigator who made Visit 1/Day 1 (Baseline) 
assessments will assess the application site reactions, grade them according to a 5-point scale 
and a designated staff will record them in the source document and eCRFs at each subsequent 
visit. This assessment must be conducted by qualified individuals listed on the Form FDA 1572 
who have been delegated this task by the PI. 
 
 
  
 
At baseline (prior to initial dosing) and each subsequent visit, application site reactions of 
erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration 
are to be recorded in the source document and eCRFs.   
 
Application site reactions (erythema, flaking/scaling, crusting, swelling, vesiculation/ 
pustulation, and erosion/ulceration) are not to be recorded as adverse events unless they result 
in either: 
 The temporary discontinuation of the study medication.  
 The discontinuation of the subject from the study. 
 The use of a new concomitant medication in order to treat this event. 
 
Any other application site reaction not listed above (such as pain, pruritus and infection) should 
be recorded as adverse events in the source document and eCRFs. 
 
The following scale will be used for the Application Site Reaction Assessment: 
 
Site Reaction  
Description 
Erythema 
 
Flaking/scaling 
  
Crusting 
 
 
Swelling  
 
Erosion/ulceration  
 
 
Vesiculation/Pustulation  
  
 
 
 
 
 
 
 
 
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Site  
Reaction 
Grading Criteria 
 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.11 Study Medication Use, Patient Instructions and Diary 
Each subject’s drug kit box contains 
 0.47 gram tubes.  At the baseline visit, the subject will 
apply the contents of one of the tubes at the site under study staff supervision and that tube 
will be placed back in the drug kit box.  The second tube will be given to the subject to take 
home with them for their second application along with a diary. Their Day 2 application should 
be applied at approximately the same time as the Day 1 application.  Additionally, the study 
staff must ensure subjects understand the instructions for applying the study medication and 
refrigerate the study medication at home all times.     
 
Subjects must not use the study medication for more than 2 consecutive days.  
 
At Visit 2/Day 3 the study medication will be collected to visually assess compliance.  
Compliance will also be determined from the diary, in which the subject will be instructed to 
record if they applied their second dose of medication or not. After the compliance evaluation, 
empty, filled and partially used tubes will be collected and kept by the site.   
 
Subjects will wash the designated treatment area with a mild soap by using only the hands and 
pat dry with a soft towel 
 before applying the study 
medication.  The study medication from one tube will be applied to the selected treatment 
area, one contiguous skin area of 25 cm2 area. After spreading the study medication 
 over 
the treatment area, 
. Subjects should wash their 
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Protocol No: PRG-NY-15-002 
 
 
  
 
     Page 24 of 51 
 
hands with mild soap and water immediately after applying the study medication gel and take 
care not to transfer the applied study medication gel during and after application to other 
areas, including the eyes. If the treatment area is on the back of the hands (not palm), the 
subject should wash only the fingertip which was used for applying the gel.  
 
 
 
   
 
Subjects will be instructed to not use any other topical treatments or products other than the 
study medication gel or approved moisturizer in the selected treatment area during the two-
day treatment period.  
 
Diaries will be dispensed for each enrolled subject.  The subjects will be instructed to complete 
their diary after applying the subsequent dose of study medication.  At  Visit 2/Day 3, the study 
personnel will review the diary to determine subject dosing compliance, confirm use of any 
prohibited medications, assess AEs and a new diary will be dispensed to all subjects. At each 
subsequent visit, study personnel will review the diary card to determine if the subject used any 
prohibited medications, assess AEs and dispense a new diary (a diary will not be dispensed at 
Visit 4/ Day 57).  In addition, each study subject will be reminded to return the previously 
dispensed tube (regardless of content) at Visit 2/Day 3 and the completed diary at the next 
visit.  Study personnel will schedule the subject’s next visit prior to the subject’s departure. 
 
5.12 Visit Specific Procedures 
The following sections outline the procedures required at each visit. 
 
5.12.1 Visit 1/Day 1 (Baseline) 
Prospective subjects will visit the study center and will be examined by the principal 
investigator or delegated staff. The following procedures will be performed at the baseline visit: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.12.2 Visit 2/Day 3 (±1 day) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.12.3 Follow-up Phone Call /Day 15 (± 3 days) 
 
 
 
 
 
 
 
 
 
5.12.4 Visit 3/Day 29 (± 3 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.12.5 Visit 4/Day 57 (± 2days) End of Study /Early Termination Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.12.6 Unscheduled 
An unscheduled visit is allowed at any time if in the investigator’s opinion it is warranted.  If the 
investigator assesses the subject’s condition and determines that the subject’s condition has 
worsened to the degree that it is unsafe for the subject to continue in the study, the subject 
may be discontinued from the study as a treatment failure, and a standard of care treatment 
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5.14 Screen Failures 
A screen failure is a subject who received information about the study, including signing an 
informed consent/assent, and possibly performing some study related procedures but was not 
enrolled, dispensed and applied study medication. Screen failures information will not be 
entered in the database and will not be included in any data analyses. 
 
