Clinical trial NCT03538951
Conditions: Actinic Keratosis
Keywords: actinic keratosis efficacy safety VDA-1102
Sponsor: Vidac Pharma
Start date: 2018-05-23; Completion date: 2018-12-10
Enrollment: 83 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 2 clinical study in patients with actinic keratosis involving daily application of 1 of 2 strengths of VDA-1102 topical ointment for approximately 12 weeks (84 days). This study has no placebo and the subjects enrolled in the study will know exactly what they are receiving. The objectives of the study are to evaluate the safety and benefit of these two strengths.

Detailed description:
This Phase 2 clinical trial is a 3-part, open-label, multi-center study involving a non-occluded, daily topical dermal application of 1 of 2 strengths of VDA-1102 ointment for approximately 12 weeks (84 days) to an initial 2 cohorts of subjects. The first 40 eligible subjects will be enrolled into Cohort 1 (Part A). Cohort 1 subjects will be assigned to receive approximately 200 mg of 10% VDA-1102 twice-daily (BID). Once approximately 40 subjects have been enrolled in Cohort 1, Cohort 1 will be closed to enrollment and Cohort 2 (Part B) will be opened for enrollment. Cohort 2 subjects will be assigned to receive approximately 200 mg of 20% VDA-1102 once-daily (QD). Once approximately 40 subjects have been enrolled in Cohort 2, an additional 70 subjects will be randomly assigned to Cohort 1 or Cohort 2 (Part C) in a 1:1 ratio.

To qualify for the study, subjects aged 18 (inclusive) or older must have signed informed consent and met the study enrollment criteria that include having 4-8 actinic keratosis (AK) lesions within an approximate 25 cm2 area on the cheek, forehead, or hairless scalp (the "Treatment Field").

Arms: arm 1: 10% VDA-1102 arm 2: 20% VDA-1102
Interventions: intervention 1: 10% VDA-1102 intervention 2: 20% VDA-1102
Intervention descriptions: intervention 1: 200 mg twice-daily for 12 weeks intervention 2: 200 mg once-daily for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 1 OF 78 
CLINICAL STUDY PROTOCOL 
1. 
COVER AND SIGNATURE PAGES 
1.1. 
Title Page 
Clinical Study Number: 
VDA-CP-05 
 
Original Clinical Protocol Date: 
30 April 2018 
Clinical Protocol Amendment 
N/A 
Clinical Protocol Amendment Date 
N/A 
Study Drug Identification: 
VDA-1102 
Clinical Protocol Version 
1.0 
Clinical Protocol Title: 
A Phase 2B Open-Label Study to Evaluate the Efficacy, 
Safety, and Tolerability of Topical VDA-1102 Ointment 
in Subjects with Actinic Keratosis 
Study Phase: 
Phase 2B 
U.S. IND Number 
125468 
Sponsor: 
Vidac Pharma Ltd. 
10 Hartom Street, 2nd floor 
Har Hotzvim, Jerusalem, Israel 9777510 
Sponsor Signatory: 
Oren M. Becker, Ph.D. 
Vidac Pharma Ltd. 
Chief Executive Officer 
Sponsor Medical Monitor: 
Chaim M. Brickman, M.D. 
Vidac Pharma Ltd.  
Chief Medical Officer 
Study Principal Investigator 
Mark Lebwohl, M.D.  
Mount Sinai School of Medicine 
New York, New York USA 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) as set forth in the 
International Conference on Harmonization (ICH) guidelines on GCP (ICH E6), and applicable local regulatory 
requirements. The concepts and information contained herein are confidential and proprietary to Vidac Pharma 
Limited and shall not be distributed or disclosed in whole or in part without the expressed written permission of 
Vidac Pharma Ltd. 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 2 OF 78 
1.2. 
 Signature Pages 
1.2.1. 
Clinical Signature Page 
Title: A Phase 2B Open-Label Study to Evaluate the Efficacy, Safety, and Tolerability of 
Topical VDA-1102 Ointment in Subjects with Actinic Keratosis 
Oren M. Becker, Ph.D. 
Signature: 
Chief Executive Officer or designee 
Date: 
Chaim M. Brickman, M.D. 
Signature: 
Chief Medical Officer or designee 
Sponsor Medical Monitor 
Date: 
 
 
 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 3 OF 78 
1.2.2. 
Investigator Signature Page 
Clinical Study Number: 
VDA-CP-05 
Original Clinical Protocol Date: 
Clinical Protocol Version: 
30 April 2018 
1.0 
Clinical Protocol Amendment: 
N/A 
Clinical Protocol Amendment Date: 
N/A 
Study Drug Identification: 
VDA-1102 
Clinical Protocol Title: 
A Phase 2B Open-Label Study to Evaluate the Efficacy, 
Safety, and Tolerability of Topical VDA-1102 Ointment 
in Subjects with Actinic Keratosis 
I have read and understand this protocol and concur with the study design. I agree to participate as an 
Investigator and to conduct the study in accordance with the protocol, the Food and Drug Administration 
(FDA) Code of Federal Regulations (CFR) for Good Clinical Practice (GCP), the International Conference 
on Harmonization (ICH) Guidelines and local regulations. I will make a reasonable effort to complete the
study in the time noted. I will provide the contents of this protocol to study staff under my direct 
supervision that need to know the contents to conduct the study. I will discuss this information with the 
study staff to ensure they are fully informed about the study and the test articles. I will provide the contents 
of the protocol to the responsible Institutional Review Board(s). These disclosures may be made, providing 
the contents are not used in any other clinical study and they are not disclosed to any other person or entity 
without prior written consent from the Sponsor or designee. This condition does not apply to disclosure 
required by government regulations or laws; however, I agree to give prompt notice to the Sponsor or 
designee of any such disclosure. 
I understand the study may be terminated or enrollment suspended at any time by the Sponsor, with or 
without cause, or by me if it becomes necessary to protect the interests of the study subjects. I understand 
that any changes to the protocol must be approved in writing by Vidac Pharma and the relevant Institutional 
Review Board before implementation, except where necessary to eliminate apparent immediate hazards to 
the subjects. 
Investigator’s Name:  
_____________________________________________________ 
Investigator’s Signature: _______________________________________________ 
Date:  __ __  / __ __ __  / __ __ __ __ Site Number: ______ 
 
