Clinical trial NCT02446223
Conditions: Actinic Keratosis
Keywords: Actinic Keratosis AKs Chest Pre-Cancer
Sponsor: Goldman, Butterwick, Fitzpatrick and Groff
Start date: 2015-01-01; Completion date: 2016-09-01
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Evaluate the Efficacy and Safety of Large-Scale Field-Directed Topical Therapy of Actinic Keratosis of the Chest w/Ingenol Mebutate 0.015%

Detailed description:
This will be an open-label study to evaluate the efficacy and safety of ingenol mebutate gel, 0.015% used in topical therapy of actinic keratosis on the chest. Subjects that present with 4 or more actinic keratosis in one continuous 100cm2 area of the chest and meet all inclusion/exclusion criteria will be enrolled into this study.

Treatment with the investigational product (IP) will be applied for three continuous days. The investigator will guide application of the IP in-office at Day 0 and the subject will be instructed to self-administer the IP at Days 1 and 2. Follow-up visits will be scheduled at Days 1, 3, 10, 17, 24 and 59.

Prior to treatment and at each visit, the investigator will assess the subject's treatment area for lesion counts and at follow up visits 4, 5, 6 and 7 evaluation of clearance. Pre-treatment photography will also be collected at baseline and at each follow up visit.

Arms: arm 1: None
Interventions: intervention 1: Inggenol Mebutate 0.015%
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
PI: Mitchel P. Goldman, MD.  
                                                   Version Date 17MAR2014 
LEO Pharma, Inc. 
 
Protocol: PICATO-2013-01 
A PILOT PROSPECTIVE CLINICAL TRIAL TO EVALUATE 
THE EFFICACY AND SAFETY OF LARGE-SCALE FIELD-
DIRECTED TOPICAL THERAPY OF ACTINIC KERATOSIS OF 
THE CHEST WITH INGENOL MEBUTATE 0.015% 
 
Protocol Number: PICATO-2013-01 
 
 
PRINCIPAL INVESTIGATOR: Mitchel P. Goldman, MD 
 
 
 
 
Dermatology Cosmetic Laser Medical Associates of La Jolla, Inc. 
 
 
 
 
9339 Genesee Ave, Ste 300 
 
 
 
 
San Diego, CA 92121 
 
 
 
 
(858) 657-1004 
 
 
 
 
www.clderm.com 
 
 
PROTOCOL VERSION: 
March 17, 2014 – Final 
 
 
 
 
 
 
The study will be conducted according to the protocol and in compliance with International Conference of 
Harmonization Good Clinical Practice Guidelines and all other applicable regulatory requirements. 
CONFIDENTIALITY STATEMENT 
THE INFORMATION PROVIDED IN THIS STUDY PROTOCOL IS INTENDED FOR REVIEW BY 
THE PRINCIPAL INVESTIGATOR, ALL RESEARCH RELATED PERSONNEL, ETHICS 
COMMITTEE(S) AND HEALTH AUTHORITIES. INFORMATION PROVIDED AND CAPTURED 
IN THIS PROTOCOL IS STRICTLY CONFIDENTIAL AND WILL ONLY BE DISCLOSED WITH 
WRITTEN CONSENT FROM THE SPONSORS. 
 
 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 2 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
TABLE OF CONTENTS 
 
PAGE 
PROTOCOL SIGNATURE PAGE  ...............................................................................................  
4 
PROTOCOL SYNOPSIS  ...............................................................................................................  
5 
1. BACKGROUND AND RATIONALE  ...............................................................................................  
6 
2. STUDY OBJECTIVE .....................................................................................................................  
7 
3. STUDY DESIGN ............................................................................................................................  
7 
4. STUDY POPULATION  
4.1 
NUMBER  .........................................................................................................................  
8 
4.2 
INCLUSION CRITERIA  .....................................................................................................  
8 
4.3 
EXCLUSION CRITERIA  ....................................................................................................  
8 
5. MATERIALS AND METHODS  
5.1 
PRODUCT ........................................................................................................................  
9 
5.2 
APPLICATION OF THE STUDY PRODUCT .........................................................................  
9 
6. CLINICAL ASSESSMENTS  
6.1 
SCHEDULE OF VISITS ......................................................................................................  10 
6.2 
STUDY PERIOD ................................................................................................................  11 
6.3 
STUDY ENDPOINT CRITERIA ...........................................................................................  13 
A. Subject Completion of Study ................................................................................  13 
B. Subject Discontinuation ........................................................................................  13 
C. Study Termination ................................................................................................  13 
        6.4    POTENTIAL RISKS AND BENEFITS  ....................................................................................  13 
A. Potential Risks  .....................................................................................................  13 
B. Adverse Events and Reporting .............................................................................  14 
C. Unknown Unforeseeable Risks ............................................................................  14 
D. Benefits  ................................................................................................................  15 
7. DATA HANDLING AND RECORD KEEPING  
7.1 
DATA HANDLING & RECORD KEEPING  .........................................................................  15 
8. REGULATORY OBLIGATIONS  ....................................................................................................  15 
8.1 
INSTITUTIONAL REVIEW BOARD ....................................................................................  15 
8.2 
PROTOCOL  .....................................................................................................................  15 
8.3 
INFORMED CONSENT ......................................................................................................  15 
8.4 
PROTOCOL AND INFORMED CONSENT FORM (ICF) CHANGES  ......................................  15 
8.5 
STUDY PRODUCT ACCOUNTABILITY  .............................................................................  16 
8.6 
STUDY MONITORING  .....................................................................................................  16 
9. CONFIDENTIALITY OF RECORDS  ..............................................................................................  16 
10. DELEGATION OF RESPONSIBILITIES  ........................................................................................  16 
11. DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS  ...........................................................  16 
12. Statistical Hypotheses and Methods of Analyses 
12.1 STATISTICAL HYPOTHESES .............................................................................................  16 
12.2 STATISTICAL METHODS  .................................................................................................  17 
 
A. STATISTICAL METHODS  ............................................................................................  17 
 
B. EFFICACY ANALYSIS   .................................................................................................  17 
 
C. SATISFACTION ANALYSIS   ..........................................................................................  17 
 
D. SAFETY ANALYSIS   ....................................................................................................  17 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 3 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
13. References ..................................................................................................................................  18 
APPENDICES: 
 
APPENDIX A (PHOTOS) ................................................................................................................  19 
APPENDIX B (Modified Alexiades-Armenakas Comprehensive Grading Scale of Skin Aging)…………... ..    20 
 
APPENDIX C (SUBJECT’S TSQM AND SATISFACTION OF IMPROVEMENT SCALE) ...........................  21 
 
APPENDIX D (SUBJECTS TAKE HOME INSTRUCTION SHEET) ...........................................................  26 
 
APPENDIX E (LOCAL SKIN RESPONSE GRADING SCALE) .................................................................  27 
 
APPENDIX F (RESPONSIBILITIES OF THE INVESTIGATOR) ...............................................................  29 
APPENDIX G (PICATO PACKAGE INSERT)……………..…………………………………………………31 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 4 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
PROTOCOL SIGNATURE PAGE 
 
 
PROTOCOL TITLE: 
A PILOT PROSPECTIVE CLINICAL TRIAL TO EVALUATE THE 
EFFICACY AND SAFETY OF LARGE-SCALE FIELD-DIRECTED 
TOPICAL THERAPY OF ACTINIC KERATOSIS OF THE CHEST 
WITH INGENOL MEBUTATE 0.015% 
 
PROTOCOL NUMBER:  
PICATO-2013-01 
 
 
 
PRINCIPAL INVESTIGATOR: Mitchel P. Goldman, MD 
 
 
 
 
Dermatology Cosmetic Laser Medical Associates of La Jolla, Inc. 
 
 
 
 
9339 Genesee Ave, Suite 300 
 
 
 
 
San Diego, CA 92121 
 
 
 
 
(858) 657-1002 
 
 
 
 
www.clderm.com 
 
 
PROTOCOL VERSION: 
March 17, 2014 – Final 
 
 
 
 
APPROVED BY: 
 
 
_________________________________________ 
_____/_____/_____ 
 
Mitchel P. Goldman, MD 
 
 
 
Date 
 
 
Medical Director 
Dermatology Cosmetic Laser Medical Associates of La Jolla, Inc. 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 5 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
PROTOCOL SYNOPSIS 
 
Protocol Title:  A Pilot Prospective Clinical Trial to Evaluate the Efficacy and Safety of Large-Scale, 
Field-Directed Topical Therapy of Actinic Keratosis of the Chest with Ingenol Mebutate 0.015% 
 
Protocol Number:  PICATO-2013-01 
 
Principal Investigator:  Mitchel P. Goldman, MD 
 
Study Duration:  Seven (7) scheduled in-office visits over a 59-day period. Visits will be conducted at 
days 0, 1, 3, 10, 17, 24 and 59. 
 
Study Population:  Twenty (23) eligible male or female subjects 18 years of age or older with the 
presence of 4 or more actinic keratosis in one continuous 100cm2 area of the chest. 
 
Investigational Product (IP):  Ingenol mebutate gel, 0.015% (Picato®, LEO Pharma, Parsippany, NJ). 
 