5.15 Protocol Deviations/Violations 
This study will be conducted as described in this protocol except for an emergency situation in 
which the protection, safety, and well-being of the subject requires immediate intervention, 
based on the judgment of the investigator or a responsible, appropriately trained and 
credentialed professional(s) designated by the investigator.  In the event of a significant 
deviation from the protocol due to an emergency, accident or mistake, the investigator or 
designee must contact Perrigo/
 contacts in Section 14 (Appendix A) at the earliest 
possible time. 
 
 
 
 
 
 
 
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Subjects with any variation from the protocol that would not interfere with the effect of or the 
accurate assessment of the assigned study treatment, may be included in both PP and mITT 
analyses. 
 
5.16 Subject/Treatment Compliance 
Subjects will apply the medication to the designated treatment area at approximately the same 
time once daily for 2 consecutive days. 
 
 
 
.  Compliance will be determined from the diary card, in which the subject will be 
instructed to record all applications made or missed.  The first and last dates of treatment 
should be recorded in the source document and eCRFs.  The total number of applied and 
missed applications should also be recorded.  Applications will be considered missed if the 
study medication was not applied on Day 1 or Day 2 of the treatment period.  Subjects will be 
considered compliant if they apply both daily doses on study Days 1-2.  Subjects will be 
considered non-compliant if one (1) or more doses are missed.  The study medication tube will 
be collected by the study site at appropriate visits or early termination. 
 
5.17 Discontinuation/Withdrawal of Study Subjects 
Subjects will be removed from the study for any of the following reasons: 
 The subject withdraws his or her consent/assent for any reason. 
 The subject’s condition has worsened to the degree that the investigator feels it is 
unsafe for the subject to continue in the study. 
 Subject did not meet entry criteria. 
 The subject’s medication code is unblinded. 
 An adverse event (AE) including inter-current illness, occurs for which the subject 
desires to discontinue treatment or the investigator determines that it is in the subject’s 
best interest to be discontinued. 
 The subject is lost to follow-up.  The investigator will document efforts to attempt to 
reach the subject twice by telephone and will send a certified follow-up letter before 
considering that subject lost to follow-up. All attempts must be thoroughly recorded. 
 The subject becomes pregnant during the course of the trial. 
 Lack of efficacy (treatment failure) (subject’s own withdrawal or investigator removal  
from study) 
 Investigator Discretion  
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 Significant protocol violation or non-compliance with the study protocol that could 
interfere with the effect or accurate assessment of the assigned study treatment. 
 
A subject will not be allowed to re-enroll in the study after they have been discontinued.  
 
The reasons for a subject being discontinued will be documented in the source document, 
eCRFs and the enrollment log. 
 
If a subject is discontinued from the study for any reason, the Visit 4/ Day 57 End of Study 
Visit/Early Termination Visit procedures should be completed and any outstanding data and 
study medication should be collected.  Data, in addition to the primary reason for 
discontinuation and the date of removal, will be recorded in the source document and the End 
of Study eCRF. 
 
 
 
 
 
 
 
 
 
 
  
 
6. MATERIALS AND SUPPLIES 
6.1 
Study Medication 
The study medication supplied by Perrigo Israel Pharmaceuticals, Ltd. will consist of: 
 
 
Test Product:   Ingenol Mebutate Topical Gel 0.05%, 
Perrigo New York, Inc. 
 
 
Reference Product:  Picato® Topical Gel 0.05% (Ingenol Mebutate Topical Gel 0.05%), 
manufactured by Leo Pharma Inc.  
 
Vehicle:  Vehicle of test product 
Perrigo New York, Inc 
 
 
6.2 
Medication Management 
6.2.1 Labeling, Packaging and Distribution 
The study medication assigned to each subject number will be determined by a computer-
generated randomization schedule.  Study medication is labeled and packaged, according to the 
random code, so that neither the subject nor the investigator can identify the treatment. 
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All study medications will be supplied to the subjects in 0.47 gram tubes.  Each subject’s 
treatment unit will consist of one kit box containing 
 tubes of study medication.  The 
outer label of the box will not contain any information that could identify the treatment group 
to which the subject was assigned.  The kit box labels will include the name of Perrigo Israel 
Pharmaceuticals, Ltd., study protocol number, subject number and initials, directions for use 
and storage, and warnings:  “For Topical Use Only.”  “Not for Ophthalmic, Oral, or Intravaginal 
Use” and “Caution: New Drug - Limited by Federal (or United States) law to investigational use.” 
 
The tear-off portion of each label contains the identity of the medication in the tube.  The 
investigator will not remove the occluding layer of the label unless absolutely necessary to 
provide medical treatment to a subject in an emergency and preferably with prior authorization 
from Perrigo or designee whenever possible.  If the occluded portion of the label is removed, 
each involved subject(s) will be discontinued from the study and the reason will be noted on 
the source document and eCRFs. 
 
The tear-off portion has an adhesive backing to affix to the study medication dispensing log that 
will be maintained at the investigator site.  The individual boxes are numbered sequentially and 
should be dispensed in order. 
 