 
D  D      M M M     Y  Y  Y  Y 
 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 4 OF 78 
2. 
PROTOCOL SYNOPSIS 
Title of Study:  A Phase 2B Open-Label Study to Evaluate the Efficacy, Safety, and 
Tolerability of Topical VDA-1102 Ointment in Subjects with Actinic Keratosis 
Study Center(s):  Approximately 8 sites in the US 
Study Duration: Approximately 12 months 
Phases of Development: Phase 2 
Study Objectives  
Primary Objectives:  
• To assess the percent of subjects with complete clearance of the actinic keratosis 
(AK) lesions in their Treatment Field at Week 16  
• To assess the percent of subjects who have facial Treatment Fields who have 
complete clearance of actinic keratosis (AK) lesions at Week 16 
• To evaluate the systemic and local (skin) safety and tolerability of topical application 
of VDA-1102 ointment in adult subjects with AK. 
Secondary Objectives: 
• To assess the percent of subjects with partial (≥75%) clearance of the actinic keratosis 
(AK) lesions in their Treatment Field on Week 16  
• To assess the percent of subjects with facial Treatment Fields who have partial 
(≥75%) clearance of the actinic keratosis (AK) lesions on Week 16  
• To assess the reduction in the number of the actinic keratosis (AK) lesions in the 
Treatment Field on Week 16 
• To assess the reduction in the number of the actinic keratosis (AK) lesions on Week 
16 of subjects with facial Treatment Fields 
Study Design 
This Phase 2 clinical trial is a 3-part, open-label, multi-center study involving a non-
occluded, daily topical dermal application of 1 of 2 strengths of VDA-1102 ointment for 
approximately 12 weeks (84 days) to an initial 2 cohorts of subjects. The first 40 eligible 
subjects will be enrolled into Cohort 1 (Part A). Cohort 1 subjects will be assigned to receive 
approximately 200 mg of 10% VDA-1102 twice-daily (BID). Once approximately 40 
subjects have been enrolled in Cohort 1, Cohort 1 will be closed to enrollment and Cohort 2 
(Part B) will be opened for enrollment. Cohort 2 subjects will be assigned to receive 
approximately 200 mg of 20% VDA-1102 once-daily (QD). Once approximately 40 subjects 
have been enrolled in Cohort 2, an additional 70 subjects will be randomly assigned to 
Cohort 1 or Cohort 2 (Part C) in a 1:1 ratio. 
To qualify for the study, subjects aged 18 (inclusive) or older must have signed informed 
consent and met the study enrollment criteria that include having 4-8 actinic keratosis (AK) 
lesions within an approximate 25 cm2 area on the cheek, forehead, or hairless scalp (the 
“Treatment Field”).  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 5 OF 78 
Parts A, B, and C of this clinical trial will each include the same 3 study periods, a Screening 
Period (Day -21 through Day 1 Pre-Dose), a Treatment Period (Day 1 Dosing through Week 
12), and a Post-Treatment Follow-Up Period (Week 13 through Week 16).   
During the Screening Visit (up to 21 days pre-dose) subjects who have given written 
informed consent will undergo safety assessments, Treatment Field identification, and other 
qualifying procedures.  
At the Day 1 Pre-Dose Visit, eligible subjects will return to the investigative site for baseline 
assessments as well as final eligibility screening.  Subjects who continue to meet the 
enrollment criteria will be enrolled and will continue to the Day 1 Dosing Visit.  The number 
of AK lesions within the Treatment Field will be recorded. 
During the Treatment Period, enrolled subjects (or their dosing partner) will apply the first 
dose of the study drug on Day 1 under the supervision of the site personnel to assure proper 
application. After release from the research clinic on Day 1, subjects (or their dosing partner) 
will continue the prescribed VDA-1102 dosing regimen at home. Subjects will visit their 
respective investigative sites on Week 4 and Week 8 for safety and efficacy (AK lesion 
count) assessments, drug accountability, and re-training in proper application of the study 
drug. On the Week 12 Visit, subjects will return to the clinic for their final safety and 
efficacy assessments as well as final study drug accountability. 
During the Post-Treatment Follow-up Period, subjects will visit their respective 
investigative sites on Week 13 and Week 16 for safety and efficacy assessments. Subjects 
will exit the study following completion of their Week 16 assessments. Subjects with 
continuing AEs will be scheduled for follow-up evaluation, as appropriate.  
Subjects will have Post-Treatment Follow-Up visits to their respective investigative sites on 
Week 13 and Week 16 for safety and efficacy assessments.  All AK lesions within the 
Treatment Field will be counted. At the Week 13 Visit site personnel will review with each 
subject the study instructions and the date of their next study visit.  
Subject Population:   
Men or women 18 years of age or older with a diagnosis of Actinic Keratosis with between 
4 and 8 Grade 1 or Grade 2 AK lesions within a single contiguous 25 cm2 area of skin on 
their face or balding scalp. 
Number of Enrolled Subjects (planned):   
A maximum of approximately 150 subjects will be enrolled in this 2-cohort clinical trial. In 
each cohort, approximately 75 eligible subjects will be enrolled in order to complete each 
cohort with safety and efficacy data from at least 70 subjects who received study drug.  
Maximum Time Subjects May Remain in the Study:  
Subjects may participate in this study for a maximum of 143 days (21 days Screening Period 
+ 89 days Treatment Period + 33 days Post-Treatment Follow-Up Period). 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 6 OF 78 
Study Endpoints: 
Primary Efficacy Endpoints:    
• Percentage of subjects achieving complete clearance of AK lesions within their 
Treatment Field on Week 16  
• Percentage of subjects with facial Treatment Fields achieving complete clearance of AK 
lesions on Week 16  
Secondary Efficacy Endpoints:  
• Percentage of subjects achieving partial (≥75%) clearance of AK lesions within their 
Treatment Field on Week 16  
• Percentage of subjects with facial Treatment Fields achieving partial (≥75%) clearance 
of AK lesions on Week 16   
• Change from baseline in the number of AK lesions in the Treatment Field of each subject 
by Weeks 16 
• Change from baseline in the number of facial AK lesions in the Treatment Field of each 
subject by Weeks 16 
Safety Endpoints:  
• AEs, clinical laboratory parameters, vital signs, physical examinations, Local Skin 
Reaction (LSR) Scores, electrocardiograms, and drug exposure.  
Statistical Analyses:  
Sample Size 
The study is designed to evaluate the efficacy, safety, and tolerability of topical VDA-1102 
ointment in subjects with actinic keratosis. Approximately 150 subjects will be enrolled in 
this 2-cohort clinical trial. In each cohort, approximately 75 eligible subjects will be enrolled 
in order to complete each cohort with safety and efficacy data from at least 70 subjects who 
received study drug. Considering the results from a previous Phase 2 parallel, randomized, 
placebo-controlled study with a sample size of 29 to 32 subjects per treatment group, this 
sample size is considered adequate to evaluate the stated objectives. A formal sample size 
calculation was not performed. 
Efficacy Analyses 
Efficacy endpoints will be summarized by cohort and visit on the modified Intent-to-Treat 
(mITT) population and Per Protocol (PP) population, as well as on pre-defined subgroups of 
the modified Intent-to-Treat population and Per Protocol population including subjects 
whose Treatment Field was on their face (i.e., cheek or forehead, not scalp).  
Given that the study does not contain a control arm, formal statistical analyses of the efficacy 
data are not planned.  
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 7 OF 78 
Safety Analysis 
The safety endpoint data will be summarized for the Safety Population.  AEs will be 
categorized by System Organ Class (SOC) and Preferred Terms (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.1 or higher.  The incidence of 
AEs, as well as the intensity and relationship to study drug, will be summarized by cohort.  
Safety will also be assessed by evaluating findings of vital signs, physical examinations, 
Local Skin Reaction Scores, clinical laboratory test results, 12-lead ECG tracings, drug 
exposure/compliance, concomitant medications, pregnancy testing, dose adjustments, and 
withdrawals / terminations. These findings will be summarized and compared to findings 
from Baseline (Day 1 Pre-Dose) evaluations. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 8 OF 78 
3. 
TABLE OF CONTENTS 
1. 
COVER AND SIGNATURE PAGES .............................................................................. 1 
1.1. 
Title Page .............................................................................................................. 1 
1.2. 
Signature Pages ..................................................................................................... 2 
1.2.1. 
Clinical Signature Page.......................................................................... 2 
1.2.2. 
Investigator Signature Page ................................................................... 3 
2. 
PROTOCOL SYNOPSIS ................................................................................................. 4 
3. 
TABLE OF CONTENTS .................................................................................................. 8 
4. 
LIST OF ABBREVIATIONS ......................................................................................... 13 
5. 
BACKGROUND AND RATIONALE ........................................................................... 16 
5.1. 
Indication ............................................................................................................ 16 
5.2. 
Actinic Keratosis and Current Approaches to Treatment ................................... 16 
5.3. 
Unmet Medical Need .......................................................................................... 16 
5.4. 
Nonclinical Summary ......................................................................................... 17 
5.4.1. 
Oral toxicity studies in male and female rats....................................... 17 
5.4.2. 
Topical dermal toxicity studies in male and female minipigs ............. 18 
5.5. 
VDA-1102 Clinical Summary ............................................................................ 19 
5.5.1. 
Phase 1A Clinical Trial (Completed) .................................................. 19 
5.5.2. 
Phase 2 Clinical Trial (Completed) ..................................................... 20 
5.5.3. 
Phase 1B Clinical Trial (Ongoing) ...................................................... 21 
5.6. 
Rationale for Study Design and Subject Population ........................................... 22 
5.6.1. 
Efficacy ................................................................................................ 22 
5.6.2. 
Safety ................................................................................................... 22 
5.6.3. 
Pharmacokinetics ................................................................................. 23 
5.6.4. 
Study Design Rationale ....................................................................... 24 
5.7. 
Dose and Posology Justification ......................................................................... 25 
6. 
STUDY OBJECTIVES ................................................................................................... 26 
7. 
STUDY DESIGN............................................................................................................ 27 
7.1. 
Study Design: Study Weeks and Visits .............................................................. 27 
7.2. 
Study Design: Periods ......................................................................................... 27 
7.2.1. 
Screening Period (Day -21 through Day 1 Pre-Dose) ......................... 28 
7.2.2. 
Treatment Period (Day 1 Dosing Visit through Week 12) .................. 28 
7.2.3. 
Post-Treatment Follow-Up Period (Week 13 through Week 16) ........ 28 
7.3. 
Study Assessments .............................................................................................. 30 
7.4. 
Dose Holidays and Dosing Adjustments ............................................................ 33 
7.5. 
Study Withdrawals and Discontinuations ........................................................... 33 
8. 
STUDY ENDPOINTS .................................................................................................... 34 
9. 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ..................................... 35 
9.1. 
Inclusion Criteria ................................................................................................ 35 
9.2. 
Exclusion Criteria ............................................................................................... 35 
9.3. 
Study Medical Monitor Enrollment Consultation .............................................. 36 
9.4. 
Subject Replacement........................................................................................... 37 
9.5. 
Subjects Leaving the Trial .................................................................................. 37 
9.5.1. 
Termination by the Investigator........................................................... 37 
9.5.2. 
Subjects Who Wish to Withdraw ........................................................ 37 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 9 OF 78 
9.5.3. 
Subjects Lost to Follow-Up ................................................................. 38 
10. PROCEDURES FOR SAFETY EVALUATIONS ........................................................ 39 
10.1. Medical History .................................................................................................. 39 
10.2. Prior Concomitant Medications .......................................................................... 39 
10.3. Safety Measures .................................................................................................. 39 
10.3.1. 
Adverse Events .................................................................................... 39 
10.3.2. 
Vital Signs, Weight, and Height .......................................................... 39 
10.3.3. 
Physical Examination .......................................................................... 39 
10.3.4. 
Clinical Laboratory Tests .................................................................... 40 
10.3.5. 
Urine Pregnancy Test .......................................................................... 41 
10.3.6. 
Electrocardiogram................................................................................ 41 
10.3.7. 
Local Skin Reaction Score .................................................................. 42 
11. PROCEDURES FOR EFFICACY EVALUATIONS .................................................... 43 
11.1. AK Lesions ......................................................................................................... 43 
11.1.1. 
AK Lesion Count ................................................................................. 43 
11.1.2. 
Definition of AK Lesion Clearance ..................................................... 43 
11.1.3. 
AK Lesion Eligibility .......................................................................... 43 
11.2. Treatment Field Selection ................................................................................... 44 
11.3. Study Tools ......................................................................................................... 44 
12. CONDUCT OF THE STUDY ........................................................................................ 46 
12.1. Study Blinding and Randomization .................................................................... 46 
12.1.1. 
Study Blinding ..................................................................................... 46 
12.1.2. 
Randomization ..................................................................................... 46 
12.2. Pre-Screening ...................................................................................................... 46 
12.3. Subject Informed Consent .................................................................................. 46 
12.4. General Considerations ....................................................................................... 46 
12.4.1. 
Demographics ...................................................................................... 46 
12.5. Study Periods ...................................................................................................... 47 
12.6. Study Procedures per Period and Visit ............................................................... 47 
12.6.1. 
Screening Period .................................................................................. 47 
12.6.2. 
Treatment Period ................................................................................. 49 
12.6.3. 
Post-Treatment Follow-Up Period ....................................................... 51 
12.6.4. 
Early Termination Visit ....................................................................... 52 
12.7. Once-Monthly Subject Contact .......................................................................... 53 
12.8. Unscheduled Visits ............................................................................................. 53 
12.9. General Restrictions ............................................................................................ 54 
12.9.1. 
Medication and Other Therapeutic Restrictions .................................. 54 
12.9.2. 
Topical Non-Medicinal Product Restrictions ...................................... 55 
12.9.3. 
Sun Protection and Tanning................................................................. 55 
12.9.4. 
Dietary Restrictions ............................................................................. 55 
12.9.5. 
Nicotine and Alcohol Restrictions ....................................................... 55 
12.9.6. 
Physical Exercise Restrictions ............................................................. 55 
12.10. Childbearing Potential ........................................................................................ 55 
12.10.1. Definitions ........................................................................................... 55 
12.10.2. Contraception ....................................................................................... 56 
13. STUDY MEDICATION ................................................................................................. 57 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 10 OF 78 
13.1. Description of Study Medication ........................................................................ 57 
13.2. Drug Packaging................................................................................................... 57 
13.3. Drug Labeling ..................................................................................................... 57 
13.4. Study Drug Distribution...................................................................................... 57 
13.5. Study Drug Storage ............................................................................................. 57 
13.6. Study Drug Dispensing and Administration ....................................................... 58 
13.6.1. 
Study Drug Dispensing ........................................................................ 58 
13.6.2. 
Study Drug Dosing Cards .................................................................... 58 
13.6.3. 
Study Drug Measurement and Application Review ............................ 58 
13.6.4. 
Study Drug Administration at Home ................................................... 59 
13.7. Study Drug Accountability and Dosing Compliance ......................................... 60 
13.7.1. 
Study Drug Site Accountability ........................................................... 60 
13.7.2. 
Study Drug Accountability and Dosing Compliance .......................... 60 
13.7.3. 
Study Drug Weighing .......................................................................... 61 
14. CONCOMITANT MEDICATION ................................................................................. 62 
15. ADVERSE EVENTS ...................................................................................................... 63 
15.1. Adverse Event Definitions .................................................................................. 63 
15.1.1. 
General ................................................................................................. 63 
15.1.2. 
Local Skin Reactions ........................................................................... 63 
15.1.3. 
Laboratory and ECG Data ................................................................... 63 
15.1.4. 
Miscellaneous Definitions ................................................................... 63 
15.2. Clarification of the Difference between “Severe” and “Serious” ....................... 64 
15.3. AE Reporting ...................................................................................................... 64 
15.4. Relationship to Study Treatments ....................................................................... 64 
15.5. Follow-up of Adverse Events ............................................................................. 64 
16. SERIOUS ADVERSE EVENTS .................................................................................... 65 
16.1. Definition ............................................................................................................ 65 
16.2. Reporting of Serious Adverse Events ................................................................. 65 
17. STATISTICAL PLAN .................................................................................................... 67 
17.1. Sample Size Rationale and Justification ............................................................. 67 
17.2. Statistical analysis ............................................................................................... 67 
17.3. Secondary Efficacy Analyses ............................................................................. 67 
17.3.1. 
Primary Efficacy Analyses .................................................................. 67 
17.3.2. 
Secondary Efficacy Analyses .............................................................. 67 
17.4. Safety Assessments ............................................................................................. 68 
17.5. Pharmacokinetic Parameters ............................................................................... 68 
17.6. Missing Data ....................................................................................................... 68 
17.7. Data Sets ............................................................................................................. 68 
17.7.1. 
Safety Population ................................................................................. 68 
17.7.2. 
Modified ITT (mITT) Population ........................................................ 68 
17.7.3. 
Per Protocol Population ....................................................................... 68 
17.7.4. 
Face Subpopulation ............................................................................. 68 
17.7.5. 
Pharmacokinetic Population ................................................................ 69 
17.8. Definitions of the Terms Violation and Deviation ............................................. 69 
17.9. Subject Compliance ............................................................................................ 69 
17.10. Demographic and Baseline Characteristics ........................................................ 69 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 11 OF 78 
18. STUDY MANAGEMENT AND DATA COLLECTION ............................................. 70 
18.1. Data Collection Methods .................................................................................... 70 
18.2. Monitoring .......................................................................................................... 70 
18.3. Data Retention .................................................................................................... 70 
19. CLINICAL STUDY ADMINISTRATION, ETHICS, AND CONDUCT ..................... 71 
19.1. Good Clinical Practice ........................................................................................ 71 
19.2. Confidentiality .................................................................................................... 71 
19.2.1. 
Study Confidentiality ........................................................................... 71 
19.2.2. 
Subject Anonymity .............................................................................. 71 
19.3. Subject Information and Informed Consent........................................................ 71 
19.4. Study Closure ...................................................................................................... 72 
19.5. Early Termination of the Clinical Trial .............................................................. 72 
20. INVESTIGATOR’S OBLIGATIONS ............................................................................ 73 
20.1. General ................................................................................................................ 73 
20.2. Institutional Review Board ................................................................................. 73 
20.3. Investigator Protocol Adherence ........................................................................ 73 
20.4. Protocol Amendments......................................................................................... 74 
20.5. Audits and Inspections ........................................................................................ 74 
21. REFERENCES ............................................................................................................... 75 
22. APPENDICES ................................................................................................................ 77 
22.1. Local Skin Reaction Score .................................................................................. 77 
22.2. Subjective Local Skin Reaction Score ................................................................ 77 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 12 OF 78 
LIST OF TABLES 
Table 1: Schedule of Study Assessments .............................................................................................. 30 
 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schematic – Cohort 1 and Cohort 2 ............................................................ 29 
 