Study Design: This will be an open-label study to evaluate the efficacy and safety of ingenol mebutate 
gel, 0.015% used as topical therapy for actinic keratosis on the chest. Subjects that present with 4 or more 
actinic keratosis in one continuous 100cm2 area of the chest and meet all inclusion/exclusion criteria will 
be enrolled into this study. 
 
Treatment with the investigational product (IP) will be applied for three continuous days. The investigator 
will guide application of the IP in-office at Day 0 and the subject will be instructed to self-administer the 
IP at Days 1 and 2. Follow-up visits will be scheduled at Days 1, 3, 10, 17, 24 and 59. 
 
Prior to treatment the investigator will assess the subject’s treatment area for lesion counts and 
appearance of photodamage/skin aging.  At follow-up visits, subjects will be evaluated for lesion 
clearance at (visits 4, 5, 6 and 7), local skin reaction and changes in appearance of photodamage/skin 
aging using defined scales. 
 
Photography will also be collected pre-treatment at Baseline and at each follow up visit. 
 
During the treatment phase, application of the study drug will be administered at days 0 (investigator 
guided), 1 and 2 (home application by subject). For the follow-up phase, follow-up visits will be 
conducted at days 1, 3, 10, 17, 24 and 59. 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 6 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
1. BACKROUND AND RATIONALE 
 
Actinic keratosis are common, premalignant lesions in light-skinned individuals found on the face, chest, 
and upper extremities that result from chronic, cumulative ultraviolet exposure and over time may 
progress to invasive squamous cell carcinoma [1,2]. Lesion-directed treatment, usually via cryosurgery, is 
limited by the potential for scarring and significant recurrence rates [2,3]. Topical, field-directed therapies 
(imiquimod, fluorouracil, and diclofenac) allow for the treatment of entire photodamaged areas, targeting 
clinically visible and subclinical lesions concurrently. However, the need for a prolonged course of 
treatment associated with sustained local reactions and poor patient compliance has classically limited the 
effectiveness of topical, field-directed therapies [2,4]. 
   
Ingenol mebutate gel (Picato, Leo Pharma, Parsippany, NJ) derived from the sap of the Euphorbia peplus 
plant is a novel topical, field-directed therapy for actinic keratosis in facial and non-facial sites [2,4-7]. 
The destruction of actinic keratosis is mediated by rapid lesion necrosis and subsequent lesion-specific, 
neutrophil-mediated, antibody-dependent cellular cytotoxicity [6]. Ingenol mebutate gel 0.015% applied 
once daily to the face for 3 consecutive days is an effective field-directed treatment for actinic keratosis 
demonstrating clearance rates comparable to other topical therapies with the advantage of rapid resolution 
of local cutaneous reactions and high patient compliance [4,5]. The local cutaneous reactions in the 
largest randomized-controlled trial of ingenol mebutate gel for actinic keratosis to date peaked on day 4 
(application on days 1-3), were nearly resolved by day 15, and returned to baseline by day 29 [2]. 
 
Field-directed application of ingenol mebutate to contiguous areas is essential to target both clinically 
observable and subclinical lesions. Prior studies have only treated areas as large as 25 cm2 [8]. We aim to 
evaluate the efficacy and safety of ingenol mebutate applied to contiguous areas of the chest as large of 
100 cm2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 7 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
2. STUDY OBJECTIVE 
 
The primary efficacy endpoint will be complete clearance of all clinically visible AKs and no 
development of any new AKs on day 59. Lesion clearance will be determined on day 59 (visit 7) by 
comparing pretreatment lesion count with current lesion count on day 59, with primary efficacy endpoint 
being clearance of all lesions in treatment field and no growth of new lesions.   
 
Secondary efficacy endpoints (all at day 59) will include stratification of patients into groups based on 
percent clearance. If patient is not found to have 100% clearance, total number of lesions present in the 
treatment field will be counted and percent clearance will be calculated.  The percent clearance 
calculated, will then be used to defined what patients response as defined by defined percentage grading 
scale: complete clearance (no clinically evident residual disease and no new lesions), partial clearance 
(≥75% lesion clearance), mild clearance (10 to 74% lesion clearance), minimal to no clearance (<10%), 
worsened (clinically observable growth), or unable to be assessed.  
 
The number of clinically observable AKs within the treatment area will be documented at baseline and at 
follow-up visits 2, 3, 4, 5, 6 and 7.  
 
Subject satisfaction will also be assessed at visits 4, 5, 6 and 7 with a 7-point scale (0= Completely 
Dissatisfied, 1= Moderately Dissatisfied, 2= Mildly Dissatisfied, 3= Neither Dissatisfied Nor Satisfied 
(Neutral), 4= Mildly Satisfied, 5= Moderately Satisfied, 6= Completely Satisfied). 
 
Secondary efficacy endpoints will also grade changes in photodamaged/skin aging in the following 
categories: Dyschromia, Erythema (E), Telangiectasia (T), Keratosis, Texture and Rhytides as compared 
to baseline and follow-up visits 6 and 7 using an 8-point grading scale with 0 indicating no presence and 4 
indicating a severe presence. (Please see attached Modified Alexiades-Armenakas Comprehensive 
Grading Scale of Skin Aging for reference.)  
 
Safety endpoints will be documented at each subject visit by the investigator. Local skin reactions will be 
evaluated quantitatively with the use of a clearly defined grading scale with a photographic guide to 
ensure consistent recording. The scale will range from 0 to 4 (based on increasing severity) for the 
following criteria: erythema, flaking or scaling, crusting, swelling, vesiculation or pustulation, and 
erosion or ulceration. Other adverse events and any evidence of scarring in the treatment field will also be 
assessed and documented at each subject visit. 
 
Demographic data and study variables will be analyzed by appropriate statistical methods.   
 
3. STUDY DESIGN 
 
This will be an open-label study to evaluate the efficacy and safety of ingenol mebutate gel, 0.015% used 
in topical therapy of actinic keratosis on the chest. Subjects that present with 4 or more actinic keratosis in 
one continuous 100cm2 area of the chest and meet all inclusion/exclusion criteria will be enrolled into this 
study. 
 
Treatment with the investigational product (IP) will be applied for three continuous days. The investigator 
will guide application of the IP in-office at Day 0 and the subject will be instructed to self-administer the 
IP at Days 1 and 2. Follow-up visits will be scheduled at Days 1, 3, 10, 17, 24 and 59. 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 8 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
 
Prior to treatment and at each visit, the investigator will assess the subject’s treatment area for lesion 
counts and at follow up visits 4, 5, 6 and 7 evaluation of clearance. Pre-treatment photography will also 
be collected at baseline and at each follow up visit.  
 
4. STUDY POPULATION 
 
 
4.1 NUMBER 
 
Twenty (23) eligible Male or female subjects 18 years of age or older with the presence of 4 or 
more actinic keratosis in one continuous 100cm2 area of the chest. 
 
4.2 INCLUSION CRITERIA 
 
 
1. Male or female of at least 18 years of age. 
2. Subjects willing to comply with study requirements. 
3. The presence of four or more clinically typical actinic keratosis within one contiguous area of 
the chest that is 100cm2. 
4. For female subjects of childbearing potential willing to use an acceptable form of birth 
control during the entire course of the study. All systemic birth control measures must be in 
consistent use at least 30 days prior to entry into the study. 
 
A female is considered NOT to be of childbearing potential if she is postmenopausal for 
at least one (1) year, without a uterus, without both ovaries or has had a bilateral tubal 
ligation. 
 
Acceptable methods of birth control are: oral contraceptives, contraceptive 
patches/rings/implants Norplant, Depo-Provera, double-barrier methods (e.g. condoms 
and spermicide) and abstinence. 
 
5. Subjects willing to refrain from the use of topical products containing alpha-hydroxy acids, 
retinoic acid, retinol, salicylic acid, and vitamins C/D (or their derivatives) in the treatment 
area 7 Days prior to and during the entire study period 
 
4.3 EXCLUSION CRITERIA 
 
1. Known hypersensitivity, prior allergic reaction, or prior chest treatment with ingenol 
mebutate gel. 
2. Treatment area containing hypertrophic or hyperkeratotic lesions, cutaneous horns or lesions 
that had previously not responded to other standard treatments. 
3. Presence of any skin condition or disease that might interfere with the diagnosis and 
evaluation of study parameters (i.e., atopic dermatitis, eczema, psoriasis, seborrheic 
dermatitis). 
4. Subjects receiving ablative laser treatments on their chest must have discontinued the 
treatment at least 6 months prior to entering the study. 
5. Subjects receiving Intense Pulse Light treatments on their chest must have discontinued the 
treatment at least 30 days prior to entering the study. 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 9 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
6. Within 3 months of study entry treatments that may interfere with evaluation of the 
treatment area (e.g. other topical therapies for actinic keratosis of the chest, topical 
corticosteroids, topical retinoids, ultraviolet B phototherapy, or immunosuppressive, 
immunomodulating, or cytotoxic medications) or expected use of any of the above-mentioned 
therapies in the treatment area listed during the duration of the study. 
7. Within 3 months of study entry topical treatment in the treatment area for actinic keratosis 
including, but not limited to imiquimond, 5- fluorouracil, diclofenac or liquid nitrogen. 
8. Within 6 months of study entry treatments with Poly-L-lactic acid (PLLA; Sculptra 
Aesthetic) that may interfere with the evaluation of the treatment area. 
9. Within 7 days of study entry use of self-tanners, excessive exposure to sunlight or artificial 
UV light (e.g.: use of tanning beds/booths and/or sunbathing) or expectations of any listed 
during the time of the study within the treatment area. 
10. Any systemic disease that is not yet stabilized for at least six (6) Months prior to entering 
study. 
11. A significant history or current evidence of a medical, psychological or other disorder that, in 
the investigator’s opinion, would interfere with the objectives of the study 
12. Pregnant or nursing women or women planning a pregnancy during the study period. 
13. Any unhealed skin lesions or wounds within the treatment area. 
14. Existence of one (1) or more suspected basal cell carcinoma or squamous cell carcinoma 
within the treatment area. 
15. Current participation or participation within 30 days prior to the start of this study in a 
drug or investigational device research study. 
 