6.2.2 Retention Samples 
Each investigational site where study medication is dispensed to at least one subject will be 
required to randomly select 
 
 retain samples.  The retention samples must be stored under labeled 
conditions [in a refrigerator at 36o-46oF (2-8oC); excursions permitted to 32o-59oF (0o-15oC)] 
even after the study has concluded. The investigator will maintain one randomly selected block 
of study medication for each shipment of study medication received.  As per the Code of 
Federal Regulations Part 21, Section 320.38(e), “Each reserve sample shall be stored under 
conditions consistent with product labeling and in an area segregated from the area where 
testing is conducted and with access limited to authorized personnel. Each reserve sample shall 
be retained for a period of at least 5 years following the date on which the application or 
supplemental application is approved, or, if such application or supplemental application is not 
approved, at least 5 years following the date of completion of the bioavailability study in which 
the sample from which the reserve sample was obtained was used.”  The investigator will store 
the retain sample study medication until such time as notification is received from Perrigo that 
the samples are no longer required. 
 
6.2.3 Storage and Test Article Accountability 
Study articles used to conduct this study will be maintained under adequate security by the 
investigator or designee.  Study test articles will be stored in a refrigerator at a temperature of 
36o- 46oF (2-8oC); excursions permitted between 32o- 59oF (0o-15oC) in a secured area. Subjects 
must be instructed to keep the study medication refrigerated at home.  Each investigator site 
will ensure that the temperature of study drug is monitored and recorded throughout the 
study. The medication should not be frozen, kept away from heat and kept tightly closed.  The 
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investigator will not supply study test articles to any person not enrolled in this study, or to any 
physician or scientist except those named as sub-investigators. 
 
The clinic personnel at each investigator site will keep a running inventory of study test articles 
dispensed that will include subject numbers assigned and the date each is dispensed and used.  
A study medication accountability form will be provided to the investigator to document all 
medications received, dispensed by and used by each subject.  At the conclusion of the study all 
unused, partially used, and empty containers must be inventoried by the monitor and returned 
to Perrigo or designee, for destruction, except for the retention samples that must remain at 
the Investigator site. 
 
6.2.4 Randomization 
Randomization will be performed according to a computer generated randomization scheme 
where the treatment group designation has been assigned to the subject number.  The 
treatment designation will remain blinded until the final database is closed.  An independent 
third party will hold the randomization code throughout the study.  The randomization scheme 
will be a block randomization, with each 
 subjects assigned to Test: Reference: 
Placebo 
. 
 
6.2.5 Procedure for Breaking the Blind 
The investigator, staff at the study site, study monitors, and data analysis/management 
personnel are blinded to the subject assignment.  In the event of an emergency, the specific 
subject treatment may be identified by removing the overlay of the blinded label for each 
subject at each investigator site, which is attached to the study medication log.  However, every 
effort should be made to maintain the blind.  The investigator must not scratch off the 
occluding layer of the label unless absolutely necessary to provide medical treatment to a 
subject in an emergency situation.  When possible, the investigator site should inform Perrigo 
or designee.  The reason for breaking the blind must be clearly documented in the source 
documentation and eCRFs and the subject discontinued from the study. 
 
7. ADVERSE REACTIONS 
The potential adverse reactions of generic Ingenol Mebubate Topical Gel 0.05% are anticipated 
to be similar to those observed in Picato® Topical Gel (Ingenol Mebutate Topical Gel 0.05%).  
The most common adverse reactions related to treatment with Picato® Topical Gel include local 
skin reactions, application site pain, application site pruritus, application site irritation, and 
nasopharyngitis . Eye disorders, including severe eye pain, eyelid edema, eyelid ptosis,  and 
periorbital edema can occur after exposure.  Severe local skin reactions such as 
vesiculation/pustulation, erosion/ulceration can occur. 
 
7.1 
Departure from the Protocol for Individual Subjects 
When an emergency occurs requiring a departure from the protocol for a subject, departure 
will be only for that subject.  In such circumstances, the investigator or other physician in 
attendance will contact the Medical Monitor or Perrigo by telephone and follow up with a 
written description within one day.  The overseeing IRB should also be notified. 
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     Page 32 of 51 
 
 
7.2 
Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered 
a medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (for 
example, an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to this medicinal product. 
 
A serious adverse event (SAE) is an adverse event that results in any of the following outcomes: 
 
 death 
 life-threatening event (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an event that, 
had it occurred in a more severe form, might have caused death) 
 requires in-subject hospitalization or prolongs hospitalization 
 a persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
 congenital anomaly/birth defect 
 Other adverse events that may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject or may require medical or 
surgical intervention to prevent one of the previously listed outcomes. 
 
Immediately Reportable Adverse Events (IRAE): Any serious AE or any AE that necessitates 
discontinuation of study medication, including pregnancy. 
 
Unexpected Adverse Event:  An unexpected event is any adverse drug experience, the 
specificity or severity of which is not consistent with the current approved product labeling 
(package insert, Appendix D) for the study medication, the Investigator’s Brochure, or as 
described in the clinical protocol and consent materials.    
 
Intensity of Adverse Events:  The maximum intensity of an AE during a day should be recorded 
on the eCRF. If the intensity of an AE changes over a number of days, then separate entries 
should be made having distinct onset dates for the changes in severity. 
 
Mild - AEs are usually transient, requiring no special treatment, and do not interfere with 
subject’s daily activities. 
 
Moderate - AEs typically introduce a low level of inconvenience or concern to the subject 
and may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures. 
 
Severe - AEs interrupt a subject’s usual daily activity and traditionally require systemic 
drug therapy or other treatment. 
 