 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 13 OF 78 
4. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ß 
Beta 
°C 
Degrees Celsius 
µg 
Microgram 
µL 
Microliter 
µm 
Micron 
AE 
AIDS 
AK 
Adverse event 
Acquired Immunodeficiency Syndrome 
Actinic keratosis 
ALT 
Alanine aminotransferase 
AM 
API 
Morning 
Active Pharmaceutical Ingredient 
aPTT 
Activate Partial Thromboplastin  
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve from time zero (t0) to the 
time of the last measured sample (tlast) 
AUC0-τ 
Area under the plasma concentration-time curve from time zero to the last 
measurable concentration 
BID 
Twice daily 
BL 
BMI 
Baseline 
Body Mass Index 
CFR 
cm 
Code of Federal Regulations 
Centimeter 
Cmax 
Peak plasma concentration 
COA 
Certified Ophthalmic Assistant 
COT 
Certified Ophthalmic Technician 
CPK 
Creatinine phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
cSCC 
Cutaneous Squamous Cell Carcinoma 
D5W 
5% Dextrose 
dL 
Deciliter 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediamine tetra-acetic acid  
eg 
Exempli gratia, for example 
EP 
Electrophysiology 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
estimated glomerular filtration rate 
Hr(s) 
Hour(s) 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEA 
Interim Efficacy Analysis 
I.e. 
IID 
Id est, in other words 
FDA’s database on Inactive Ingredients 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 14 OF 78 
Abbreviation 
Definition 
IND 
Investigational New Drug 
INR 
International Normalized Ratio  
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Responsive Technology 
ITT 
Intent-to-Treat 
IU 
International Units 
IV 
Intravenous 
IWRS 
Interactive Web Randomization 
Kg 
Kilogram 
Ki 
Inhibition constant 
L 
Liter 
LLOQ 
Lower Level of Quantification 
LSR 
Local skin reaction 
mcg 
Microgram(s) 
MedDRA 
Medical Dictionary for Regulatory Activities  
Mg 
Milligram 
Min 
Minutes 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
Ms 
Milliseconds 
MTD 
Maximally Tolerated Dose 
NA 
NCE 
Not applicable 
New chemical entity 
NEI 
National Eye Institute 
Ng 
Nanogram 
nM 
Nanomoles 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Non-steroidal anti-inflammatory drugs 
OD 
Right eye 
Oz / ozs 
Ounce / ounces 
PBS 
Phosphate buffered saline 
PDT 
Photodynamic Therapy  
pg 
Picogram 
PI 
Primary Investigator 
pH 
hydrogen ion concentration 
PK 
Pharmacokinetic 
PM 
Evening 
prn 
Pro re nata (as needed) 
PSA 
Prostate-Specific Antigen 
PT 
Prothrombin Time or Preferred term 
QAM 
Each morning 
QD 
QOL 
Once daily 
Quality of Life 
QPM 
Each evening 
QS 
Quantum statis, the amount which is needed. 
QTcB 
QTc interval corrected using Bazett’s formula 
QTcF 
QTc interval corrected using Fridericia’s formula 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 15 OF 78 
Abbreviation 
Definition 
SD 
Standard Deviation 
SAE 
Serious adverse even 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
TEAE 
Standard Operating Procedure 
Treatment-emergent adverse event 
t½ 
Terminal plasma half-life 
Tmax 
Time of the peak plasma concentration 
ULN 
UPT 
US 
UVB 
Upper limit of normal 
Urine Pregnancy Test 
United States 
Ultraviolet B light 
Vss 
Volume of distribution at steady state 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 16 OF 78 
5. 
BACKGROUND AND RATIONALE 
5.1. 
Indication 
VDA-1102 is a small molecule new chemical entity (NCE) under development for the 
treatment of patients with actinic keratosis (AK).  
5.2. 
Actinic Keratosis and Current Approaches to Treatment 
Actinic keratosis (AK) is one of the most common dermatologic diagnoses and affects an 
estimated 58 million people in the United States. Estimated treatment costs in 2004 were $1.2 
billion (Warino 2006). AK is generally present as rough patches or papules with erythema and 
scaling on sun-exposed skin, predominantly in older individuals with fair skin (Fitzpatrick skin 
types I-III). The lesions are often asymptomatic, but they may itch or be tender to the touch. 
Histologically, AK is characterized by keratinocyte atypia in the deeper epidermis, with 
defective maturation of the superficial epidermis (Cohen, 2010). The most common reason for 
treatment is to prevent cutaneous squamous cell carcinoma (cSCC). Although the risk of 
progression to invasive SCC for a specific lesion may be low, it is widely regarded that 60% 
to 97% of SCCs originate from AK’s (Hurwitz 1995, Mittelbronn, 1998). This estimate is 
supported by considerable genetic analysis that demonstrates shared chromosomal 
abnormalities and progressive changes in gene expression between AK and SCC (Kanjilal, 
1995, Ortonne, 2002, Kanellou, 2008, Padilla, 2010). Consequently, AK is often referred to as 
cSCC in situ (Heaphy, 2000, Oppel, 2004, Röwert-Huber, 2007) and is part of the continuum 
of transformation from normal skin to AK and cSCC (Ziegler, 1994, Stockfleth, 2013).  
Since AK results from malignant processes in sun-exposed skin (mainly face, scalp, and 
extremities), it is often necessary to treat entire fields and not only the individual lesions. 
Cryosurgery and laser-based therapies are less effective for this indication. Currently the most 
common topical drugs and treatments for field-treatments of AK are 5-fluorouracil (5FU), 
imiquimod cream, ingenol mebutate gel, photodynamic therapy (PDT), and diclofenac sodium 
in hyaluronic acid (Chetty, 2015).  
5.3. 
Unmet Medical Need 
Current AK therapies are inadequate and pose significant challenges to public health. Nearly 
all field treatments are associated with painful severe local skin reactions ranging from necrosis 
to inflammation which reduce treatment compliance (Shergill 2014). Cryotherapy and surgery 
are used to treat a limited number of lesions. However, these may leave unsightly scars or 
hypopigmentation and patients often require repeat treatments.  
The limited tolerability of most current treatments greatly decreases the willingness of patients 
to be retreated. Diclofenac sodium is the only drug available that is well tolerated. However, it 
requires daily application for prolonged periods, shares the contraindications and potential side 
effects of the non-steroidal anti-inflammatory drug, and its long-term efficacy is still unknown. 
Consequently, AK patients often elect to avoid treatment and seek medical help only after their 
lesions have become esthetically intolerable or have advanced to invasive cSCC tumors.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 17 OF 78 
In contrast, VDA-1102 has the potential for a significantly more desirable benefit-risk ratio. 
The drug induces neither necrosis nor an inflammatory reaction. VDA-1102 would mitigate 
people’s avoidance of treatment and the often-required re-treatment of their chronic, recurrent 
skin disease.   
5.4. 
Nonclinical Summary 
The four GLP toxicology studies performed were the 28-day and 13-week repeated dose oral 
toxicity studies in male and female rats (with a recovery phase and toxicokinetics), and the 28-
day and 3-month topical dermal toxicity studies in male and female minipigs (with a recovery 
phase and toxicokinetics). 
5.4.1. 
Oral toxicity studies in male and female rats  
• 28-day repeated dose with a recovery phase and toxicokinetics 
Oral administrations of 800 mg/kg/day of VDA-1102 once daily for 28 days to male and 
female SD rats was associated with clinical signs and intestinal-tract related inflammation 
in the non-glandular stomach (forestomach), cecum, and colon. These findings were either 
resolved or trending towards remission at the end of the 2-week recovery phase. These 
gastrointestinal effects may be related to irritant properties associated with repeated oral 
gavage administration of VDA-1102. The No Observed Adverse Effect Level (NOAEL) 
was 300 mg/kg/day (this approximately equates to a human equivalent dose (HED) of 48 
mg/kg/day). Systemic exposure to VDA-1102 was not detected, but substantial blood levels 
of its metabolite jasmonic acid were found, suggestive of a rapid metabolism of VDA-1102 
by this route of administration. 
• 13-week repeated dose with a recovery phase and toxicokinetics 
A 13-week study was conducted to evaluate the potential toxicity of VDA-1102 after daily 
oral administration of 75, 150, and 300 mg/kg/day (HED 12, 24, and 48 mg/kg/day, 
respectively) of VDA-1102 for 13 weeks to male and female SD rats with a 6 weeks 
recovery period and toxicokinetics. All the animals in this study have completed their 13-
week dosing period and 6-week recovery period. There were no deaths, no observed 
changes in food consumption, nor decrease in body weight in any of the rats. No treatment-
related changes were recorded in organ weights or macroscopic examinations in treated 
animals, when compared with controls. Laboratory investigation (i.e. hematology, 
coagulation, blood chemistry and urinalysis) failed to show toxicologically relevant 
modifications at any of the tested doses. The only clinical observation was salivation in 
most of the animals in the high-dose group and in some animals in the mid-dose group.  
Non-adverse histopathological changes were observed in the duodenum and spleen of 
male and female animals dosed at 300 mg/kg/day (high dose level).  These findings were 
not observed at the end of a 6-week treatment-free recovery period. Therefore, the NOAEL 
(No Observed Adverse Effect Level) for this study was considered to be 300 mg/kg/day. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 18 OF 78 
5.4.2. 
Topical dermal toxicity studies in male and female minipigs 
• 28-day repeat dose with a recovery phase and toxicokinetics 
In the 28-day minipig study, there were no noteworthy systemic toxicity effects observed 
following once-daily dermal application of VDA-1102 ointment to 10% of their body 
surface area, even at the highest strength tested of 20%, which is also the maximum feasible 
dose in this formulation. The NOAEL for systemic toxicity was thus 20% VDA-1102 
ointment, corresponding to a topical dose level of 60 mg/kg/day (HED 43 mg/kg/day). The 
NOAEL for local application site effects was 5% VDA-1102 ointment. The only notable 
findings were observed in animals treated with 10% and 20% VDA-1102 ointment, where 
very slight to slight erythema was reported, that progressed after approximately 2 weeks to 
mild/moderate erythema, edema, desquamation, and/or scabs. These findings appeared to 
be reversible with cessation of the treatment. A maximum tolerated dose (MTD) for the 
local application of VDA-1102 was not reached even at the highest dose tested of 20%. 
• 13-week repeat dose with a recovery phase and toxicokinetics 
A 13-week study was conducted to evaluate the potential toxicity of VDA-1102 when 
administered on the skin in male and female minipigs after daily unoccluded topical 
administration to 10% of the body surface area at concentrations 2.5, 5 and 15% of VDA-
1102 ointment (corresponding to 7.5, 15, and 45 mg/kg/day, HED 11, 21, and 32 
mg/kg/day, respectively). No treatment-related changes of significance were observed in 
mortality, clinical signs of systemic toxicity, body weight, food consumption, 
ophthalmoscopy, electrocardiography, clinical pathology investigations, organ weights, or 
macroscopic/microscopic examinations apart from changes at the dermal application site. 
Erythema (sometimes multifocal) at the treatment site of similar magnitude and severity 
were observed in both VDA-1102-treated and vehicle control animals. Erythema was of 
similar magnitude and severity in all treatment groups with a mean severity score of “very 
slight” to “slight/well-defined.” In single cases and for a limited period of time, “moderate” 
erythema was observed. On occasion crust/scabs accompanied the erythema, particularly 
in animals receiving 15%VDA-1102. In addition, dose-related “very slight” edema was 
only occasionally observed in animals receiving VDA-1102.  
Skin reactions, in general, appeared within the first two weeks of the study, increased up to 
Week 4 and remained stable or showed a tendency to a slight improvement thereafter. 
During recovery a clear trend to recovery was observed and a complete recovery was noted 
at Week 4 of the recovery period. 
The undetectable (or very low) concentrations of VDA-1102 measured on Day 1 and the 
low blood levels detected on Week 13 along with the low concentrations of jasmonic acid 
detected on Day 1 and the large exposure to this metabolite measured on Week 13, suggest 
that VDA-1102 is slowly absorbed from the skin of the minipigs and rapidly metabolized. 
The Week 13 jasmonic acid systemic exposure in minipigs following dermal application of 
5% VDA-1102 in the present study was comparable to that obtained in minipigs receiving 
5% VDA-1102 for 4 weeks in a previous study (RTC Study A0608), suggesting that at this 
dose level, there is no accumulation with an increase in duration of topical application. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 19 OF 78 
The NOAEL (No Observed Adverse Effect Level) for systemic toxicity was 15% VDA-
1102, the highest concentration tested. The NOAEL for the local effects was 5% VDA-
1102 (15.2 mg/kg/day). 
As discussed below in Section 5.7, the relative doses of VDA-1102 fed to rats and applied to 
the skin of minipigs were significantly higher than the exposures in the current planned clinical 
study. 
Full details of the non-clinical studies performed to date are found in the accompanying 
Investigator’s Brochure.  
5.5. 
VDA-1102 Clinical Summary 
Three clinical trial have been conducted with VDA-1102 topical (dermal) ointment, a first-in-
human Phase 1a single-dose study in older-adult healthy volunteers, a Phase 2a study in which 
93 subjects with actinic keratosis received a once-daily application of study drug (5% or 10% 
VDA-1102, or Placebo) for 4 weeks, and an ongoing Phase 1b multiple-dose preliminary safety 
trial in AK subjects to evaluate a more frequent applications, higher strength of VDA-1102, 
and longer treatment durations (8-12 weeks).  
5.5.1. 
Phase 1A Clinical Trial (Completed) 
Study VDA-CP-01 was a single-center, randomized, double-blinded, placebo-controlled, 
single-dose, dose-escalation study in 3 unique cohorts (4 active, 1 placebo randomized per 
cohort) of older healthy adult subjects. The objectives of the study were assessment of the local 
and systemic safety of the study drug as well and the pharmacokinetics of VDA-1102 and its 
primary metabolite (jasmonic acid) after application of VDA-1102 (5, 10 or 20%) or placebo 
to a 25 cm2 area of the skin of each subject’s forehead for 24 hours.  
The conclusions of this study were as follows: 
• Topical application of VDA-1102 at concentrations of 5%, 10%, and 20% versus placebo 
were well-tolerated following a single application of approximately 250 mg to a 25 cm2 
Treatment Field (forehead area) of healthy older-adult subjects. 
• Detailed and frequent examination of the Treatment Field for local skin reactions did not 
reveal any treatment-emergent findings at concentrations as high as 20% VDA-1102. 
• There were no TEAEs related to study drug in any subject with the exception of mild left 
eye pain that occurred approximately 4 hours after the drug was applied to the forehead in 
1 subject receiving 10% VDA-1102.  This event was short-lived and resolved without 
sequelae. 
• There were no treatment emergent changes in any subject in clinical laboratory, vital signs, 
physical examination, or ECG evaluations. 
• Undetectable plasma concentrations of VDA-1102 or its primary metabolite (jasmonic 
acid) at any time point (using a sensitive LC-MS/MS validated assay) during or after a 24-