5. MATERIALS AND METHODS 
5.1 PRODUCT 
 
Ingenol Mebutate Picato® gel is an inducer of cell death indicated for the topical 
treatment of Actinic Keratosis 
 
5.2 APPLICATION OF THE STUDY PRODUCT  
At visit 1 Day 0, an Investigator will use placebo samples supplies by LEO Pharma to 
demonstrate to the subject the correct method of application. The Investigator will then watch the 
subject apply the first treatment in office. For subject home product application (See Appendix G) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 10 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
6. SCHEDULE OF EVENTS  
6.1 Schedule of Visits 
VISIT 
1 
2 
3 
4 
5 
6 
7 
DAY 
0 
1 
3 +/-1 
10 +/-2 
17 +/-3 
24 +/-3 
59 +/- 5 
INFORMED CONSENT AND 
PHOTO RELEASE 
X 
 
 
 
 
 
 
INCLUSION/EXCLUSION CRITERIA 
X 
 
 
 
 
 
 
REVIEW MEDICAL HISTORY AND 
CONCURRENT MEDS 
X 
 
 
 
 
 
 
INVESTIGATOR ASSESSMENT OF 
LESION COUNT  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
INVESTIGATOR - EVALUATION OF 
TREATMENT AREA CLEARANCE 
 
 
 
X 
X 
X 
 
X 
INVESTIGATOR LOCAL SKIN 
RESPONSE GRADING  
 
X 
X 
X 
X 
X 
 
X 
INVESTIGATOR - EVALUATION OF 
PHOTODAMAGE 
 
X 
 
 
 
 
 
 
 
 
X 
    
    X 
INVESTIGATOR GUIDED 
APPLICATION OF THE INGENOL 
MEBUTATE (B) 
X 
 
 
 
 
 
 
PHOTOGRAPHS(A) 
X(A) 
X 
X 
X 
X 
X 
X 
PREGNANCY TEST 
(IF APPLICABLE) 
   
    X 
 
 
 
 
 
 
     X 
SUBJECT TSQM QUESTIONNAIRE  
 
 
X 
 
 
 
      
     X 
SUBJECT SATISFACTION 
QUESTIONNAIRE 
 
 
 
X 
X 
X 
     X 
DISPENSATION OF INGENOL 
MEBUTATE AND SUBJECT 
INSTRUCTIONS FOR HOME 
APPLICATION(C) 
X(C) 
 
 
 
 
 
 
 
SUBJECT REVIEW OF HOME 
INGENOL MEBUTATE 
APPLICATION  
 
 
X 
X 
 
 
 
 
REVIEW OF ADVERSE EVENTS 
 
X 
X 
X 
X 
X 
      X 
REVIEW OF CONCOMMITANT 
MEDICATIONS 
 
    
    X 
 
X 
 
X 
 
X 
    
X 
 
      X 
A. One (1) photo to be done Pre-treatment, Post-marking of treatment area. 
B. See Section 5.3 
C. See Appendix D 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 11 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
6.2 Study Period 
Screening (Baseline, Day 0) 
A prospective subject is to be examined to determine if they qualify for entry into the study.  This 
initial examination will include: 
 Obtain written Informed Consent, HIPPA and photographic release 
 Review of Inclusions Exclusions Criteria 
 Review of Medical History and Concomitant Medications  
 Investigator Assessment of Lesion Count 
 Investigator - Evaluation of Photodamage 
 Urine Pregnancy Test (if applicable) 
 Photography (Pre-Treatment Application - after markings)  
 Investigator  guided Application of the ingenol Mebutate 
 Dispensation of Ingenol Mebutate and Subject Instructions for home application 
 
Each qualified subject as they are enrolled in to the trial will be sequentially assigned a Subject ID 
number. Each subject will be instructed to return to the investigator's office, for follow-up visits at days 1, 
3, 10, 17, 24 and 59 following the baseline visit. 
The subject will be instructed to return in 1 Day for their next scheduled visit 
Visit 2 (Day 1) This follow-up examination will include: 
 Investigator Assessment of Lesion Count  
 Investigator Local Skin Response Grading  
 Photography 
 Subject review of home Ingenol Mebutate application 
 Review of Adverse Events  
 Review of Concomitant Medications  
 
The subject will be instructed to return in 3 Days +/- 1 for their next scheduled visit 
Visit 3 (Day 3 +/- 1) This follow-up examination will include: 
 Investigator Assessment of Lesion Count  
 Investigator Local Skin Response Grading  
 Photography 
 Subject TSQM Questionnaire 
 Subject review of home Ingenol Mebutate application 
 Review of Adverse Events  
 Review of Concomitant Medications  
 
The subject will be instructed to return 10 Days +/- 2 From Baseline for their next scheduled visit 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 12 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Visit 4 (Day 10 +/- 2) This follow-up examination will include: 
 Investigator Assessment of Lesion Count  
 Investigator Local Skin Response Grading  
 Investigator - Evaluation of Treatment area Clearance 
 Photography 
  Subject Satisfaction Questionnaire 
 Review of Adverse Events  
 Review of Concomitant Medications  
 
The subject will be instructed to return 17 Days +/- 3 from Baseline for their next scheduled visit 
Visit 5 (Day 17 +/- 3) This follow-up examination will include: 
 Investigator Assessment of Lesion Count  
 Investigator Local Skin Response Grading  
 Investigator - Evaluation of Treatment area Clearance 
 Photography 
  Subject Satisfaction Questionnaire 
 Review of Adverse Events  
 Review of Concomitant Medications 
  
The subject will be instructed to return 24 Days +/-3 from Baseline for their next scheduled visit 
 
Visit 6 (Day 24 +/- 3) This follow-up examination will include: 
 Investigator Assessment of Lesion Count  
 Investigator Local Skin Response Grading  
 Investigator - Evaluation of Treatment area Clearance 
 Investigator - Evaluation of Photodamage 
 Photography 
  Subject Satisfaction Questionnaire 
 Review of Adverse Events  
 Review of Concomitant Medications 
  
The subject will be instructed to return 59 Days +/-5 from Baseline for their next scheduled visit 
Visit 7 (Day 59 +/- 5) - Final Visit 
 Investigator Assessment of Lesion Count  
 Investigator Local Skin Response Grading  
 Investigator - Evaluation of Treatment area Clearance 
 Investigator - Evaluation of Photodamage 
 Urine Pregnancy Test (if applicable) 
 Photography 
 Subject TSQM Questionnaire  
  Subject Satisfaction Questionnaire 
 Review of Adverse Events  
 Review of Concomitant Medications 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 13 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
6.3 STUDY ENDPOINT CRITERIA 
a. 
Subject Completion of Study 
If a subject has completed the final visit (Visit 7) of the study, they are considered to have 
completed the study. 
b. 
Subject Discontinuation 
Each subject may voluntarily discontinue the study at any time they choose.  Subjects who 
cannot complete the study for any reasons (e.g., non-compliance, failure to meet visit schedule, 
etc.) will be discontinued from the study.  These subjects will be asked to return for completion 
of visit 7.  
c. 
Study Termination 
The investigator with appropriate notification may terminate the study.  If, after clinical 
observations, the investigator feels that it may be unwise to continue the study, he or she may 
stop the study. 
6.4 Potential Risks and Benefits 
A.   Possible adverse events from Ingenol Mebutate treatment (during, immediately following 
treatment and possibly several weeks after) 
 