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Causal Relationship to Study Medication: The following criteria should be used in assessing the 
apparent causal relationship of an AE to study medication.  
 
Definitely - The AE: 
• 
follows a reasonable temporal sequence from study medication administration 
• 
abates upon discontinuation of the study medication (dechallenge) 
• 
is confirmed by reappearance of the reaction on repeat exposure 
 
Probably - The AE: 
• 
follows a reasonable temporal sequence from study medication administration 
• 
abates upon discontinuation of the study medication (dechallenge) 
• 
cannot be reasonably explained by the known characteristics of the subject’s state 
 
Possible - The AE: 
• 
follows a reasonable temporal sequence from study medication administration 
• 
but that could readily be produced by a number of other factors 
 
Unlikely - The AE: 
 follows a reasonable temporal sequence from study medication administration 
 could have been produced by either the subject’s clinical state or by study medication 
administration 
 
Not related - The AE: 
 does not have a reasonable temporal association with the administration of study 
medication  
 has some other obvious explanation for the event 
 
7.3 Eliciting and Reporting of Adverse Events 
The investigator will periodically assess subjects for the occurrence of adverse events.  In order 
to avoid bias in eliciting adverse events, the subject or parent/legally authorized representative 
should be asked a non-specific question (e.g., “How have you been feeling since your last 
visit?”) to assess whether any AE has been experienced since the last visit.  All adverse events 
(as defined in Section 7.2), either observed by the Investigator or one of his/her medical 
collaborators, or reported by the participant spontaneously, or in response to direct 
questioning, will be reported and documented in the source and the study reporting forms. 
When reporting an adverse event, the Investigator must assign a severity grade to each event 
and declare an opinion on the relatedness of the event to the study medication or procedure.  
Serious or unexpected adverse events must be reported to Perrigo and 
 within 24 hours 
of when the Investigator first learns of the occurrence of the event.  
 
Adverse events will be documented in source and recorded in a timely manner on eCRFs.  
Adverse events (i.e., worsening of Actinic Keratosis*) that are identified at the last assessment 
visit (or the early termination visit), must be recorded on the AE eCRF with the status of the AE 
noted.  
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Protocol No: PRG-NY-15-002 
 
 
  
 
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* Worsening of the subject’s Actinic Keratosis may be expected from application of the study 
medication. Therefore, this will not be considered an AE unless one or more of the following 
occurs: 1) alternative treatment required; 2) subject is discontinued by the Principal Investigator 
for worsening of AK.  
 
Adverse event reporting begins from the signing of informed consent/assent.  Adverse events 
should be followed until resolved or 30 days after the final study treatment.  In any case, 
serious adverse events that are not resolved or considered to be chronic within 30 days of the 
final study treatment must be followed by the investigator until they become resolved or are 
considered to be chronic (stabilized for at least 30 days).  All events that are ongoing at this 
time will be recorded as ongoing on the eCRF. 
 
7.3.1 Expedited Reporting Responsibilities of the Study Center 
For any serious or unexpected adverse event, Perrigo must be notified within 24 hours of when 
the Investigator first learns of the occurrence of the event. Expedited reporting requirements 
for serious adverse events are described below. Adequate information must be collected with 
supporting documentation to complete a standard report for submission to Perrigo. The 
adverse event term on the AE eCRF and the SAE report should agree exactly. Special attention 
should be given to recording hospitalizations and concomitant medications.   
 
Subjects with unresolved adverse event(s) or serious adverse event(s) should be followed by 
the investigator until the events are resolved, events determined to be chronic or the subject is 
lost to follow-up.  Resolution means the subject has returned to the baseline state of health, or 
the investigator does not expect any further improvement or worsening of the adverse event.  
The investigator should continue to report any significant follow-up information to Perrigo up 
to the point that the event has resolved.  Any serious adverse event reported by the subject to 
the investigator that occurs within 30 days after the last assessment, and are determined by the 
investigator to be reasonably associated with the use of the study medication, should be 
reported to Perrigo within 24 hours of when the Investigator first learns of the occurrence of 
the event.   
 
When reporting a serious adverse event (SAE) the Investigator (or the designated staff) will 
promptly report any serious adverse event or pregnancy by telephone to 
immediately after the investigator 
becomes aware of the event.  An SAE form should be completed and sent by fax, email, or 
overnight courier to 
 within 24 hours of knowledge of the event by the site.  In many 
cases, only preliminary information will be available. Appropriate follow up information should 
be sought (hospital discharge summaries, operative reports etc.) and a follow up SAE report 
form submitted.  A designation of causality from the study medication should always be 
included with a follow up report.  Assess and report the causality of the event. 
 
7.3.2 Submitting an Expedited Safety Report to the IRB 
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     Page 35 of 51 
 
Once 
 receives all supporting documentation for the reported event, the Medical 
Monitor, in conjunction with Perrigo, will determine if the safety report is eligible for expedited 
review. 
 will log the initial event and will notify Perrigo that an event has been reported 
within 1 business day after initial receipt.  
 will complete the review of the event, enter 
information into their safety database and generate the report. This form, as well as other 
supporting documentation, will be forwarded to 
 Medical Monitor for review.  
 
will finalize the report and distribute it to Perrigo within 2 days after initial receipt. When 
expedited safety reporting to regulatory authorities is indeed required, the Investigator should 
review and update any newly available materials at once.  Follow-up queries may be issued to 
the study center to further clarify the event. 
 