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 20 OF 78 
hour topical exposure to up to 20% VDA-1102 suggest minimal systemic absorption of 
VDA-1102 under the conditions of this study. 
5.5.2. 
Phase 2 Clinical Trial (Completed) 
Study VDA-CP-03 was a Phase 2, multi-center, randomized, double-blind, placebo-controlled, 
multiple-dose, parallel-cohort study involving the once-daily non-occluded, topical dermal 
application of VDA-1102 ointment for 28 to subjects with AK. Eligible subjects were required 
to present with a minimum of 4 and a maximum of 8 discrete Grade 1-2 AK lesions within a 
single 25 cm2 area of skin on their scalp or face that met specific criteria for the AK Lesions 
and Treatment Field.  Ninety-three (93) eligible subjects in Israel and the United States were 
randomly assigned in a double-blind fashion to 1 of 3 parallel treatment groups (5%, or 10% 
VDA-1102, or placebo) in a ratio of 1:1:1. Randomized subjects applied approximately 200 
mg of study drug each evening to a 25 cm2 Treatment Field on their face or scalp. Subjects 
underwent safety and efficacy assessments during the Treatment Period on Days 7, 14, and 28 
and during the Observation Period on Days 35 and 56 (and Day 84 for subjects who consented 
to Amendment 2). A sub-group of 12 subjects, who met additional more stringent enrollment 
criteria, participated in the PK Study Sub-Cohort.  
The overall conclusions from this proof-of-concept study that included a relatively short 28-
days of double-blind, placebo-controlled treatment with study drug are as follows: 
• VDA-1102 at dosage strengths of 5% or 10% given as 200 mg topical doses daily for 28 
days was well-tolerated both from a systemic as well as a local skin area (site of application) 
perspective.  This is consistent with the good dosing compliance and low level of early 
discontinuations without the need to adjust the dosing regimen for any subject. 
• There were no deaths, serious adverse events related to study drug, or early study 
discontinuations for AEs related to study drug in this study.   
• In the AK patient population evaluated in this study, 28 days of once daily dosing of a 
predefined Treatment Field on the face or scalp with 200 mg of either VDA-1102 5% or 
10% did not result in a statistically significant decrease in the number of AK lesions 
compared to placebo treatment.  However, the mean decrease was greater in the VDA-1102 
10% treatment group compared to the placebo treatment group.  
• The differences between the VDA-1102 10% treatment group and the placebo treatment 
group on the 4 exploratory efficacy endpoints consistently favored VDA-1102 10% across 
all 3 analysis populations.  These differences (ITT population) were statistically 
significantly different (versus placebo) for change from baseline in the number of lesions 
with a grade ≥ 2 (P = 0.03) and change from baseline in the adjusted number of lesions 
weighted by grade (P = 0.02). 
• There were no statistically or clinically relevant differences on any exploratory endpoint 
between the VDA-1102 5% and placebo treatment groups. 
• Post-hoc analysis of an efficacy subset of patients who were only treated for AK Treatment 
Field lesions on the face (ie, not scalp) and represented approximately 75% of enrolled 
patients demonstrated that the VDA-1102 10% treatment group (ITT population) had a 
statistically significant greater reduction in the number of AK lesions compared to the 
placebo treatment group (P = 0.02). 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 21 OF 78 
• The positive finding for VDA-1102 10% treatment group in the efficacy subset of patients 
with AK Treatment Fields only on the face was supported by similar treatment effect 
differences versus the placebo treatment group on the exploratory endpoints evaluated in 
the originally planned exploratory analyses. 
• A post-hoc analysis of treatment group differences (ITT population) for progression of AK 
to Grade 3 indicated 2 subjects in the placebo treatment group progressed to grade 3 versus 
no subjects in the 2 VDA-1102 treatment groups. 
• The inability to detect plasma concentrations of VDA-1102 or jasmonic acid using sensitive 
methodology in the subjects included in the PK sub-cohort suggests no systemic absorption 
of 200 mg VDA-1102 when applied once-daily topically for up to 28 days in a 25 cm2 
Treatment Field. 
Further details of the results of this trial are provided in the VDA-1102 Investigator’s brochure. 
5.5.3. 
Phase 1B Clinical Trial (Ongoing) 
Study VDA-CP-04 is an ongoing single-center, open-label, 2-cohort, dose-escalation study in 
patients with AK. Cohort 1 of the study is complete; Cohort 2 is ongoing. In the completed 
Cohort 1, five subjects applied 200 mg of 10% VDA-1102 twice-daily for 8 weeks to a 25 cm2 
Treatment Field located on their face, forehead, or balding scalp. Subjects underwent safety 
and efficacy assessments at Baseline and at Week 2, 4, 6, 8, 9, and 12 Visits. The following is 
a summary of the available safety data from the completed Cohort 1 of this study: 
• There have been no systemic safety signals as demonstrated by a lack of clinically 
significant changes in vital signs, physical examinations, clinical laboratory results, and 
electrocardiographic data.  
• There were no deaths or SAEs and no subject withdrew consent from the trial prematurely, 
although 1 subject described below prematurely stopped the study drug due to an AE.  
• The mean maximum Local Skin Reaction (LSR) composite score was 1.2 (0=no reaction; 
1=trace; 2=mild; 3=moderate; 4=severe).  
• Three of the 5 subjects reported treatment-related AEs. For 2 of these subjects the AEs 
were mild in severity (conjunctivitis right eye and itchy and painful scalp).  For 1 subject 
the AE of contact dermatitis was considered severe.  For this latter subject, the Treatment 
Field was on their right forehead. The subject received topical 5-FU and photodynamic 
therapy (major deviations) to numerous AKs located over a large area of her upper chest 
during Week 3 and developed a severe facial dermatitis at Week 4 that involved the right 
forehead, ipsilateral periorbital area, and bilateral cheeks. Throughout, the individual LSR 
scores remained mild to moderate. The eruption completely resolved with cessation of the 
study drug 2 days after the Week 4 Visit (2 weeks) and application of a topical steroid 
cream (1 week). 
• Neither the parent molecule VDA-1102 nor its primary metabolite jasmonic acid was 
detected in timed blood samples assayed with a validated and sensitive bioanalytical 
method. 
In Cohort 2, six subjects will apply 200 mg of 20% VDA-1102 to their Treatment Field for 12 
weeks. This cohort is currently enrolling.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 22 OF 78 
5.6. 
Rationale for Study Design and Subject Population 
5.6.1. 
Efficacy 
VDA-1102 has shown relevant pharmacological effects in vivo in the UVB-induced SKH-1 
hairless mice model of actinic keratosis and skin cancer. In this pre-clinical study, dermal 
application of VDA-1102 led to a significant (p < 0.0001) reduction in the number of lesions 
relative to vehicle, that was comparable to the reduction noted with the comparative control 
compound ingenol mebutate (Picato®) 0.05%. Clinical effects were observed within 1–2 
weeks of treatment initiation, although full clinical benefit was observed after 3-4 weeks.  
In the Phase 2a study (Section 5.5.2, above) subjects treated once-daily with 10% VDA-1102 
or placebo for 4 weeks (28 days) had a modest reduction from baseline in the total number of 
AK lesions (32.1% versus 27.8%, respectively). The decrement in the number of lesions of 
subjects in the per protocol population who had Treatment Fields located on their face (not 
scalp) was more impressive and statistically significantly (median 50%; mean 41.3% ±38.5% 
for the VDA-1102 10% treatment group versus median 10%; mean 29.4% ±32.5%, for the 
placebo treatment group, P = 0.022 adjusted for age, gender and site).   
In the small (N=5) completed Cohort 1 of the Phase 1B trial summarized in Section 5.5.3, 
subjects treated with 10% VDA-1102 twice-daily for 8 weeks had a 74% reduction in the 
number of AK lesions in their Treatment Field. Aside from 2 subjects with reversible skin 
reactions, the drug was well-tolerated and safe. Together, these data suggest VDA-1102 has 
therapeutic effects and further evaluation of the dosing regimen/dose and longer duration of 
treatment is warranted.  
In contrast to the aforementioned Phase 2a study where 200 mg of 10% VDA-1102 ointment 
was applied once-daily for 4 weeks and the completed Cohort 1 of the small ongoing Phase 1b 
study where 200 mg of 10% VDA-1102 ointment was applied twice-daily for 8 weeks, the 
dosing frequency in Part A (Cohort 1) of the current clinical trial remains 200 mg of 10% VDA-
1102 ointment twice-daily; however, the treatment duration will be extended to 12 weeks.  
In Part B (Cohort 2) of the current trial, the strength of the VDA-1102 ointment increases from 
10% to 20% but the dosing frequency drops from twice-daily to once-daily. The treatment 
duration will be the same as in Part A, 12 weeks.  
Subjects enrolled in Part C of the current trial will be randomized to receive approximately 200 
mg of either 10% VDA-1102 BID as was given to Cohort 1 in Part A or 20% VDA-1102 QD 
as was applied by Cohort 2 in Part B.   
5.6.2. 
Safety 
The results from the toxicology studies and the estimated safety margins indicate that daily 
dermal application of 200 mg of VDA-1102 ointment for 12 weeks at doses as high as 20% to 
an area of 25 cm2 does not pose an untoward risk for evaluation in the target patient population. 
Specifically, topical application once-daily for 13-weeks of approximately 5 grams of 2.5%, 
5%, 15% VDA-1102 ointment to 10% of the minipigs body surface area in the nonclinical 
toxicology program resulted in no systemic safety findings. Only mild to moderate skin 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 23 OF 78 
findings (almost exclusively erythema; no ulceration, vesiculation or pustulation) were seen in 
the VDA-1102 treated groups as well as in the control groups. Transient mild edema and 
isolated scabs/crust were reported in a minority of 15% VDA-1102-treated animals. All lesions 
were self-limited and reversible.  
In the completed Study VDA-CP-01 in healthy subjects (Section 5.5), no safety concerns were 
identified following a single-dose of approximately 250 mg of 5%, 10%, or 20% VDA-1102 
applied once to a 25 cm2 area on the forehead of healthy older-adult volunteers.  PK analysis 
demonstrated that there were no detectable concentrations of VDA-1102 or its primary 
metabolite jasmonic acid.  
In the completed Study VDA-CP-03 in AK patients (Section 5.6.1), 200 mg of 5% or 10% 
VDA-1102 ointment was applied once-daily for 4 weeks to an area of 25 cm2 on the cheek, 
forehead, or scalp. No safety concerns were identified. VDA-1102 5% and 10% were well-
tolerated when applied once-daily for 4 weeks. There was no clinically significant change in 
the Local Skin Reaction individual component scores or total scores. PK analyses of plasma 
from timed pre- and post-dose blood samples demonstrated that there were no detectable 
concentrations of VDA-1102 or its primary metabolite jasmonic acid.  
In the competed Cohort 1 of the ongoing Study VDA-CP-04 (Section 5.5.3) in AK patients, 
subjects applied 200 mg of 10% VDA-1102 twice-daily to their facial or scalp Treatment Field 
for 8-weeks. No significant systemic safety findings were reported. Two subjects experienced 
reversible skin eruptions attributed to the study drug: one of whom underwent extensive 
prohibited treatments (topical 5FU and photodynamic therapy) to AK lesions on her upper 
chest during the Treatment Period coincident with the initiation of the facial eruption and a 