Erythema and inflammatory response  
 
Soreness/Pain 
 
Edema  
 
Infection  
 
Changes in skin pigmentation  
 
Flaking/Scaling 
 
Erosion/Ulceration 
 
Blistering 
 
Pruritus 
 
   B. Serious and/or Adverse Events and Reporting  
A serious adverse event is any untoward medical occurrence, that: 
- 
Results in death; 
-  
is life-threatening; 
- 
requires in-subject hospitalization or prolongation of existing hospitalization; 
- 
Results in persistent or significant disability/incapacity;  
- 
is a congenital anomaly/birth defect; or is an important medical event.  
An unexpected adverse event is any treatment-related adverse event, which is not identified in 
nature, severity, or frequency in current literature on the test product. 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 14 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Any serious adverse event occurring in this study must be reported to the IRB within 24 hours of 
awareness of the event. Initial reports must be made by telephone, followed by the completion of 
a Serious Adverse Event Report and submission by facsimile.    
Throughout the study, subjects will be monitored for signs and symptoms of adverse events.  An 
adverse event is any pathological or unintended change in the structure, function or chemistry of 
the body that occurs during the study, irrespective of causality, including any illness, injury, 
toxicity, sensitivity, or sudden death.  The condition must either not be present pre-study or must 
worsen in either intensity or frequency during the study. 
All adverse events, including serious and treatment related or unexpected adverse events, must 
be recorded by the Investigator. Serious and unexpected device-related adverse events should be 
reported immediately to ThermiAesthetics.   
Subjects who have had a serious adverse event must be followed clinically until all parameters, 
including laboratory values, have either returned to normal or are otherwise explained. 
If death was the outcome of the event on the initial SAE Report, a Follow-up/Final Report, 
including autopsy report, when performed, must be completed. 
C.  Unknown/Unforeseeable Risks 
In addition to the risks listed above, there may be some unknown or infrequent and unforeseeable risks 
associated with Subjects will be informed both verbally and in writing in a timely manner of any new 
information, findings or changes to the way the research will be performed that might influence their 
willingness to continue their participation in this study. 
Pregnancy/Fetal Risks:  The effects of have not been studied in pregnancy and therefore may be 
hazardous.   
If a subject becomes pregnant, the study doctor will refer the subject to seek obstetric care and will 
request to track the pregnancy to term. We will report the pregnancy to the Sponsor and IRB. 
D. Benefits of Ingenol Mebutate 
Ingenol Mebutate is FDA approved for the topical treatments of actinic keratosis. 
7. Data Handling and Record Keeping  
7.1 Data Handling and Record Keeping  
The Investigator must ensure that proper source documentation for all study activities are diligently 
maintained and securely kept.  The Investigator will sign the source documents for completeness, 
accuracy and integrity of the data collected.  The Investigator will maintain reliable study 
Medication/Device dispensing/dosing records and will store study supplies in a secure, locked location. In 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 15 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
addition, the Investigator will ensure that all study-related source documentation will be maintained for a 
period of two years after the conclusion of the study.   
8. Regulatory Obligations 
8.1 Institutional Review Board 
The study protocol, informed consent forms (all versions), and any specific advertising will be submitted 
to and approved by the Investigational Review Board (IRB) before the start of the study.  A form must be 
signed by the chairman or designee of the IRB noting the approvals.  This notification will be provided to 
the sponsor. 
8.2 Protocol 
Protocols will be noted as approved by the Investigator by placement of his signature on the Investigator’s 
Signature Page.  Copies of the IRB approved protocol and informed consents will be provided to the 
Sponsor. 
8.3 Informed Consent 
An Informed Consent (IC) that includes all of the relevant elements currently required by FDA or state 
regulations will be provided to each prospective study subject at screening before enrollment into the 
study.  The type and method of study, any potential or possible hazards, and the subject’s right to 
withdraw from the study at any time will be explained to the subjects by the Investigator and/or the  
designee.  Once the Investigator is assured that an individual candidate understands the implications of 
participating in this study, the subject will be asked to give consent by signing and dating in the 
appropriate areas of the Informed Consent form.  The Investigator and/or Designee will also sign and date 
the form where indicated.  A copy of the IRB approved IC form will also be provided to the Sponsor. 
8.4 Protocol and Informed Consent Changes 
Changes to the protocol or Informed Consent form(s) will be implemented as amendments to the original 
document and approved by the IRB.  The approvals will be processed in accordance with the established 
IRB procedures.  Copies of all protocol and IC amendments/revisions, along with letters noting IRB 
approval, will be submitted to the Sponsor, as this may affect safety.  Any addenda, amendment or 
revision that substantially alters the study design or increases potential risk to the subject requires the 
subject’s consent to continue in the study. 
8.5 Investigational Product Accountability 
The Investigational product to be used for this study is the sole property of the Sponsor.  All provided 
products to be used for this study and their receipt, inventory, dispensing, and reconciliation records will 
be maintained in compliance with Federal Regulations. The study supplies will be dispensed by the 
Investigator or designee to qualified study subjects according to established procedures.  Upon 
completion or termination of the study the site will be responsible for retaining all partial and unused 
products under FDA regulations. 
8.6 Study Monitoring 
All monitoring activities are the responsibility of the study doctor.  Monitoring is for the purpose of 
confirming adherence to the protocol and to verify complete and accurate data collection.  The site will be 
responsible for internal verification of data throughout the study.   
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 16 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
9. Confidentiality of Records  
Information about the subject’s health taken during this study may be used and given to others by the 
study coordinators, the medical staff, the respective study center and by the subject’s doctors and their 
other health care providers (together, they are called “providers”). These providers may share health 
information about the subject with the study coordinator. The study coordinator and the providers may 
share that information with: 
- Researchers participating in this Study laboratories conducting tests for this Study; 
- The U.S. Food and Drug Administration (FDA) 
- Department of Health and Human Services (DHHS) agencies; 
- Other U.S. and foreign government agencies that watch over quality, safety, and effectiveness 
of research 
 
10. Delegation of Responsibilities 
The Investigator should ensure that all persons assisting with the trial are qualified and are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-related 
duties and functions.  The investigator should maintain a list of Co-Investigators and other appropriately 
qualified persons to whom he has delegated significant trial-related duties. 
11. Direct Access to Source Data and Documents 
The Investigator must ensure that institutional regulations, the Informed Consent Form, and the HIPAA 
Authorization clearly permit study-related monitoring, audits, REB review, and regulatory inspections 
providing direct access to source data and documents. 
12. 
Statistical Hypotheses and Methods of Analyses 
12.1 
Statistical Hypotheses  
The Null Hypothesis:  There are no differences in number of actinic keratosis in treatment field after 
treatment with ingenol mebutate. 
Alternative Hypothesis: The number of actinic keratosis in the treatment field is decreased after treatment 
with ingenol mebutate. 
12.2 Statistical Methods 
A. Statistical Methods 
All statistical tests will be two-sided and interpreted at a 5% significance level.  Descriptive statistics (i.e., 
mean, standard deviation, etc.) will be provided for all continuous variables, frequencies for all 
categorical variables. 
In order to track changes for individual variables across all relevant visits, single-factor Analysis of 
Variance (ANOVA) tests will be used, while comparisons between two individual visits will be done 
using two-sample t-tests assuming equal variance. 
P-values <0.05 will be considered clinically significant. 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 17 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
B. Efficacy Analyses 
i. 
The primary analyses of efficacy will be based on the change in investigator assessed lesion count from 
Baseline to Day 59. 
ii. Secondary analysis of efficacy variables will include the stratification by percent clearance of all patients, 
based on the count of lesions remaining at follow-up visits 4, 5, 6, and 7 compared to Baseline, and grade 
changes in Dyschromia, Erythema (E), Telangiectasia (T), Keratosis, Texture and Rhytides between 
baseline and follow-up visits 2, 3, 4, 5, 6 and 7. 
C. Satisfaction Analyses 
Subject satisfaction will be assessed based on surveys taken at follow-up visits 4, 5, 6, and 7. 
D. Safety Analyses 
The type, severity, duration and frequency of reported adverse events will be tabulated.  Adverse events 
will also be summarized for events that were considered treatment-related. 
 
13. REFERENCES 
 
1. Berman B. New developments in the treatment of actinic keratosis: focus on ingenol mebutate gel. Clin 
Cosmet Investig Dermatol. 2012; 5: 111-22. 
2. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol Mebutate Gel for Actinic Keratosis. N Engl J 
Med. 2012; 366 (11): 1010-9. 
3. Krawtchenko N, Roewert-Huber J, Ulrich M, al. A randomised study of topical 5% imiquimod vs. 
topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison 
of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007; 157 (Suppl 2): 34-
40. 
4. Berman B, Cohen DE, Amini S. What is the role of field-directed therapy in the treatment of actinic 
keratosis? Part 1: overview and investigational topical agents. Cutis. 2012; 89 (5): 241-50. 
5. Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-
controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 
2009; 60 (6): 934-43. 
6. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical 
treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am 
Acad Dermatol. 2012; 66 (3): 486-93. 
7. Ramsay JR, Suhrbier A, Aylward JH, et al. The sap from Euphorbia peplus is effective against human 
nonmelanoma skin cancers. Br J Dermatol. 2011; 164 (3): 633-6. 
8. Martin G, Swanson N. Clinical findings using ingenol mebutate gel to treat actinic keratoses. J Am 
Acad Dermatol. 2013; 68 (1): S39-S48. 
9. Alexiades-Armenakas M. Rhytides, laxity and photoaging treated with a combination of 
radiofrequency, diode laser, and pulsed light and assessed with a comprehensive grading scale. J 
Drugs Derm. Sept 2006; 5 (8): 731-738. 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 18 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
 
 
 
 
 
Appendix A 
PHOTOS: 
 
Photos will be taken in a standardized fashion: 
 
             
 
 
Prior to taking photos the subjects will be instructed to clean with a baby wipe and dry the entire 
area of the chest to ensure lotions and/or sunscreens will not interfere with any evaluations. 
 