Each expedited safety report will routinely include a brief cover memorandum, the completed 
report, and any additional pertinent information recommended by 
, Perrigo, or study 
Medical Monitor. Once the report is assembled, the Principal Investigator must submit the 
expedited safety report to the IRB within the required reporting timeframe. Follow-up reports 
should be submitted when requested or when pertinent information becomes available.  
 
When a Principal Investigator receives an expedited safety report from 
 or Perrigo 
detailing adverse events occurring at other study centers under this protocol, it must be 
promptly submitted to the study center’s IRB.  The Principal Investigator must retain a copy of 
such reports as submitted to their IRB in the site’s study Regulatory Binder. 
 
 
7.4 
SAE & AEs Requiring Discontinuation of Study Drug, including Pregnancies 
ANY SAE, WHICH OCCURS AFTER A SUBJECT HAS ENTERED THE STUDY, WHETHER OR NOT 
RELATED TO STUDY MEDICATION, MUST BE REPORTED TO 
 AND PERRIGO 
IMMEDIATELY (WITHIN 24 HOURS) VIA TELEPHONE OR FACSIMILE. IF INITIALLY REPORTED VIA 
TELEPHONE, THIS MUST BE FOLLOWED-UP BY A FACSIMILE OF THE WRITTEN SAE REPORT 
WITHIN 24 HOURS OF THE CALL TO 
. 
 
Non-serious events that require discontinuation of study medication (including laboratory 
abnormalities) should be reported to Perrigo immediately and within 1 working day. 
Subjects who discontinue due to experiencing adverse events should be followed clinically until 
their health has returned to baseline status, or until all parameters have returned to normal.  It 
is expected that the investigator will provide or arrange appropriate supportive care for the 
subject. 
 
A subject who experiences a severe adverse event related to study drug will be discontinued 
from the study. 
 
The notification about any serious adverse event should be directed to: 
 
 
 
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7.4.1 Pregnancy 
At the time a Principal Investigator or delegated staff becomes aware that a study participant 
became pregnant following study participation, the Principal Investigator or Study Coordinator 
will report the pregnancy immediately by phone and/or by faxing a completed Pregnancy 
Report to 
 within one working day of being notified of the pregnancy report. 
 
The report will include the following elements: 
 Participant (mother’s) coded study identifier; 
 Date of participant’s last menstrual period; 
 Total accumulated dose of study treatment administered to date; 
 Date of study medication administration 
 
The investigator will follow the subject until completion of the pregnancy and must assess the 
outcome in the shortest possible time but not more than 30 days within completion of the 
pregnancy. 
 
Upon delivery, miscarriage or abortion, the Principal Investigator or Study Coordinator must 
forward a follow-up Pregnancy Report with any relevant information on the present condition 
of the fetus to 
 , including: 
 Mother’s coded study identifier(s); 
 Gestational age at delivery, miscarriage or abortion; 
 Birth weight, gender, length and head circumference, if available; 
 Apgar scores recorded after birth, if available; 
 Any abnormalities. 
 
If the outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to 
be documented], stillbirth, neonatal death, or congenital anomaly), the investigator will report 
the event by phone and by faxing a completed SAE report form to 
 within one working 
day of being notified of the pregnancy report. 
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     Page 37 of 51 
 
 
If the trial is completed before the outcome of the pregnancy is known, 
 will assume the 
responsibility for following up on the pregnancy.   
will contact the Investigator or Study 
coordinator on or around the potential expected date of delivery to follow-up on the outcome 
of pregnancy and will also check on the status of the infant 8 weeks post-delivery.  Upon 
awareness of the pregnancy outcome and known status of the infant following 8 weeks of 
delivery, the investigator will complete the applicable pregnancy report forms and fax to 
 within 1 day of being notified.  
 
7.5 
Post Study Adverse Events 
7.5.1 Non-serious Adverse Events 
Adverse events that are identified at the last assessment visit (or the early termination visit) 
must be recorded on the AE eCRF with the status of the AE noted.   
 
7.5.2 Serious Adverse Events 
Serious adverse events that are identified on the last assessment visit (or the early termination 
visit) must be recorded on the AE eCRF page and reported to Perrigo according to the 
procedures outlined above. Subjects with unresolved previously reported serious adverse 
events, or any new serious adverse events identified on the last assessment visit, should be 
followed by the investigator until the events are resolved, or the subject is lost to follow-up.  
Resolution means the subject has returned to the baseline state of health, or the investigator 
does not expect any further improvement or worsening of the adverse event.  The investigator 
should continue to report any significant follow-up information to Perrigo up to the point that 
the event has resolved.  Any serious adverse event reported by the subject to the investigator 
that occurs after the last assessment, and are determined by the investigator to be reasonably 
associated with the use of the study drug, should be reported to Perrigo. 
 
8. STATISTICAL ANALYSIS 
The sections that follow highlight sample size determination and the planned analyses for this 
study.  A statistical analysis plan (SAP) will be prepared separately from this protocol which 
gives descriptions of the statistical methods, models, hypotheses and subject populations to be 
analyzed.  The SAP will be completed and approved before locking the database and unblinding 
the study and will serve as a companion to the protocol and the de facto documentation of the 
proposed statistical evaluation.  The SAP will be completed and finalized prior to breaking the 
blind. 
 