second subject who experienced a mild, self-limited scalp eruption. PK analyses of plasma 
from timed pre- and post-dose blood samples demonstrated that there were no detectable 
concentrations of VDA-1102 or its primary metabolite jasmonic acid in the plasma samples.  
In the current study, 10% VDA-1102 will be applied twice-daily for 12 weeks in Cohort 1 and 
20% VDA-1102 will be applied once-daily for 12 weeks in Cohort 2. Given the lack of 
systemic absorption in subjects treated with 10% VDA-1102 BID for 8 weeks in Study VDA-
CP-04 (Section 5.5.3), we believe that any potential safety concerns in either of these 2 cohorts 
would not be systemic and will be limited to the Treatment Field and perhaps the surrounding 
skin. To date, all adverse reactions in and around the Treatment Field have been reversible and 
the great majority were mild, short-lived, and self-limited.   
5.6.3. 
Pharmacokinetics 
In preclinical PK studies, VDA-1102 was rapidly metabolized, forming jasmonic acid (JA) as 
its inactive primary metabolite, regardless of the animal species or the route of administration. 
In all cases, the amount of JA in the blood equaled or exceeded the concentrations of VDA-
1102 in the blood.  In a 28-day dermal toxicity study in male and female minipigs, 5%, 10% or 
20% of VDA-1102 ointment was applied once daily to 10% of the body surface area. Blood 
levels of VDA-1102 were essentially below the LLOQ on Day 1 and very low and highly 
variable on Day 28. Blood concentrations of the primary metabolite jasmonic acid on Day 1 
were detected only in the 20% VDA-1102 ointment group On Day 28, blood levels of jasmonic 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 24 OF 78 
acid were detected at all dose levels and were higher than that on Day 1, likely related to slow 
transdermal absorption as it appeared that steady state levels were present on Day 28.  
In the 13-week topical dermal toxicity study performed in minipigs, low levels of both VDA-
1102 and the major metabolite JA were detected on Day 1. However, by Week 13 high 
concentrations of JA (Cmax= 954 and 1830 ng/mL for male and female minipigs, respectively) 
were found in plasma while VDA-1102 concentrations remained low which suggested a slow 
absorption of VDA-1102 and rapid metabolism of the parent drug to JA. 
In the completed Phase 1a, 1b, and 2a clinical trials, plasma levels of VDA-1102 and its 
primary metabolite jasmonic acid (JA) were below the lowest level of detection at all 
timepoints sampled. 
5.6.4. 
Study Design Rationale 
The results from the Phase 2a (VDA-CP-03; Section 5.5.2) clinical trial support the safety and 
tolerability of 200 mg of 10% VDA-1102 ointment when applied once-daily for 4 weeks (28 
days), but the efficacy was moderate. In the completed Cohort 1 of the ongoing Phase 1B trial 
(VDA-CP-04; Section 5.5.3) subjects treated with 10% VDA-1102 twice-daily for 8 weeks the 
efficacy was improved, while safety and tolerability were maintained. These studies suggest 
that higher study drug concentrations, more frequent dosing, and/or a longer treatment duration 
are likely to improve efficacy. The non-clinical and clinical data support the safety of this 
approach as well. 
In Cohort 1 (Part A) of the current study 40 subjects will apply approximately 200 mg of 10% 
VDA-1102 twice-daily, the same dose applied in Cohort 1 of trial VDA-CP-04. However, 
subjects enrolled in the current study (VDA-CP-05) will apply the study drug to their Treatment 
Field for 12 weeks instead of 8 weeks.   
Once approximately 40 subjects have been enrolled in Cohort 1 (Part A), this cohort will be 
closed to enrollment and Cohort 2 (Part B) will be opened for enrollment.  
The reason for the initial split into Part A and Part B is due to the drug product manufacturer’s 
schedule (i.e., drug supply). 
In Cohort 2 (Part B) approximately 40 subjects will apply approximately 200 mg of 20% 
VDA-1102 once-daily to their Treatment Field for 12 weeks.  
Following completion of enrollment of approximately 40 subjects into Cohort 2 (Part B), Part 
C will be opened to enrollment wherein 70 subjects will be randomized in a 1:1 ratio to either 
Cohort 1 or Cohort 2. Thus, the trial will close with a total of approximately 75 subjects in each 
cohort.  
The goals and rationale of this open-label, dose-escalation trial are to assess the tolerance, 
safety, and efficacy of two different dosing strategies for VDA-1102 ointment. The results of 
this study will be applied to the study design and dose selection for the pivotal Phase 3 trials.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 25 OF 78 
5.7. 
Dose and Posology Justification 
Vidac is assessing the dose-response curve and therapeutic index of VDA-1102 ointment in 
AK subjects to further determine the most appropriate treatment parameters to support a 
potential Phase 3 study. The Phase 2a trial (VDA-CP-03) involved once-daily 200 mg 
application of 10% VDA-1102 to a 25cm2 Treatment Field on the face or balding scalp of 
subjects with AK for 4 weeks. The study drug was well-tolerated with hardly any LSRs 
reported.  Neither VDA-1102 nor its major metabolite JA was detected in the plasma of treated 
subjects. The reduction in the number of AK lesions in this short, proof-of-concept trial was 
modest. 
In the completed Cohort 1 of the ongoing dose-ranging Study VDA-CP-04, 5 AK subjects 
applied 200 mg of 10% VDA-1102 twice-daily for 8 weeks to a 25cm2 Treatment Field on the 
face or balding scalp. In this small study, the reduction in AK lesions was considerably better 
(74%) than in the Phase 2a trial (32%) and no systemic exposure was found for VDA-1102 or 
its major metabolite, supporting an even longer (e.g., 12 week) treatment period in order to 
obtain clinically significant complete clearance.  
The goals of the current study (VDA-CP-05) are to evaluate efficacy, safety, and tolerability 
of the same total daily dose of VDA-1102 already tested in a previous clinical study (VDA-
CP-05). This total daily dose (1.67 mg/kg/day) will be given either as a divided dose of 10% 
VDA-1102 BID (Cohort 1) or a single dose of 20% VDA-1102 QD (Cohort 2) for a 12-week 
treatment period. This dose (1.67 mg/kg/day) is close to 20-fold lower than the HED of the 
NOAEL dose determined in the 13-week dermal toxicity study in minipigs (32 mg/kg/day) and 
is close to 30-fold lower than the HED of the NOAEL dose determined in the oral 13-week 
toxicology study in rats (48 mg/kg/day).  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 26 OF 78 
6. 
STUDY OBJECTIVES 
Primary Objective:  
• To assess the percent of subjects with complete clearance of the actinic keratosis (AK) 
lesions in their Treatment Field at Week 16  
• To assess the percent of subjects with facial Treatment Fields who achieved complete 
clearance of actinic keratosis (AK) lesions at Week 16 
• To evaluate the systemic and local (skin) safety and tolerability of topical application 
of VDA-1102 ointment in adult subjects with AK for 12 weeks 
Secondary Efficacy Objectives: 
• To assess the percent of subjects with partial (≥75%) clearance of the actinic keratosis 
(AK) lesions in their Treatment Field on Week 16  
• To assess the percent of subjects with facial Treatment Fields who have partial (≥75%) 
clearance of the actinic keratosis (AK) lesions on Week 16  
• To assess the reduction in the number of the actinic keratosis (AK) lesions in the 
Treatment Field on Week 16  
• To assess the reduction in the number of the actinic keratosis (AK) lesions on Week 16 
of subjects with facial Treatment Fields Study Description 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 27 OF 78 
7. 
STUDY DESIGN 
7.1. 
Study Design: Study Weeks and Visits 
This is a multi-center, open-label, 3-part, 2-cohort Phase 2b study involving daily non-
occluded, topical dermal application of VDA-1102 ointment in subjects with actinic keratosis 
(AK).  The study design is summarized in Figure 1. 
To qualify for the study, male and female subjects aged 18 (inclusive) or older must have signed 
informed consent and have met the study enrollment criteria at the Screening Visit and Day 1 
Pre-Dose Visit that include having 4-8 actinic keratosis (AK) lesion within an approximate 25 
cm2 area on the cheek, forehead or balding scalp (the “Treatment Field”).  
Part A / Cohort 1 
A total of approximately 75 subjects will be consecutively enrolled in Cohort 1. Enrolled 
subjects will apply approximately 200 mg of 10% VDA-1102 twice-daily to their Treatment 
Field for approximately 12 weeks. Safety assessments will occur on the Day 1 Pre-Dose and 
Day 1 Dosing Visits. Safety and efficacy assessments will be repeated at the Week 4, 8 and 
12 Visits. This portion of the study will be called the Treatment Period.  
Subjects will return for safety and efficacy assessments at the Week 13 and 16 Visits (Post-
Treatment Follow-Up Period).  
Once approximately 40 subjects have been enrolled in Cohort 1, enrollment into this cohort 
will be closed and Cohort 2 will be opened to enrollment.  
Part B / Cohort 2 
Cohort 2 subjects will apply approximately 200 mg of 20% VDA-1102 to their Treatment Field 
each morning (QAM) for approximately 12 weeks.  
The procedures and activities to be performed on subjects enrolled in Cohort 1 are the same as 
those to be performed on subjects in Cohort 2. 
Part C / Cohorts 1 and 2  
Once the number of subjects in Cohort 2 approximates the number in Cohort 1, Part C of the 
study will begin wherein approximately 70 eligible subjects will be randomly assigned to either 
Cohort 1 or Cohort 2. Thus, the trial will close with a total of approximately 75 subjects in each 
cohort.  
7.2. 
Study Design: Periods 
The study periods are the same for all 3 parts of the study. The study design is summarized in 
Figure 1 and further details for each study period are provided below. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 28 OF 78 
7.2.1. 
Screening Period (Day -21 through Day 1 Pre-Dose) 
During the Screening Visit (up to approximately 21 days pre-dose) subjects who have given 
written informed consent will undergo screening, safety assessments, Treatment Field 
identification, and study drug application training.    
At the Day 1 Pre-Dose Visit, eligible subjects will return to the investigative site for baseline 
assessments, final eligibility screening, Treatment Field identification, and study drug 
application training. AK lesions within the Treatment Field will be counted.  
Three times during the Screening and Day 1 Pre-Dose Visits, subjects will be trained and tested 
in proper measurement and application of the study drug to the Treatment Field with the help 
of a Dosing Card and a flexible plastic stencil (“Treatment Field Template”). Subjects unable 
to apply the study drug properly will be excluded, unless they are accompanied by a dosing 
partner willing and able to properly dose the subject each day.  
Subjects who continue to meet the enrollment criteria will be enrolled and will continue to the 
Day 1 Dosing Visit.   
7.2.2. 
Treatment Period (Day 1 Dosing Visit through Week 12)  
Subjects (or their dosing partner) will apply the first dose of the study drug during the Day 1 
Dosing Visit under the supervision of the site personnel to further assure proper application. 
Subsequently, subjects will apply the study drug (10% VDA-1102 BID or 20% VDA-1102 
QAM) to their respective Treatment Fields while at home for 12 weeks. Subjects will visit their 
respective investigative sites at Weeks 4, 8, and 12 for safety and efficacy assessments, drug 
accountability, and re-training in proper application of the study drug. 
7.2.3. 
Post-Treatment Follow-Up Period (Week 13 through Week 16) 
Subjects will undergo safety and efficacy assessments at Week 13 and 16 Visits. Subjects will 
exit the trial at the conclusion of the Week 16 Visit procedures.   