Subjects will wear a drape wrapped around the lowest point of the chest in front of a dark blue 
background as shown in the photo. A photo will be taken at every visit (at the screening visit the  
subject will have photo taken pre-treatment post marking of treatment area).  
 
The camera we will be using is a Canon EOS Rebel T4i, DSLR. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 19 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
 
 
 
 
 
 
Appendix B 
 
Modified Alexiades-Armenakas Comprehensive Grading Scale of Skin Aging  
Grade 
Dyschromia 
Erythema (E)-
Telangiectasia (T) 
Keratoses 
Texture 
Rhytides 
0 
None 
None 
None 
None 
Wrinkles Absent 
1 
Few (1-3) discrete 
small (<5mm) 
lentigenes 
Pink E or few 
localized T 
Few 
 Subtle    
irregularity 
1-6 shallow but 
visible lines 
1.5 
Several (4-6) discrete 
small lentigenes 
Pink E or several T 
in 2 sites 
Several 
 Mild      
irregularity in  few 
areas 
>6shallow but 
visible lines 
2 
Multiple (7-10) small 
lentigenes, few 
hypopigmented 
macules 
Red E or  multiple 
T localized to 2 
sites 
Multiple, 
small 
Rough in few, 
localized sites 
1-6 moderately 
deep lines 
2.5 
Multiple small and 
few large lentigenes, 
several 
hypopigmented 
macules 
Red E or multiple 
T localized to 3 
sites 
Multiple, large Rough in several 
localized areas 
> 6 moderately 
deep lines 
3 
Many (10-20) small 
and large lentigenes, 
multiple 
hypopigmented 
macules 
Violaceous E or 
many T at multiple 
sites 
Many 
Rough in multiple, 
localized sites 
1-6 deep well 
defined lines 
3.5 
Numerous (>20) small 
or multiple large 
lentigenes, many 
hypopigmented 
macules 
Violaceous E and 
numerous T, little 
uninvolved skin 
Numerous 
Mostly rough, little 
uninvolved skin 
>6 deep well 
defined lines 
4 
Numerous extensive 
lentigenes, numerous 
hypopigmented 
macules 
Deep, Violaceous 
E, numerous T 
throughout 
Numerous, 
hyperkeratosis 
present 
Rough throughout  Very deep 
wrinkles with 
redundant folds 
Few 1-3,   Several 4-6, Multiple 7-10,  Many 10-20,  Numerous >20 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 20 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
 
 
 
 
 
 
Appendix C 
                    Patient’s Evaluation of Signs of Photoaging 
 
Satisfaction of Improvement 
         0 
 
Completely 
Dissatisfied 
1 
 
Moderately 
Dissatisfied 
 
 2 
 
Mildly 
Dissatisfied 
3 
Neither 
Dissatisfied 
Nor 
Satisfied 
4 
 
 Mildly 
Satisfied 
5 
 
Moderately 
Satisfied 
6 
 
Completely 
Satisfied 
Rhytides  
(Lines/Wrinkles) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dyschromia  
(Changes is skin 
pigmentation) 
 
 
 
 
 
 
 
Telangiectasias  
(Spider Veins) 
 
 
 
 
 
 
 
Keratosis  
(Tactile Roughness) 
 
 
 
 
 
 
 
Erythema 
(Redness) 
 
 
 
 
 
 
 
Overall Satisfaction 
with treatment  
 
 
 
 
 
 
 
 
 
 
Subject Initial: _____________________________ 
Date: _____/_____/_____ 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 21 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
 TSQM (Version 1.4)  
(Subject) Treatment Satisfaction Questionnaire for Medication 
 
 Instructions: Please take some time to think about your level of satisfaction or dissatisfaction with 
the medication you used in this clinical trial. We are interested in your evaluation of the 
effectiveness, side effects, and convenience of the medication over the last three days, or since you 
last used it. For each question, please place a single check mark next to the response that most 
closely corresponds to your own experiences. 
 
 1. How satisfied or dissatisfied are you with the ability of the medication to prevent or treat 
your condition?  
□1 Extremely Dissatisfied  
□2 Very Dissatisfied  
□3 Dissatisfied  
□4 Somewhat Satisfied  
□5 Satisfied  
□6 Very Satisfied  
□7 Extremely Satisfied  
 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms?  
□1 Extremely Dissatisfied  
□2 Very Dissatisfied  
□3 Dissatisfied  
□4 Somewhat Satisfied  
□5 Satisfied  
□6 Very Satisfied  
□7 Extremely Satisfied  
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 22 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
 
3. How satisfied or dissatisfied are you with the amount of time it takes the medication to start 
working?  
□1 Extremely Dissatisfied  
□2 Very Dissatisfied  
□3 Dissatisfied  
□4 Somewhat Satisfied  
□5 Satisfied  
□6 Very Satisfied  
□7 Extremely Satisfied  
 
4. As a result of taking this medication, do you experience any side effects at all?  
□1 Yes  
□0 No (if No, then please skip to Question 9)  
 
5. How bothersome are the side effects of the medication you take to treat your condition?  
□1 Extremely Bothersome  
□2 Very Bothersome  
□3 Somewhat Bothersome  
□4 A Little Bothersome  
□5 Not at All Bothersome  
 
6. To what extent do the side effects interfere with your physical health and ability to function 
(i.e., strength, energy levels, etc.)?  
□1 A Great Deal  
□2 Quite a Bit  
□3 Somewhat  
□4 Minimally  
□5 Not at All  
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 23 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
7. To what extent do the side effects interfere with your mental function (i.e., ability to think 
clearly, stay awake, etc.)?  
□1 A Great Deal  
□2 Quite a Bit  
□3 Somewhat  
□4 Minimally  
□5 Not at All  
 
8. To what degree have medication side effects affected your overall satisfaction with the 
medication?  
□1 A Great Deal  
□2 Quite a Bit  
□3 Somewhat  
□4 Minimally  
□5 Not at All  
 
9. How easy or difficult is it to use the medication in its current form?  
□1 Extremely Difficult  
□2 Very Difficult  
□3 Difficult  
□4 Somewhat Easy  
□5 Easy  
□6 Very Easy  
□7 Extremely Easy  
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 24 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
10. How easy or difficult is it to plan when you will use the medication each time?  
□1 Extremely Difficult  
□2 Very Difficult  
□3 Difficult  
□4 Somewhat Easy  
□5 Easy  
□6 Very Easy  
□7 Extremely Easy  
 
11. How convenient or inconvenient is it to take the medication as instructed?  
□1 Extremely Inconvenient  
□2 Very Inconvenient  
□3 Inconvenient  
□4 Somewhat Convenient  
□5 Convenient  
□6 Very Convenient  
□7 Extremely Convenient  
 
12. Overall, how confident are you that taking this medication is a good thing for you?  
□1 Not at All Confident  
□2 A Little Confident  
□3 Somewhat Confident  
□4 Very Confident  
□5 Extremely Confident  
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 25 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
13. How certain are you that the good things about your medication outweigh the bad things?  
□1 Not at All Certain  
□2 A Little Certain  
□3 Somewhat Certain  
□4 Very Certain  
□5 Extremely Certain  
 
14. Taking all things into account, how satisfied or dissatisfied are you with this medication?  
□1 Extremely Dissatisfied  
□2 Very Dissatisfied  
□3 Dissatisfied  
□4 Somewhat Satisfied  
□5 Satisfied  
□6 Very Satisfied  
□7 Extremely Satisfied 
 
 
Subject Initial: _____________________________ 
Date: _____/_____/_____ 
 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 26 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
APPENDIX D 
STUDY SUBJECT TAKE HOME INSTRUCTION SHEET  
The study regimen you have been given is for you to start the day AFTER your first office visit. 
You should apply the PICATO 0.015% gel for the next two (2) days and return to your doctor’s 
office tomorrow PRIOR to your first in home application! 
Instructions for Applying Picato® gel: 
1. Open a new tube each time you use Picato® gel 
 
2. Remove cap from tube just before use 
 
3. Squeeze the gel from the tube onto your fingertip. Only use enough gel needed to cover 
the affected area, as directed by your study doctor 
 
4. Spread the gel evenly over only the skin area to be treated. Allow the treated area to dry 
for 15 minutes 
 
5. Wash your hands right away after applying Picato® gel 
 
6. Safely throw away (dispose of) the tube after use 
 
*Repeat the above steps for each day of treatment 
RESTRICTIONS: 
 Avoid touching the treatment area or doing activities that cause a lot of sweating for 6 
hours after applying Picato® 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 
 
 DO NOT cover the treated area with bandages or other dressings after you have applied 
Picato® gel 
 
 DO NOT get Picato® gel in your eyes. Do not touch your eyes while you are applying 
Picato® gel. Wash your hands well with soap and water after applying it 
 