8.1 
Statistical Analysis Plan 
8.1.1 Analysis Populations 
The following populations are defined for the purpose of analyses: 
 Intent-to-Treat (ITT) (safety population):  Any subject that was randomized and received 
and used study medication. 
 
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     Page 38 of 51 
 
 Modified Intent-to-Treat (mITT):  Any subject that was randomized, met eligibility criteria, 
received and used study medication, and that has at least one post-baseline efficacy 
assessment. 
 
 Per Protocol (PP):  Any subject: 
- 
Who met eligibility criteria 
- 
Who was randomized and received and used study medication 
- 
Who applied the study medication on Days 1-2 
 
 
- 
Who completed Visit 4/Day 57 (End of Study/Early Termination Visit) within 
window OR was discontinued from the study 
 
. 
- 
Without significant protocol violations that could have interfered with the 
administration of the treatment or the precise evaluation of treatment efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.2 Planned Analysis 
All subjects who received study medication will be evaluated for safety. The efficacy analysis 
will be conducted on both the PP and the mITT subject populations.  Two-sided hypothesis 
testing will be conducted for tests.  Resulting p-values less than 0.05 will be considered 
statistically significant.  No adjustments of p-values for multiple comparisons will be made.  No 
interim analyses are planned.  SAS software will be used for all data analyses and tabulations. 
 
The treatment response will be summarized by treatment group for the end-of-study 
evaluation. The primary efficacy endpoints will be the proportion of subjects with clinical 
response of success defined as complete clearance (absence) of all clinically visible Actinic 
Keratosis lesions identified at the Baseline visit and no new Actinic Keratosis lesions in the 
treatment area at Visit 4/Day 57.  
 
 
 
. 
 
8.1.3 Sample Size Considerations 
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8.1.4 Efficacy Measures and Analysis 
Clinical endpoints 
The primary efficacy measure will be the proportion of subjects with clinical response of 
success defined as complete clearance (absence) of all clinically visible Actinic Keratosis lesions 
identified at the baseline visit and no new Actinic Keratosis lesions in the treatment area at Visit 
4/Day 57.  
 
Equivalent efficacy 
 
For the proportion of subjects with clinical success, the Test treatment will be considered to be 
therapeutically equivalent to the Reference treatment if the 90% confidence interval on the 
difference between Test and the Reference proportions is contained within the interval –20% 
to +20%.  The confidence interval will be constructed using Wald’s method with Yates’ 
continuity correction.  
 
 
 
 
Superiority 
Superiority will be demonstrated if both the active treatments (Test and Reference) are shown 
to be superior to the vehicle.  
 
The proportion of subjects with clinical success for each active treatment will be compared to 
that of the Vehicle using a Z-test with Yates’ continuity correction. 
 
All hypothesis tests will be two-sided at a significance level of α = 0.05, except confidence 
intervals which will be based on α = 0.10 (i.e. 90% coverage).  
 
. 
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     Page 40 of 51 
 
 
8.1.5 Safety and Adverse Events Analysis 
The frequency and percent of subjects with adverse events will be summarized by MedDRA 
(Version 15.1) system organ class and preferred term and by severity and relationship to study 
drug for all three treatment groups.  The adverse events reported by at least five percent of the 
subjects in any treatment group will also be tabulated. The comparable safety of the Test and 
Reference treatments will be evaluated by statistical comparison of the proportion of subjects 
who reported any adverse events.  The test and reference treatments’ frequency and 
distribution of application site reactions of erythema, flaking/scaling, crusting, swelling, 
vesiculation/postulation, and erosion/ulceration will be summarized and compared 
descriptively.  Safety comparisons will be performed only for the safety intent-to-treat 
population. 
 
8.2 
Comparability of Subjects at Baseline 
The statistical significance of any treatment group difference in the distribution of categorical 
variables such as gender will be tested using Cochran–Mantel–Haenszel (CMH) test for general 
association adjusted for site.   Continuous variables, such as age, will be analyzed using a two-
way analysis of variance (ANOVA) model with site and treatment as a fixed effect. 
 
9. CONSENT/ASSENT CONSIDERATIONS AND PROCEDURES 
It will be made clear to the subject that, for the purposes of the study, they are consenting only 
for topical application of medication or vehicle.  Investigators may discuss the availability of the 
study and the possibility for entry with a potential subject without first obtaining 
consent/assent. However, informed consent/assent must be obtained and documented prior to 
initiation of any procedures that are performed solely for the purpose of determining eligibility 
for research, including withdrawal from current medication(s).  When this is done in 
anticipation of, or in preparation for, the research, it is considered to be part of the research. 
 
The study must be approved in writing by an appropriate IRB as defined by FDA regulations.  A 
copy of the Letter of Approval from the IRB, which also contains specific identification of the 
documents approved, must be received by Perrigo prior to study commencement. 
 
Periodic status reports must be submitted to the IRB at least annually as required by the site’s 
IRB, as well as notification of completion of the study and a final report within three months of 
study completion or termination.  A copy of all reports submitted to the IRB must be sent to 
Perrigo. 
 