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 29 OF 78 
Figure 1. 
Study Design Schematic – Cohort 1 and Cohort 2 
 
 
 
 
 
 
 
 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 30 OF 78 
7.3. 
Study Assessments 
The Table of Assessments appears below. The number preceding the √ denotes the number of times this procedure will be performed at that visit 
(e.g. 3√ means 3 times). If the √ is not preceded by a number, then the procedure will be performed only once.   
Table 1: Schedule of Study Assessments 
ASSSESSMENTS 
STUDY PERIODS, STUDY VISITS, AND STUDY DAYS 
SCREENING PERIOD 
TREATMENT PERIOD 
POST-TREATMENT 
FOLLOW-UP PERIOD 
Screening Visit 
Day 1 Visits 
Week 4 Visit 
Week 8 Visit 
Week 12 / Early 
Termination 
Visit 1 
Week 13 Visit 
Week 16 Visit 
Day -21 to 
Day -1 
Day 1 
Pre-Dose  
Day 1 
Dosing 
Day 29 ±4 
Day 57 ±5 
Day 85 ±5 
Day 92 ±5 
Day 113 ±5 
Informed Consent  
√ 
 
 
 
 
 
 
 
Enrollment criteria and safety data review 
√ 
√ 
 
 
 
 
 
 
Demographics & Medical History 
√ 
 
 
 
 
 
 
 
Adverse events recording 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
Concomitant medications recording 
√ 2 
√ 
 
√ 
√ 
√ 
√ 
√ 
Vital signs 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
                                                 
1 Subjects attending an Early Termination Visit (Section 7.5) will undergo Week 12 Visit procedures.  In addition, women will undergo a Urine Pregnancy Test.  
2 Prior concomitant medications will be recorded at Screening, which includes all ongoing medications and medicinal products or with a stop date within 2 months preceding 
Screening. All topical skin treatments (i.e., medicinal or physical) received in the 4 months prior to Screening will be recorded.  
 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 31 OF 78 
ASSSESSMENTS 
STUDY PERIODS, STUDY VISITS, AND STUDY DAYS 
SCREENING PERIOD 
TREATMENT PERIOD 
POST-TREATMENT 
FOLLOW-UP PERIOD 
Screening Visit 
Day 1 Visits 
Week 4 Visit 
Week 8 Visit 
Week 12 / Early 
Termination 
Visit 1 
Week 13 Visit 
Week 16 Visit 
Day -21 to 
Day -1 
Day 1 
Pre-Dose  
Day 1 
Dosing 
Day 29 ±4 
Day 57 ±5 
Day 85 ±5 
Day 92 ±5 
Day 113 ±5 
Physical examination 
 
√ 
 
√ 
√ 
√ 
 
√ 
Height / Weight 
√ 
 
 
 
 
 
 
 
12-Lead ECG 3 
√ 
√ 
 
 
 
√ 
√   
√  
Clinical laboratory testing 3, 4 
√ 
√ 
 
 
 
√ 
√  
√  
Treatment Field Selection 
√ 
√ 
 
 
 
 
 
 
AK lesions numbering, counting and grading 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
Local Skin Reaction Score 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
Treatment Field photograph, Template, and 
Map prepared 
 
√ 
 
 
 
 
 
 
Urine Pregnancy Test (UPT) 5  
√ 
√ 
 
 
 
(√6) 
√ 
 
                                                 
3 Clinical laboratory testing and 12-lead ECG will only be performed at Week 13 and/or Week 16 Visits if the results from the previous visit were abnormal and clinically 
significant.  
4 Hematology, Chemistry, Coagulation, and Urinalysis. A sample for coagulation will not be collected at Day 1. Blood sampling for all clinical laboratory tests should be 
performed following a fasting period of approximately 8 hours with the exception of the Screening blood sampling that may be performed randomly (i.e., with or without 
fasting). The fasting status will be noted.  
5 All women will be tested at the Screening, Day 1 Pre-Dose, and Week 13 Visits.   
6 Urine Pregnancy Test will be performed on females undergoing an Early Termination Visit only. All other women will undergo a UPT at the Week 13 Visit.  
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 32 OF 78 
ASSSESSMENTS 
STUDY PERIODS, STUDY VISITS, AND STUDY DAYS 
SCREENING PERIOD 
TREATMENT PERIOD 
POST-TREATMENT 
FOLLOW-UP PERIOD 
Screening Visit 
Day 1 Visits 
Week 4 Visit 
Week 8 Visit 
Week 12 / Early 
Termination 
Visit 1 
Week 13 Visit 
Week 16 Visit 
Day -21 to 
Day -1 
Day 1 
Pre-Dose  
Day 1 
Dosing 
Day 29 ±4 
Day 57 ±5 
Day 85 ±5 
Day 92 ±5 
Day 113 ±5 
Supervised study drug measurement and 
application training at site 7 
√ 
2√ 
 
 
 
 
 
 
Supervised study drug application at site  
 
 
√ 
√ 
√ 
 
 
 
Telephone contact by site personnel 
 
 
 
√ 
√ 
√ 
 
 
Study drug accountability / dosing compliance 
 
 
√ 
√ 
√ 
√ 
 
 
Study drug weighing 8 
 
 
√ 
√ 
√ 
√ 
 
 
Subject instructions reviewed 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
                                                 