 After applying Picato® gel, be careful to keep Picato® gel on the treated area from coming 
into contact with your eyes. Irritation may happen if you get Picato® gel in your eyes.  
If you accidentally get Picato® gel in your eyes, flush them with large amounts of water 
and get medical care as soon as possible 
 
 
If you have any questions about the study, you may contact the doctor's office at: 858-657-1004 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 27 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Appendix E 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 28 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 29 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
APPENDIX F 
RESPONSIBILITIES OF THE INVESTIGATOR 
 
1. ADHERENCE TO THE STUDY PROTOCOL 
The Investigator must ensure adherence to the procedures outlined in this Study Protocol.  The procedures 
set out in this study protocol, pertaining to the conduct, evaluation, and documentation of this study, are 
designed to ensure that the Investigator abides by GCP as described in the ICH Guidelines Topic E6: 
“Guideline for Good Clinical Practice.”  Compliance with these regulations also constitutes compliance 
with the ethical principles described in the current revision of the Declaration of Helsinki.  The study will 
also be carried out in keeping with local legal and regulatory requirements. 
2. DATA HANDLING AND RECORD KEEPING 
The Investigator must ensure that proper source documentation for all study activities are diligently 
maintained and securely kept.  The Investigator will sign the source documents for completeness, 
accuracy and integrity of the data collected.  The Investigator will maintain reliable study 
Medication/Device dispensing/dosing records and will store study supplies in a secure, locked location. In 
addition, the Investigator will ensure that all study-related source documentation will be maintained for a 
period of two years after the conclusion of the study.   
3.  Regulatory Obligations 
a.  Institutional Review Board 
The study protocol, informed consent forms (all versions), and any specific advertising will be submitted 
to and approved by the Investigational Review Board (IRB) before the start of the study.  A form must be 
signed by the chairman or designee of the IRB noting the approvals.  This notification will be provided to 
the sponsor. 
9 
Protocol 
Protocols will be noted as approved by the Investigator by placement of his signature on the Investigator’s 
Signature Page.  Copies of the IRB approved protocol and informed consents will be provided to the 
Sponsor. 
10 Informed Consent 
An Informed Consent (IC) that includes all of the relevant elements currently required by FDA or state 
regulations will be provided to each prospective study subject at screening before enrollment into the 
study.  The type and method of study, any potential or possible hazards, and the subject’s right to 
withdraw from the study at any time will be explained to the subjects by the Investigator and/or the  
designee.  Once the Investigator is assured that an individual candidate understands the implications of 
participating in this study, the subject will be asked to give consent by signing and dating in the 
appropriate areas of the Informed Consent form.  The Investigator and/or Designee will also sign and date 
the form where indicated.  A copy of the IRB approved IC form will also be provided to the Sponsor. 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 30 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
11 Protocol and Informed Consent Changes 
Changes to the protocol or Informed Consent form(s) will be implemented as amendments to the original 
document and approved by the IRB.  The approvals will be processed in accordance with the established 
IRB procedures.  Copies of all protocol and IC amendments/revisions, along with letters noting IRB 
approval, will be submitted to the Sponsor, as this may affect safety.  Any addenda, amendment or 
revision that substantially alters the study design or increases potential risk to the subject requires the 
subject’s consent to continue in the study. 
12 Investigational Product Accountability 
The Investigational product to be used for this study is the sole property of the Sponsor.  All provided 
products to be used for this study and their receipt, inventory, dispensing, and reconciliation records will 
be maintained in compliance with Federal Regulations. The study supplies will be dispensed by the 
Investigator or designee to qualified study subjects according to established procedures.  Upon 
completion or termination of the study the site will be responsible for retaining all partial and unused 
products under FDA regulations. 
13 Study Monitoring 
All monitoring activities are the responsibility of the study doctor.  Monitoring is for the purpose of 
confirming adherence to the protocol and to verify complete and accurate data collection.  The site will be 
responsible for internal verification of data throughout the study.   
4. Confidentiality of Records 
Information about the subject’s health taken during this study may be used and given to others by the 
study coordinators, the medical staff, the respective study center and by the subject’s doctors and their 
other health care providers (together, they are called “providers”). These providers may share health 
information about the subject with the study coordinator. The study coordinator and the providers may 
share that information with: 
- researchers participating in this Study laboratories conducting tests for this Study; 
- The U.S. Food and Drug Administration (FDA) 
- Department of Health and Human Services (DHHS) agencies; 
- Other U.S. and foreign government agencies that watch over quality, safety, and effectiveness 
of research 
5. DELEGATION OF INVESTIGATOR RESPONSIBILITIES (ADHERENCE TO THE STUDY PROTOCOL) 
The Investigator should ensure that all persons assisting with the trial are qualified and are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-related 
duties and functions.  The investigator should maintain a list of Co-Investigators and other appropriately 
qualified persons to whom he has delegated significant trial-related duties. 
 
6. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator must ensure that institutional regulations, the Informed Consent Form, and the HIPAA 
Authorization clearly permit study-related monitoring, audits, REB review, and regulatory inspections 
providing direct access to source data and do 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 31 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
APPENDIX G 
IMPORTANT SAFETY INFORMATION FOR  
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
PICATO® gel safely and effectively. See full prescribing information for 
PICATO® gel. 
PICATO® (ingenol mebutate) gel, 0.015% for topical use 
PICATO® (ingenol mebutate) gel, 0.05% for topical use 
Initial U.S. Approval: 2012 
----------------------------INDICATIONS AND USAGE--------------------------- 
Picato® gel is an inducer of cell death indicated for the topical treatment of 
actinic keratosis. (1) 
----------------------DOSAGE AND ADMINISTRATION-----------------------  
For topical use only; not for oral, ophthalmic, or intravaginal use. (2)  
Actinic keratosis on the face and scalp: Apply Picato® gel, 0.015% to the 
affected area once daily for 3 consecutive days. (2)  
Actinic keratosis on the trunk and extremities: Apply Picato® gel, 0.05% 
to the affected area once daily for 2 consecutive days. (2) 
---------------------DOSAGE FORMS AND STRENGTHS---------------------- 
Gel containing ingenol mebutate, 0.015% or 0.05% (3) 
-------------------------------CONTRAINDICATIONS------------------------------ 
None. (4) 
-----------------------WARNINGS AND PRECAUTIONS------------------------ 
Eye disorders, including severe eye pain, eyelid edema, eyelid ptosis, 
periorbital edema can occur after exposure. Avoid contact with the periocular 
area. If accidental exposure occurs, flush eyes with water and seek medical 
care. (5.1) 
Local skin reactions can occur including severe reactions (e.g., 
vesiculation/pustulation, erosion/ulceration). Administration of Picato® gel is 
not recommended until skin is healed from any previous drug or surgical 
treatment. (5.2) 
------------------------------ADVERSE REACTIONS------------------------------- 
The most common adverse reactions (≥2 %) are local skin reactions, 
application site pain, application site pruritus, application site irritation, 
application site infection, periorbital edema, nasopharyngitis and headache. 
(6.1) 
To report SUSPECTED ADVERSE REACTIONS, contact LEO Pharma 
Inc. at 1-877-494-4536 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. 
See 17 for PATIENT COUNSELING INFORMATION and FDA approved 
patient labeling. 
Revised: 01/2012 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 32 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
___________________________ 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 INDICATIONS AND USAGE 
2 DOSAGE AND ADMINISTRATION 
3 DOSAGE FORMS AND STRENGTHS 
4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
5.1 Eye Exposure 
5.2 Local Skin Reactions 
6 ADVERSE REACTIONS 
6.1 Clinical Trials Experience 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.4 Pediatric Use 
8.5 Geriatric Use 
10 OVERDOSAGE 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.2 Pharmacodynamics 
12.3 Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 CLINICAL STUDIES 
14.1 Actinic Keratosis of the Face and Scalp 
14.2 Actinic Keratosis of the Trunk and Extremities 
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
*Sections or subsections omitted from the Full Prescribing Information are not 
listed. 
______________________________________________________________________________ 
Reference ID: 3075879 
FULL PRESCRIBING INFORMATION 
1 INDICATIONS AND USAGE 
Picato® gel is indicated for the topical treatment of actinic keratosis. 
2 DOSAGE AND ADMINISTRATION 
For topical use only; Picato® gel is not for oral, ophthalmic, or intravaginal use. 
For the treatment of actinic keratosis on the face and scalp Picato® gel, 0.015% should be 
applied to the affected area once daily for 3 consecutive days. 
For the treatment of actinic keratosis on the trunk and extremities Picato® gel, 0.05% should be 
applied to the affected area once daily for 2 consecutive days. Picato® gel may be applied to the 
affected area, up to one contiguous skin area of approximately 25 cm2 (e.g., 5 cm x 5 cm) using 
one unit dose tube. After spreading evenly over the treatment area, the gel should be allowed to 
dry for 15 minutes. Patients should wash their hands immediately after applying Picato® gel and 
take care not to transfer the applied drug to other areas, including the eye. Patients should avoid 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 33 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
washing and touching the treated area for a period of 6 hours after application of Picato® gel. 
Following this time, patients may wash the area with a mild soap. 
3 DOSAGE FORMS AND STRENGTHS 
Gel, 0.015% or 0.05%, in a clear colorless gel base. 
4 CONTRAINDICATIONS 
None. 
5 WARNINGS AND PRECAUTIONS 
5.1 Eye Exposure 
Eye disorders, including severe eye pain, eyelid edema, eyelid ptosis, periorbital edema can 
occur after exposure [see Adverse Reactions (6)]. Patients should wash hands well after applying 
Picato® gel, and avoid transfer of the drug to the periocular area during and after application [see 
Patient Counseling Information (17)]. If accidental exposure occurs, the area should be flushed 
with water and the patient should seek medical care as soon as possible [see Adverse Reactions 
(6)]. 
5.2 Local Skin Reactions 
Severe skin reactions in the treated area, including erythema, crusting, swelling, 
vesiculation/postulation, and erosion/ulceration, can occur after topical application of Picato® 
gel 
[see Adverse Reactions (6)]. Administration of Picato® gel is not recommended until the skin is 
healed from any previous drug or surgical treatment. 
6 ADVERSE REACTIONS 
Reference ID: 3075879 
6.1 Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in clinical practice. 
The data described below reflect exposure to Picato® gel in 499 subjects with actinic keratosis, 
including 274 subjects exposed to Picato® gel field treatment (skin area of 25 cm2 in the face or 
scalp regions) at a concentration of 0.015% once daily for 3 consecutive days, and 225 subjects 
exposed to Picato® gel field treatment (skin area of 25 cm2 in the trunk or extremities regions) at 
a concentration of 0.05% once daily for 2 consecutive days. 
Local skin reactions, including erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration were assessed within the selected treatment area 
and graded by the investigator on a scale of 0 to 4. A grade of 0 represented no reaction present 
in the treated area, and a grade of 4 indicated a marked and severe skin reaction that extended 
beyond the treated area. 
 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 34 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Table 1 Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area 
during the 57 Days Post Treatment Period (face/scalp trials) 
SKIN REACTIONS 
FACE AND SCALP 
(N=545) 
PICATO® GEL, 0.015% 
ONCE DAILY FOR 3 
DAYS 
ANY GRADEA > 
BASELINE 
GRADE 4 
PICATO® 
GEL  
(N=274) 
VEHICLE  
(N=271) 
PICATO® 
GEL  
(N=274) 
VEHICLE  
(N=271) 
Erythema 
258 (94%) 
69 (25%) 
66 (24%) 
0 (0%) 
Flaking/Scaling 
233 (85%) 
67 (25%) 
25 (9%) 
0 (0%) 
Crusting 
220 (80%) 
46 (17%) 
16 (6%) 
0 (0%) 
Swelling 
217 (79%) 
11 (4%) 
14 (5%) 
0 (0%) 
Vesiculation/Pustulation 
154 (56%) 
1 (0%) 
15 (5%) 
0 (0%) 
Erosion/Ulceration 
87 (32%) 
3 (1%) 
1 (0%) 
0 (0%) 
aMild (grade 1), Moderate (grade 2-3) or Severe (grade 4). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 35 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Table 2 : Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area 
during the 57 Days Post Treatment Period (trunk/extremities trials) 
SKIN REACTIONS 
TRUNK AND 
EXTREMITIES (N=457) 
PICATO® GEL, 0.05% 
ONCE DAILY FOR 2 
DAYS 
ANY GRADEA > 
BASELINE 
GRADE 4 
PICATO® 
GEL  
(N=225) 
VEHICLE  
(N=232) 
PICATO® 
GEL  
(N=225) 
VEHICLE  
(N=232) 
Erythema 
207 (92%) 
43 (19%) 
34 (15%) 
0 (0%) 
Flaking/Scaling 
203 (90%) 
44 (19%) 
18 (8%) 
0 (0%) 
Crusting 
167 (74%) 
23 (10%) 
8 (4%) 
0 (0%) 
Swelling 
143 (64%) 
13 (6%) 
7 (3%) 
0 (0%) 
Vesiculation/Pustulation 
98 (44%) 
2 (1%) 
3 (1%) 
0 (0%) 
Erosion/Ulceration 
58 (26%) 
6 (3%) 
2 (1%) 
0 (0%) 
aMild (grade 1), Moderate (grade 2-3) or Severe (grade 4). 
 