The investigator(s) has both ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the protocol.  This shall be 
documented on a written informed consent/assent form, which shall be approved by the same 
Institutional Review Board (IRB) responsible for approval of this protocol.  Each informed 
consent/assent form shall include the elements required by FDA regulations in 21 CFR Part 50.  
The investigator agrees to obtain approval from Perrigo of any written informed consent/assent 
form used in the study, preferably prior to submission to the IRB. 
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Once the appropriate essential information has been provided to the subject and fully 
explained by the investigators (or a qualified designee) and it is felt that the subject 
understands the implications of participating, the IRB-approved written informed 
consent/assent form shall be signed by the subject (or their parent/legally authorized 
representative) and the person obtaining consent/assent (investigator or designee).  The 
subject shall be given a copy of the signed informed consent/assent form and the investigator 
shall keep the original on file. 
 
If the subject fails to meet the inclusion/exclusion criteria at the conclusion of the screening 
phase, the subject will be withdrawn from screening.  In the event that the subject is re-
screened for study participation, a new informed consent/assent form must be signed. 
 
9.1 Subject Confidentiality 
All participants are concerned for the individual subject’s privacy and, therefore, all subject 
data will be identified only by a subject identification number and subject initials.  However, in 
compliance with federal guidelines regarding the monitoring of clinical studies and in fulfillment 
of his/her obligations to Perrigo, it is required that the investigator permit the study monitor, a 
Perrigo authorized representative, and/or FDA representative to review that portion of the 
subject’s medical record that is directly related to the study.  This shall include all study relevant 
documentation including subject medical histories to verify eligibility, laboratory test result 
reports to verify transcription accuracy, admission/discharge summaries for hospital stays 
occurring while the subject is enrolled in the study and autopsy reports for deaths occurring 
during the study. 
 
As part of the required content of informed consent/assent, the subject must be informed that 
his/her medical chart may be reviewed by Perrigo, Perrigo authorized representative, or a 
representative of the FDA.  Should access to the medical record require a separate waiver or 
authorization, it is the investigator’s responsibility to obtain such permission from the subject in 
writing before the subject is entered into the study. 
 
To preserve the subject's confidentiality, the data collected will be available only to the 
investigators of the study, their support staff, Perrigo, and possibly the FDA. 
 
All reports and communications relating to the subject in the study will identify each subject 
only by the subject’s initials and by the subject number.  The investigator agrees to furnish 
Perrigo with complete subject identification, if necessary on a confidential follow-up form, 
which will be used for the purpose of a long-term follow-up, if needed.  This will be treated with 
strict adherence to professional standards of confidentiality and will be filed at Perrigo under 
adequate security and restricted accessibility. 
 
10. RECORDS MANAGEMENT 
10.1 
Data Collection 
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Database set-up will be performed by 
 in collaboration with the Electronic Data Capture 
(EDC) vendor, using an appropriate fully validated, 21 CFR Part 11 compliant Electronic Data 
Capture (EDC) system. eCRFs will be provided to each site via a secured web link. All applicable 
study data collected on each subject will be recorded by approved site personnel into the eCRF.  
Only authorized site personnel will be able to enter/modify/correct data to the eCRF. 
Approved staff at 
 will verify all data entered into eCRFs for completeness and accuracy 
with reference to the source documents and records and will issue manual data queries to 
correct missing data or discrepancies found against the source within the EDC system. 
Data validation will consist of automated and manual edit checks that are created directly into 
EDC. Automated edit checks will be executed on all data points defined and documented by the 
study team and data management. Study metrics will be reported from the EDC system. 
After all data have been verified by approved staff at 
, an Investigator or Sub-
Investigator (listed on Form FDA 1572) is required to review and approve all eCRFs prior to 
database lock and breaking of the blind.  
After database lock, each site will be provided with a CD that will include the eCRF data from 
their site for local archival purposes. 
Quality assurance verification via a 10% database audit of eCRF data will be conducted before 
the treatment assignment code is broken. 
 
10.2 Source Documents 
Source documents are defined as the results of original observations and activities of a clinical 
investigation.  Source documents will include, but are not limited to, progress notes and 
screening logs.  All source documents pertaining to this study will be maintained by the 
investigators and made available for inspection by authorized persons.  The original signed 
informed consent form for each participating subject shall be filed with records kept by the 
investigators and a copy given to the subject. 
 
10.3 File Management at the Study Site 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with Section 8 of the International Conference on Harmonization (ICH) Guideline for 
Good Clinical Practices (GCP). 
 
10.4 Records Retention at the Study Site 
FDA regulations require all investigators participating in clinical drug studies to maintain 
detailed clinical data for one of the following periods: 
 
a) A period of at least two years following the date on which a New Drug Application is 
approved by the FDA; 
b) A period of two years after Perrigo New York notifies the investigator that no further 
application is to be filed with the FDA. 
 
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The investigator must not dispose of any records relevant to this study without either (1) 
written permission from Perrigo New York or (2) providing an opportunity for Perrigo to collect 
such records.  The investigator shall take responsibility for maintaining adequate and accurate 
electronic or hard copy source documents of all observations and data generated during this 
study, including any data clarification forms (DCFs) received from Perrigo.  Such documentation 
is subject to inspection by Perrigo and the FDA. 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Monitoring 
Perrigo has ethical, legal and scientific obligations to carefully follow this study in a detailed and 
orderly manner in accordance with established research principles and FDA regulations.  All 
medical records (source documents) of the subjects participating in this study must be 
presented for review and verification of eCRFs. 
 