7 Subjects will be trained on study drug measurement and application using the study tools and a placebo demo kit; however, NO placebo ointment will be applied on the 
treatment field. 
8 New (unused) study drug tubes assigned to the subject at Day 1, Week 4, and Week Visits must be weighed before the first dosing. Used study drug returned by the 
subject at Week 4, Week 8, and Week 12 must also be weighed. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 33 OF 78 
7.4. 
Dose Holidays and Dosing Adjustments 
If for any reason a subject or an Investigator decides to alter the prescribed dosing of the study 
drug due to a local skin reaction and/or AE, subjects may be offered the following options at 
the Investigator’s discretion.  
a) Subjects may be offered to continue the study drug, adding a bland moisturizer. The 
bland moisturizer should be applied no sooner than 6 hours after dosing and the 
Treatment Field should be washed with mild soap before the next study drug 
application.    
b) Subjects may temporarily stop the study drug for up to 7 days and to re-assess within 
that period; 
c) Subjects may be offered to reduce the dosage, for example from 200 mg to 150 mg per 
once-daily application; 
d) Subjects applying the study drug BID may be offered to apply their medication once-
daily while subjects applying the study drug QD may be offered to apply their study 
drug every other day; and/or 
e) Subjects may be offered to stop the study drug permanently.  
Subjects may be offered one of the above options or combinations thereof.  
7.5. 
Study Withdrawals and Discontinuations 
Subjects may withdraw their consent from participation in the study at any time. The date and 
reason for withdrawal should be recorded.  
Subjects who wish to withdraw from the study due to an AE related to the study drug should 
be encouraged to remain in the study and consider the options offered in Section 7.4 instead of 
withdrawing completely from the study. Subjects who decide to withdraw from the study 
should be encouraged to undergo Early Termination Visit assessments (Section 12.6.4).  
Subjects who permanently discontinue applying their study drug for any reason (whether on 
their own initiative or at the behest of the investigator) should be encouraged to remain in the 
trial (not to withdraw consent from participation) so they may undergo the remaining trial 
procedures and assessments. The date and reason for the study drug discontinuation should be 
recorded. 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 34 OF 78 
8. 
 STUDY ENDPOINTS 
Primary Efficacy Endpoints:    
• Percentage of subjects achieving complete clearance of AK lesions within their Treatment 
Field on Week 16  
• Percentage of subjects with facial Treatment Fields achieving complete clearance of AK 
lesions on Week 16   
Secondary Efficacy Endpoints:  
• Percentage of subjects achieving partial (≥75%) clearance of AK lesions within their 
Treatment Field on Week 16 
• Percentage of subjects with facial Treatment Fields achieving partial (≥75%) clearance of 
AK lesions on Week 16   
• Change from baseline in the number of AK lesions in the Treatment Field of each subject 
by Weeks 16 
• Change from baseline in the number of facial AK lesions in the Treatment Field of each 
subject by Weeks 16 
Safety Endpoints:  
• AEs, clinical laboratory parameters, vital signs, physical examinations, Local Skin 
Reaction (LSR) Scores, electrocardiograms, and drug exposure. 
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 35 OF 78 
9. 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
9.1. 
Inclusion Criteria 
Subjects fulfilling all the following criteria may be eligible for study participation. 
1. Subject has signed and dated the ICF prior to any study-related procedure not part of 
normal medical care; 
2. Male and female subject aged 18 years or older at Screening; and 
3. Subject at the baseline Day 1 Pre-Dose Visit has between 4 and 8 Grade 1 or Grade 2 (see 
AK Lesion Eligibility, Section 11.1.3) AK lesions within a single contiguous 25 cm2 area 
of skin on their face or balding scalp (the Treatment Field); 
9.2. 
Exclusion Criteria 
Subjects fulfilling any of the following criteria will be excluded from study participation: 
1. Subject is the PI or any Sub-Investigator, research assistant, pharmacist, Study 
Coordinator, staff directly involved in the trial, and/or any immediate family member 
(first degree relative, spouse, adoptees, legal dependents) of any staff directly involved in 
the trial; 
2. Subject has Screening or Day 1 results that (a) are clinically significant; (b) suggest an 
unstable medical condition; (c) preclude the subject’s participation out of concern for the 
subject’s safety; or (d) suggest a condition that might confound the subject’s data in the 
opinion of the Investigator.  
(Examples of laboratory and ECG results for which the Study Medical Monitor should 
be consulted are listed in Section 9.3.) 
3. Subject (or their dosing partner) is unable to demonstrate adequate precision applying the 
study drug to the Treatment Field during the Screening and Day 1 Pre-Dose Visits.  
4. Subject is: (a) pregnant; (b) lactating; (c) planning to become pregnant during the study, 
or (d) fertile (as defined in Section 12.10.1) and she or their fertile partner is unable or 
unwilling to use the contraceptive methods discussed in Section 12.10.2; 
5. Subject has any skin pathology, known dermatologic disease, or medical condition that 
could interfere with the evaluation of the test product or requires the use of a prohibited 
topical or systemic therapy in the opinion of the Investigator (Section 12.9); 
6. Subject has in the opinion of the Investigator (a) an unstable medical, psychiatric, social 
problem, self-reported alcohol or illicit drug dependency, or any similar condition that 
could (a) place the subject at a safety risk; (b) interfere with the subject’s performance of 
the trial activities, completion of the trial, or attendance at scheduled site visits; (c) 
obfuscate the subject’s data; or (d) threaten the proper interpretation of the trial safety 
data.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 36 OF 78 
7. Subject has at any time been given a diagnosis or treatment associated with 
immunosuppression (e.g., organ transplant recipients, HIV, systemic chemotherapy, graft 
vs. host disease, dialysis, etc.); 
8. Subject has participated in a clinical trial, received an investigational drug, or been treated 
with an investigational device within 1 month prior to Baseline (Day 1). 
9. Subject is unable to comply with the sun protection techniques or the limitations placed 
on tanning, medicinal products, activities, alcoholic beverages, or foods listed in Section 
12.9. 
10. Subject is unwilling to avoid any form of therapy, emollients, moisturizers, makeup, 
sunscreens, etc. to the Treatment Field from Screening through completion of all study 
visits. 
11. Subject has a known sensitivity to propylene glycol, caprylic acid, dimethyl sulfoxide 
(DMSO), petrolatum, or paraffin wax.  
12. Subject had any type of allergic reaction or rash that resulted from application of a topical 
medicament (e.g. cream, ointment, oil, spray, lotion, moisturizer, sunscreen, makeup, 
etc.). 
13. Subject has used any of the following topical medicinal or physical treatments in the 
Treatment Field within 4 months of Day 1 Visit: topical retinoids (e.g. tazarotene, 
adapalene, tretinoin), microdermabrasion, laser ablative treatments, photodynamic 
therapy, chemical peels, 5-FU, diclofenac, imiquimod, ingenol, cryotherapy, or other 
topical treatments for AK or that might impact AK. 
14. Subject has used systemic retinoid therapy within 6 months of Day 1 Visit.  
15. Subject has a history of malignancy within 5 years of Day 1 other than adequately-treated 
carcinoma in-situ of the cervix, non-metastatic basal cell carcinoma or non-metastatic 
cutaneous squamous cell carcinoma; 
16. Subject had major surgery within 60 days of Baseline, hospitalization, or plans to have 
major surgery during the study;  
17. Subject has received VDA-1102 in the past. 
9.3. 
Study Medical Monitor Enrollment Consultation 
The Investigators are encouraged to consult with the Study Medical Monitor in cases where 
the Screening or Day 1 Visit findings suggest that the subject may have a medical condition 
that is unstable or liable to obfuscate the safety data collected. Below are examples of such 
laboratory and ECG findings.  
1. Clinical laboratory findings: 
a. Both ALT and AST are above the upper limit of normal 
b. Hemoglobin <11 gm/dL, platelet count <125,000/mL, or a low neutrophil or 
lymphocyte count 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 37 OF 78 
c. Microscopic hematuria, proteinuria, or pyuria 
d. Glucose >250 mg/dL 
2. Electrocardiographic findings: 
a. Left bundle branch block 
b. Bifascicular block – right bundle branch block with either left anterior or left 
posterior hemiblock 
c. PR interval >220 msecs 
d. QTcF >470 msecs 
e. Atrial fibrillation 
9.4. 
Subject Replacement 
Enrolled subjects who prior to completion of the Week 8 Visit are: (a) terminated by the PI or 
completely withdraw themselves from the study, (b) declared a violator or major deviator, or 
(c) lost to follow-up, may be replaced at the discretion of the Sponsor.   
9.5. 
Subjects Leaving the Trial 
Subjects who are terminated or who withdraw from the trial will be asked to complete Week 
12 assessments (see Early Termination Visit, Section 12.6.4). Women will also be asked to 
undergo -HCG testing at that time.  
9.5.1. 
Termination by the Investigator 
The Investigator may terminate a subject from the study at any time, due to: (a) trial 
misconduct, (b) violation of the rules of the site, (c) protocol violation; (d) pregnancy, or (e) 
unexpected personal issues that arose during the trial. Terminations must be reported verbally 
and in writing to the Study Medical monitor within 24 hours.  
In addition, if an Investigator (or designee) believes that the current dosing may be detrimental 
to a subject’s well-being, that subject may be offered any of the options discussed in Section 
7.4 (Dose Holidays and Adjustments) following consultation with the Safety Medical Monitor.  
9.5.2. 
Subjects Who Wish to Withdraw  
If a subject who received at least 1 dose of the study drug wishes to withdraw from the trial, 
that subject may be offered any of the options discussed in Section 7.4 (Dose Holidays and 
Adjustments).  These options may be offered without prior consultation with the Study Medical 
Monitor. 
Subject withdrawals must be reported verbally and in writing to the Study Medical Monitor 
within 24 hours. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 38 OF 78 
If a subject withdraws consent from the study, all data and samples (blood, urine, ECGs, etc.) 
collected prior to the time of withdrawal will be analyzed and the data will be included in the 
trial data base.  
9.5.3. 
Subjects Lost to Follow-Up 
In the case of a subject lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s files.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 39 OF 78 
10. 
PROCEDURES FOR SAFETY EVALUATIONS 
10.1. 
Medical History 
Medical history, including any diseases, all past surgeries including skin procedures, and 
psychiatric illnesses will be documented. 
Each subject will be questioned regarding any planned elective procedures that may occur 
during or following completion of the study, and these must be documented in the subject’s 
medical record and the medical history section of the CRF.   
10.2. 
Prior Concomitant Medications 
All medications or medical products taken by the subject within 2 months prior to Screening, 
whether the subject has stopped the medication or whether the subject has continued taking the 
medication, will be recorded as a Prior Concomitant Medication. This also includes 
medications taken prn.  
All topical skin treatments (i.e., medicinal or physical) received in the 4 months prior to 
Screening will be recorded.  
10.3. 
Safety Measures 
10.3.1. 
Adverse Events 
The investigator will determine at each study visit whether any AEs have occurred.  Sections 
15 and 16, respectively, contain additional information regarding AEs and SAEs. 
10.3.2. 
Vital Signs, Weight, and Height 
Throughout the study, vital signs (resting blood pressure, heart rate, temperature, and 
respiratory rate) will be obtained with the subject sitting or lying, after the subject has rested 
for at least 2 minutes.  
Heart rates are best obtained electronically, if available.  If heart rate data are obtained 
electronically, the results may not be obtained from an ECG scheduled at the same time. If 
these data are obtained manually, a minimum observation period of 30 sec is required.   
Respiratory rate will be determined following a minimum observation of 30 sec.  
The subject’s height and weight will be documented during the Screening visit. 
10.3.3. 
Physical Examination 
The physical examinations performed during the trial will include skin, external eyes, oral 
cavity, nodes, lungs, heart, abdomen, and extremities.   
The investigator will also be asked to assess whether the following neurologic functions are 
normal / abnormal.  
1. Mentation: appropriate behavior; logical thought processes 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 40 OF 78 
2. Motor: use of all 4 extremities 
3. Cerebellar: gait; balance standing and sitting 
4. Cranial nerves: speech, facial symmetry, and hearing 
If any of these is abnormal or changed from baseline, the Investigator will be asked to describe 
the findings.  
All abnormal acute and chronic findings on physical examination must be recorded whether 
they are new or were recorded previously in the medical records of the subject. For example, a 
surgical scar should be recorded on every scheduled physical examination. 
AK lesions that are outside the Treatment Field must be recorded in the physical examination. 
This applies to AK lesions on the head or on any other part of the body. However, only lesions 
that require treatment at the time of the examination should be considered clinically significant. 
Please refer to Section 12.9.1 regarding which AK treatments are allowed and prohibited during 
the trial.   
All other skin lesions must be reported on the physical examination. However, only skin lesions 
that require treatment at the time of the examination should be considered clinically significant.   
10.3.4. 
Clinical Laboratory Tests 
Blood and urine sampling will be collected and sent for analysis to CRL the central laboratory 
and will occur as listed in Section 12.6 and the Table of Study Assessments (Section 7.3).  All 
blood samples will be drawn, prepared, and maintained as per central laboratory manual. Blood 
sampling for all clinical laboratory tests should be performed following a fasting period of 
approximately 8 hours with the exception of the Screening blood sampling that may be 
performed randomly (i.e., with or without fasting).  The fasting status of the subject will be 
recorded. 
The following tests will be performed as part of the Clinical Laboratory Tests: 
a) Hematology:  The hematology analysis will consist of the following tests: 
• White Blood Cell Count 
• White Blood Cell Differential in absolute numbers only (not percent) 
• Hemoglobin 
• Hematocrit 
• Mean Corpuscular Volume (MCV) 
• Mean Corpuscular Hemoglobin Concentration (MCHC) 
• Red Blood Cell Count 
• Platelet Count 
b) Coagulation Profile:  The coagulation parameter analysis will consist of the following 
tests: 
• Prothrombin Time (PT) and/or International Normalized Ratio (INR) 
• Activate Partial Thromboplastin (aPTT) 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 41 OF 78 
c) Complete Clinical Chemistry:  The Complete Clinical Chemistry consists of the following 
tests: 
• ALT 
• AST 
• Albumin 
• Alkaline phosphatase 
• Direct bilirubin 
• Total bilirubin 
• Blood urea nitrogen or urea 
• Calcium 
• Total cholesterol 
• Chloride 
• Creatinine 
• Glucose 
• Lactate dehydrogenase  
• Inorganic phosphorus 
• Potassium 
• Total protein 
• Sodium 
• Triglycerides 
• Uric acid 
• Total CPK 
• Glomerular filtration rate, estimated (as 
per the clinical laboratory’s SOPs) 
 
d) Urinalysis:  The urinalysis consists of the following tests: 
• Glucose 
• Erythrocytes 
• Protein 
• Leucocytes 
• pH 
• Nitrites 
• Ketones 
 