Local skin reactions typically occurred within 1 day of treatment initiation, peaked in intensity 
up to 1 week following completion of treatment, and resolved within 2 weeks for areas treated on 
the face and scalp, and within 4 weeks for areas treated on the trunk and extremities. 
Adverse reactions that occurred in ≥2% of subjects treated with Picato® gel and at a higher 
frequency than the vehicle are presented in Table 3 and Table 4. 
 
 
 
 
 
 
 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 36 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Table 3 Adverse reactions occurring in ≥ 2% of subjects treated with Picato® gel and at 
higher frequency than vehicle (face/scalp trials) 
ADVERSE REACTIONS 
FACE/SCALP 
PICATO® GEL, 
0.015%  
(N=274) 
VEHICLE  
(N=271) 
Application Site Pain 
42 (15%) 
1 (0%) 
Application Site Pruritus 
22 (8%) 
3 (1%) 
Application Site Infection 
7 (3%) 
0 (0%) 
Periorbital Edema 
7 (3%) 
0 (0%) 
Headache 
6 (2%) 
3 (1%) 
 
Table 4 Adverse reactions occurring in ≥ 2% of subjects treated with Picato® gel and at 
higher frequency than vehicle (trunk/extremities trials) 
ADVERSE REACTIONS 
TRUNK/EXTREMITIES 
PICATO® GEL, 
0.05% 
(N=225) 
VEHICLE 
(N=232) 
Application Site Pruritus 
18 (8%) 
0 (0%) 
Application Site Irritation 
8 (4%) 
1 (0%) 
Nasopharyngitis 
4 (2%) 
2 (1%) 
Application Site Pain 
5 (2%) 
0 (0%) 
 
Less common adverse reactions in subjects treated with Picato® included: eyelid edema, eye 
pain, conjunctivitis. 
A total of 108 subjects treated with Picato® gel on the face/scalp and 38 subjects treated on the 
trunk/extremities were followed for 12 months. Results from these studies did not change the 
safety profile of Picato® gel. 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 37 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Pregnancy Category C 
There are no adequate and well-controlled studies of Picato® gel in pregnant women. Picato® 
gel should be used during pregnancy only if the potential benefit justifies the potential risk to the 
fetus. 
Systemic embryofetal development studies were conducted with ingenol mebutate in rats and 
rabbits. Intravenous doses of 1.5, 3, and 5 μg/kg/day (9, 18, and 30 μg/m2/day) ingenol mebutate 
were administered during the period of organogenesis (gestational days 6 – 16) to pregnant 
female rats. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 
doses up to 5 μg/kg/day (30 μg/m2/day). Intravenous doses of 1, 2, and 4 μg/kg/day (12, 24, and 
48 μg/m2/day) ingenol mebutate were administered during the period of organogenesis 
(gestational days 6 – 18) to pregnant female rabbits. An increase in embryo-fetal mortality was 
noted at 4 μg/kg/day (48 μg/m2/day). An increased incidence of fetal visceral and skeletal 
variations was noted in all three ingenol mebutate dose groups. The clinical relevance of these 
findings is unclear since systemic exposure of ingenol mebutate was not detected in subjects with 
actinic keratosis treated with Picato® gel, 0.05% applied to a 100 cm2 treatment area [see 
Clinical Pharmacology (12.3)]. 
8.4 Pediatric Use 
Actinic keratosis is not a condition generally seen within the pediatric population. 
The safety and effectiveness of Picato® gel for actinic keratosis in patients less than 18 years of 
age have not been established. 
Reference ID: 3075879 
8.5 Geriatric Use 
Of the 1165 subjects treated with Picato® gel in the clinical trials, 56% were 65 years and older 
and, 21% were 75 years and older. No overall differences in safety or effectiveness were 
observed between these subjects and younger subjects. 
10 OVERDOSAGE 
Topical overdosing of Picato® gel could result in an increased incidence of local skin reactions. 
11 DESCRIPTION 
Picato® (ingenol mebutate) gel, 0.015% or 0.05% is a clear colorless gel for topical 
administration, which contains the active substance ingenol mebutate, an inducer of cell death. 
The chemical name of ingenol mebutate is: 
2-Butenoic acid, 2-methyl-, (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-1a,2,5,5a,6,9,10,10a-octahydro- 
5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1H-2,8a-methanocyclopenta 
[a]cyclopropa[e]cyclodecen-6-yl ester, (2Z) - 
Or (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11- 
oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H 2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6- 
yl (2Z) 2 methylbut-2-enoate. The molecular formula is C25H34O6 and molecular weight is 
430.5. Ingenol mebutate is represented by the following structural formula: Ingenol mebutate is a 
white to pale yellow crystalline powder. Picato® gel, 0.015% and 0.05% contains 150 mcg and 
500 mcg of ingenol mebutate, respectively in each gram of gel consisting of isopropyl alcohol, 
hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol and purified 
water. Picato® gel is clear colorless gel and supplied in unit dose laminate tubes, for single use, 
containing a nominal fill weight of 0.47 g, with a deliverable weight of 0.25 g. The tubes should 
be discarded after single use. 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 38 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
The mechanism of action by which Picato® gel induces cell death in treating AK lesions is 
unknown. Reference ID: 3075879 
12.2 Pharmacodynamics 
The pharmacodynamics of Picato® gel is unknown. 
12.3 Pharmacokinetics 
Absorption 
The systemic exposure to Picato® gel, 0.05% was assessed in two studies in a total of 16 
subjects with AK, following application of approximately 1 g of Picato® gel, 0.05% to an area 
of 100 cm2 of the dorsal forearm once daily for two consecutive days. In these studies, the blood 
levels of ingenol mebutate and two of its metabolites (acyl isomers of ingenol mebutate) were 
measured. Blood levels of ingenol mebutate and the two metabolites were below the lower limit 
of quantification (0.1 ng/mL) in all the blood samples of the subjects evaluated. 
Drug Interactions In vitro studies demonstrated that [3H]-ingenol mebutate undergoes extensive 
metabolism in human hepatocytes. In vitro studies to assess the potential of ingenol mebutate to 
inhibit or induce human cytochrome P450 (CYP) enzymes demonstrated that ingenol mebutate 
does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP 1A2, 
2C9, and 3A4. The estimated expected systemic exposure (< 0.1 ng/mL) following topical 
application of Picato® gel, 0.05% to AK subjects in the pharmacokinetic studies described above 
is negligible compared to the concentrations of ingenol mebutate evaluated in the in vitro studies. 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Long-term animal studies have not been performed to evaluate the carcinogenic potential of 
Picato® gel or ingenol mebutate. The effects of ingenol mebutate on fertility have not been 
evaluated. 
Ingenol mebutate was negative in the Ames test, in vitro mouse lymphoma assay, and in vivo rat 
micronucleus test, but positive in the Syrian hamster embryo (SHE) cell transformation assay. 
14 CLINICAL STUDIES 
14.1 Actinic Keratosis of the Face and Scalp 
In two double-blind, vehicle-controlled, clinical trials, 547 adult subjects with AK on the face or 
scalp were randomized to treatment with either Picato® gel, 0.015% or vehicle gel for 3 
consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 
to 8 clinically typical, visible, discrete AK lesions within a 25 cm2 contiguous treatment area. 
Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled 
dosing day, the study gel was applied to the entire treatment area. A total of 536 subjects (98%) 
completed these studies. Study subjects ranged from 34 to 89 years of age (mean 64 years) and 
94% had Fitzpatrick skin type I, II, or III. Approximately 85% of subjects were male, and all 
Picato®-treated subjects were Caucasian. Reference ID: 3075879 
Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of 
subjects with no (zero) clinically visible AK lesions in the treatment area. Partial clearance rate 
was defined as the proportion of subjects with 75% or greater reduction in the number of AK 
lesions at baseline in the selected treatment area. Table 5 presents the efficacy results for each 
trial. 
 