11.2 
Auditing 
Perrigo (or representative) may conduct audits at the study center(s).  Audits will include, but 
are not be limited to, drug supply, presence of required documents, the informed consent 
process, and comparison of case report forms with source documents.  The investigator agrees 
to participate with audits conducted at a reasonable time in a reasonable manner. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study.  The 
investigator should contact Perrigo New York immediately if notified of such an audit, and must 
fully cooperate with the audits conducted at a reasonable time in a reasonable manner. 
12. ETHICS AND RESPONSIBILITY 
This study must be conducted in compliance with the protocol, the United States Food and 
Drug Administration (FDA) regulations, any other countries regulations, and ICH GCP 
Guidelines. 
 
13. USE OF INFORMATION AND PUBLICATION 
All information supplied by Perrigo in connection with this study and not previously published, 
is considered confidential information.  This information includes, but is not limited to, data, 
materials (i.e. the clinical protocol, eCRFs), equipment, experience (whether of a scientific, 
technical, engineering, operational, or commercial nature), designs, specifications, know-how, 
product uses, processes, formulae, costs, financial data, marketing plans and direct selling 
systems, customer lists and technical and commercial information relating to customers or 
business projections used by Perrigo in its business.  Any data, inventions, or discoveries 
collected or developed, as a result of this study is considered confidential.  This confidential 
information shall remain the sole property of Perrigo shall not be disclosed to any unauthorized 
person or used in any unauthorized manner without written consent of Perrigo and shall not be 
used except in the performance of the study.  As such, confidential study-related information 
should not be included on the curriculum vitae of any participating investigator or study staff. 
 
The information developed during the course of this clinical study is also considered 
confidential, and will be used by Perrigo in connection with the development of the drug.  The 
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information may be disclosed as deemed necessary by Perrigo.  To allow the use of the 
information derived from this clinical study, the investigator is obliged to provide Perrigo with 
complete test results and all data developed in the study.  The information obtained during this 
study may be made available to other investigators who are conducting similar studies. 
 
The investigator shall not make any publication related to this study without the express 
written permission of Perrigo.  
 
 
 
 
 
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INVESTIGATOR AGREEMENT 
 
PROTOCOL NUMBER:  PRG-NY-15-002  
 
PROTOCOL TITLE: 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-
Group Study to Compare Perrigo New York, Inc.’s Ingenol Mebutate 
Topical Gel 0.05% to Leo Pharma Inc. Picato® Topical Gel 0.05% (Ingenol 
Mebutate Topical Gel 0.05%), and Both Active Treatments to a Vehicle 
Control in the Treatment of Actinic Keratosis on The Trunk and 
Extremities  
 
 
 
I have carefully read the foregoing protocol and agree that it contains all the necessary 
information for conducting this study safely.  I will conduct this study in strict accordance with 
this protocol, ICH Guidelines for Good Clinical Practices, the Code of Federal Regulations, the 
Health Insurance Portability and Accountability Act (HIPAA) and any local regulatory 
requirements and will attempt to complete the study within the time designated.  I will provide 
access to copies of the protocol and all other information relating to pre-clinical and prior 
clinical experience submitted by Perrigo to all personnel responsible to me who participate in 
the study.  I will discuss this information with them to assure that they are adequately informed 
regarding the drug and conduct of the study.  I agree to keep records on all subject information 
in accordance with FDA regulations. 
 
 
 
 
 
 
 
   Principal Investigator’s Printed Name 
 
 
 
 
 
 
 
   Principal Investigator’s Signature 
 
 
 
 
 
 
 
   Date 
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APPENDICES 
Appendix A: Study Personnel Contacts 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
     
  
     
 
 
 
 
 
 
 
 
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Appendix C:  Trunk and Extremities   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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REFERENCES 
 
1. Summary Basis of Approval Picato® Topical Gel (Ingenol Mebutate Gel). 
2. Package insert Picato® Topical Gel (Ingenol Mebutate Gel) dated Jan 2011, revised 01/2012. 
3. www.picato.com 
4. Salassche SJ. Epidemiology of Actinic Keratosis and Squamous Cell Carcinoma. J Am Acam 
Dermatol. 2000, 42 (1Pt 2): 4  
5. Epidemiology, Natural History, and Diagnosis of Actinic Keratosis  
http://www. uptodate.com/Contents/epidemiology-natural-history-and-diagnostic-of-actinic-
keratosis 
6. Actinic Keratosis- Topic Overview 
http://www.webmd.com/skin-problems-and-to-treatments/tc/actinic-keratosis-topic-overview. 
7. Berman B, Bienstock L, Kuritsky L, Mayeaux E.J, Tyring S. Actinic Keratosis: Sequela and 
Treatments.  J Family Practice. May 2006: 1-8 
8. McIntyre W, Downs R. M, Bedwell S. Treatment Options for Actinic Keratosis. American Family 
Physician Web Site at www.aafp.org/afp. 2007 
9. http://aik-friendsnfamily.blogspot.com/2014/12/human-body-diagram-kids.html 
 
 
 
 
 
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