 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 39 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Table 5 Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 
57 in Each Trial 
  
STUDY 1 
STUDY 2 
PICATO® 
GEL, 
0.015%  
(N=135 ) 
VEHICLE  
(N=134 ) 
PICATO® 
GEL, 
0.015%  
(N=142) 
VEHICLE  
(N=136) 
Complete Clearance Rate 
50 (37%) 
3 (2%) 
67 (47%) 
7 (5%) 
Partial Clearance Rate ( ≥ 75%) 
81 (60%) 
9 (7%) 
96 (68%) 
11 (8%) 
 
Table 6 presents the response rates by anatomical location for each trial. 
Table 6 Number and Percent of Subjects Achieving Complete Clearance at Day 57 by 
Anatomical Location and by Trial 
  
STUDY 1 
STUDY 2 
PICATO® 
GEL, 0.015%  
(N=135 ) 
VEHICLE  
(N=134 ) 
PICATO® 
GEL, 0.015% 
(N=142) 
VEHICLE  
(N=136) 
Scalp 
4/26 (15%) 
0/25 (0%) 
9/31 (29%) 
1/25 (4%) 
Face 
46/109 (42%) 
3/109 (2%) 
58/111 (52%) 
6/111 (5%) 
 
Subjects who achieved complete clearance at Day 57 in Study 1 and Study 2 entered a 12-month 
follow-up period. Based on 108 Picato® gel-treated subjects who achieved complete clearance in 
Study 1 and Study 2, the recurrence rate at 12 months was 54% where recurrence was defined as 
the percentage of subjects with any identified AK lesion in the previously treated area who 
achieved complete clearance at Day 57. 
 
14.2 Actinic Keratosis of the Trunk and Extremities 
In two double-blind, vehicle-controlled clinical trials, 458 adult subjects with AK on the trunk or 
extremities were randomized to treatment with either Picato® gel, 0.05% or vehicle gel for 2 
consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 
to 8 clinically typical, visible, discrete AK lesions within a 25 cm2 contiguous treatment area. 
Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled 
dosing day, the study gel was applied to the entire treatment area. A total of 447 subjects (98%) 
completed these studies. Study subjects ranged from 34 to 89 years of age (mean 66 years) and 
94% had Fitzpatrick skin type I, II, or III. Approximately 62% of subjects were male, and all 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 40 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
Picato®-treated subjects were Caucasian. Efficacy was assessed at Day 57. Complete clearance 
rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the 
treatment area. The partial clearance Reference ID: 3075879 rate was defined as the proportion 
of subjects with 75% or greater reduction in the number of AK lesions at baseline in the selected 
treatment area. Table 7 presents the efficacy results for each study. 
Table 7 Number and Percent of Subjects Achieving Complete and Partial Clearance at 
Day 57 in Each Trial 
  
STUDY 3 
STUDY 4 
PICATO® 
GEL, 
0.05%  
(N=126 ) 
VEHICLE  
(N=129 ) 
PICATO® 
GEL, 
0.05%  
(N=100) 
VEHICLE  
(N=103) 
Complete Clearance Rate 
35 (28%) 
6 (5%) 
42 (42%) 
5 (5%) 
Partial Clearance Rate ( ≥ 75%) 
56 (44 %) 
9 (7 %) 
55 (55 %) 
7 (7 %) 
 
Table 8 presents the response rates by anatomical location for each study. 
Table 8 Number and Percent of Subjects Achieving Complete Clearance at Day 57 by 
Anatomical Location and by Trial 
  
STUDY 3 
STUDY 4 
PICATO® 
GEL, 0.05%  
(N=126) 
VEHICLE 
(N=129) 
PICATO® 
GEL, 0.05%  
(N=100) 
VEHICLE  
(N=103) 
Arm 
22/84 (26 %) 
4/82 (5 %) 
27/59 (46 %) 
3/67 (5 %) 
Back of Hand 
4/25 (16 %) 
0/29 (0%) 
6/28 (21 %) 
0/27 (0 %) 
Chest 
8/9 (89 %) 
1/8 (13 %) 
3/5 (60 %) 
1/3 (33 %) 
Othera 
1/8 (13 %) 
1/10 (10 %) 
6/8 (75 %) 
1/6 (17 %) 
aOther includes shoulder, back, leg. 
 
Subjects who achieved complete clearance at Day 57 in Study 4 entered a 12-month follow-up 
period. Based on 38 Picato® gel-treated subjects who achieved complete clearance in Study 4, 
the 
recurrence rate at 12 months was 50% where recurrence was defined as the percentage of 


PI: Mitchel P. Goldman, MD.  
                                Version Date 17MAR2014 
Page 41 of 41 
LEO Pharma, Inc. 
                                         Protocol: PICATO-2013-01 
 
subjects with any identified AK lesion in the previously treated area who achieved complete 
clearance at Day 57. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
Picato® gel is a clear colorless gel and is supplied in unit dose laminate tubes containing a 
nominal fill weight of 0.47 g, with a deliverable weight of 0.25 g. The tubes should be discarded 
after single use. 
Picato® gel is available in 2 dosage strengths: 0.015% and 0.05%. 
Dosage Strength Number of unit dose tubes 
per carton 
NDC# 
0.015 % 3 50222-502-47 
0.05 % 2 50222-503-47 
Reference ID: 3075879 
Store Picato® gel in a refrigerator at 36ºF – 46ºF (2ºC – 8ºC); excursions permitted between 
32ºF 
– 59ºF (0ºC – 15ºC) (see USP for controlled cold temperature). Protect from freezing. 
17 PATIENT COUNSELING INFORMATION 
“See FDA-approved patient labeling (Patient Information and Instructions for Use)” 
Picato® gel should be used as directed by a physician. 
Picato® gel is for external use only. Advise patients to avoid contact with the eyes. Inform 
patients that treatment with Picato® gel may lead to local skin reactions [see Warnings and 
Precautions (5)]. 
Patients should avoid inadvertent transfer of Picato® gel to other areas, or to another person. 
Instruct patients to:  
allow the treated area to dry for 15 minutes after application.  
avoid washing and touching the treated area, or participating in activities that cause 
excessive sweating, for 6 hours after treatment. Following this time, patients may wash 
the area with a mild soap.  
keep out of the reach of children. 
Reference ID: 3075879