10.3.5. 
Urine Pregnancy Test 
Pregnancy testing will be performed on urine samples to be processed, assayed, and reported 
by site personnel.  
All women enrolled in the trial must have a negative urine pregnancy test at their Screening 
and Day 1 Pre-Dose Visits before they can proceed to Day 1 Dosing.  
10.3.6. 
Electrocardiogram 
A standard, surface 12-lead ECG will be obtained as per the central ECG laboratory’s manual 
at the time points listed in the Schedule of Assessments (7.3).  
ECGs recorded, transmitted to the central ECG laboratory, and interpreted by that laboratory.  
The QT interval results will be adjusted for rate using the Bazett (QTcB) and Fridericia (QTcF) 
corrections. 
Cardiac dysrhythmias will be documented by occurrence (date and time), severity, type, and 
duration.  Isolated premature ventricular contractions and supraventricular extra-systolic 
waveforms will not be considered clinically significant. 
Two printouts (original copies) of each electrocardiogram will be stored in the subjects’ 
medical records. ECGs will be assessed, signed, and dated by the Investigator (or designee). 
The Investigator’s initial assessment is for purposes of screening and safety follow-up only.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 42 OF 78 
The Investigator’s findings will be included in the final data base for insertion into listings. 
However, these findings will not be tabulated, included in summary statistics, or considered 
the official reading of record for purposes of study safety assessments.   
All ECGs will be electronically transmitted to the central ECG laboratory for interpretation. 
The central ECG interpretation overrides the investigator’s and will be considered the official 
reading of record for purposes of study safety assessments.  
10.3.7. 
Local Skin Reaction Score  
The Investigator (or designee) will use the Local Skin Reaction (LSR) Score (see Section 22.1) 
to numerically assess the overall degree of erythema, edema, weeping / exudate, vesicles, 
erosions / ulcerations, scaling / dryness, scabbing / crusting as well as the Subjective LSR Score 
(Section 0) to assess  itching and pain in the Treatment Field. The assessments will use a 5-
point scale, from 0 (none/trace) to 4 (extreme).  This assessment will be performed on Day 1 
Visit and repeated at each subsequent visit. The individual scores for each potential finding 
will be recorded in the respective cells by the assessor.  
Whenever possible, the same investigator should perform all of these assessments.  
In this trial LSRs will be collected independent of AEs.  Details regarding LSR reporting are 
included in Section 15.1.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 43 OF 78 
11. 
PROCEDURES FOR EFFICACY EVALUATIONS 
11.1. 
AK Lesions 
11.1.1. 
AK Lesion Count 
At the Screening and Day 1 Pre-Dose Visits, the selected Treatment Field must include 4-8 
discrete qualifying AK lesion and no disqualifying lesions (Section 11.1.3).  
At the Day 1 Pre-Dose Visit, all AK lesions in the selected contiguous 25 cm2 Treatment Field 
will be identified, counted, and recorded. The approximate outline of each AK lesion will be 
transcribed on the Treatment Field Map on Day 1. A photograph of the subject’s Treatment 
Field will be taken and a copy given to the Subject to assist the subject in locating their 
Treatment Field.  
At visits after Day 1 specified below, the investigator will be given the Day 1 Treatment Map 
and Photograph of the Treatment Field for reference and asked to count the number of AK 
lesions identified within the Treatment Field.  
If new AK lesions appear in the Treatment Field after Day 1, they will be counted.  
If the subject has a LSR that prevents the investigator or designee from performing the AK 
count at a visit, the investigator or designee should document in the source document and CRF 
that the AK count was not obtained due to LSR local effects. 
11.1.2. 
Definition of AK Lesion Clearance 
A prior AK lesion that is no longer seen OR no longer palpable is to be considered cleared and 
will not be counted, even if a residual color or skin texture change remains in the skin. 
11.1.3. 
AK Lesion Eligibility 
To be eligible for this trial, the Treatment Field must contain 4-8 AK lesions that meet each of 
the following criteria: 
a. Grade 1 or 2 AK lesions only - not Grade 3; The definitions of AK Grades to be used 
for eligibility purposes are as follows: 
– Grade 1 – mild (slightly palpable AK that are felt better than seen)  
– Grade 2 – moderate (moderately thick AK that are easily seen and felt)  
– Grade 3 - severe (very thick, obvious, and/or hyperkeratotic AK). Treatment Fields 
selected for this trial must not contain any Grade 3 AK lesions. 
b. located on the subject’s head including the face or balding scalp but not on the lips, 
ears, submandibular area, or neck; 
c. located in an area of the subject’s head that easily visible to the subject in a mirror;  
d. discrete (i.e., no borders that are clearly touching one another);  
e. a maximum diameter 10 mm (inclusive) in any direction; and 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 44 OF 78 
f. not atrophic, pigmented, or Bowenoid. 
AK lesions grades will not be recorded in the CRF since the AK lesion grades are not an 
endpoint in this study.  
11.2. 
Treatment Field Selection 
Any 25 cm2 contiguous area on the face or scalp of the subject that contains 4-8 AK lesions 
that meet the requirements stated in AK Lesion Eligibility criteria (Section 11.1.3) may be 
selected as the study Treatment Field. The Treatment Field will be selected at Screening and 
confirmed on Day 1 Pre-Dose. If the Treatment Field selected at Screening is no longer eligible 
at Day 1 Pre-Dose, a new Treatment Field must be selected on Day 1 Pre-Dose.  
The Treatment Field must be a single, contiguous 25 cm2 area that is easily visible to the subject 
when looking in the mirror. The Treatment Field should include at least 4 but not more than 8 
AK lesions all of which must be Grade 1 or 2 AK lesions. The ideal Treatment Field should 
optimally be square or rectangular and not irregular, to simplify study drug application by the 
subject.  
The Treatment Field or its outer border must not be: 
a) An area of skin that received any AK or other medical or physical treatment within 4 
months of the Day 1 Visit (Exclusion Criterion #14);  
b) Within 2.5 cm (~1 inch) of either labial commissure of the mouth, lip vermilion border, 
palpebral fissure or a suspected malignancy; 
c) Close to another active dermatologic process that could spread to the Treatment Field 
and interfere with the proper assessment of the Treatment Field and/or its included AK 
lesions; 
d) So close to the eyebrows, beard, or other area with hair as to interfere with proper 
application of the study drug or assessment of the Treatment Field.  
NOTE: Ideally other AKs should NOT be adjacent to the border of the Treatment Field 
which could confound the AK lesion counting or identification of the Treatment Field at 
subsequent study visits. 
11.3. 
Study Tools 
The following four (4) study tools will be used for Treatment Field selection, AK Lesion 
counts, Study Drug measurement, and Study Drug Application. The preliminary tools will be 
supplied by the Sponsor. Investigators (or designee) will prepare the final tools for use by the 
sites and the subject based upon the instructions provided by the Sponsor.   
1. Treatment Field Map - This flexible, 8.5 x 11-inch plastic transparency with 1 cm x 1 
cm grid printed on the surface will be used by the Investigator (or designee) to: (a) define 
a Treatment Field at Screening and Day 1 Pre-Dose Visits; (b) count AK lesions in the 
Treatment Field; and (c) to create the Treatment Field Template. Instructions regarding 
use of this tool will be distributed to the site.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 45 OF 78 
2. Treatment Field Template – The tool consists of a clear, thin, flexible, 8.5 x 11-inch 
plastic transparency sheet supplied by the Sponsor marked by the Investigator (or 
designee) with landmarks (e.g. eyebrows, ear helix, and/or nevi) to guide the subject to 
the proper placement of the sheet. The template also includes a cut-out hole that will act 
as a stencil, guiding the Subject (or dosing partner) to the precise Treatment Field for 
application of the study drug. This template (stencil) will be used by the: 
a. Investigator (or designee) (a) to train the subject in proper identification of their 
unique Treatment Field; and (b) to train the subject in precise study drug application 
to their unique Treatment Field. 
b. Subject (or dosing partner): (a) to identify their unique Treatment Field and (b) to 
apply the study drug precisely to their Treatment Field.  
Instructions regarding use of this tool will be distributed to the site.  
3. Dosing Card – a, thin plastic card with a rectangle printed on the middle of the card. A 
strip of ointment expressed from the study drug tube that fits the clear portion of the 
rectangle is the correct approximate dose of study drug to be applied to the Treatment 
Field. A new previously unused Dosing Card will be used for each application by the 
subject to measure their proper study drug dose and will be discarded after use.  
Instructions regarding use of this tool will be distributed to the site.  
4. Treatment Field Photograph – At least 1 standard facial photograph that includes the 
Treatment Field and its surrounding landmarks may be taken of each subject. The sole 
purpose of this photography to supplement the use of the Treatment Field Template in 
guiding the site and the subject to the subject’s precise Treatment Field. The photograph 
that best represents the Treatment Field will be printed. The site personnel will label the 
photograph with “left” and “right” as well as point out landmarks on the picture to subject 
(e.g. moles, eyebrows, or nose) in order to properly orient the subject. The subject will be 
given the labelled photograph for use with the template and retention in the subject’s 
source documentation.  
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 46 OF 78 
12. 
CONDUCT OF THE STUDY 
12.1. 
Study Blinding and Randomization 
12.1.1. 
Study Blinding 
This is an open-label study. Therefore, no one will be blinded.  
12.1.2. 
Randomization 
Subjects who pass screening and are eligible for enrollment will be consecutively enrolled into 
Part A (Cohort 1) and Part B (Cohort 2). There will be no need for randomization in Part A or 
Part B.  
Subjects enrolled into Part C will be randomly assigned to Cohort 1 or to Cohort 2 at a ratio of 
1:1 to allow for equal expansion of the number of subjects into each of these cohorts. Details 
regarding the randomization technique(s) will be detailed in the SAP. On Day 1 Pre-Dose, after 
confirming the subject’s eligibility, the Investigator (or his designee) will approve the subject’s 
unblinded randomization. Subjects will be randomized in a fashion that will maintain a balance 
between the 2 cohorts across all subjects enrolled (not per site) and notify the site of the result.  
12.2. 
Pre-Screening  
Sites are encouraged to pre-screen subjects prior to consenting. The FDA guidance regarding 
which pre-screening procedures may be performed may be found on the FDA web site at: 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126430.htm.  
12.3. 
Subject Informed Consent 
No activities other than pre-screening procedures (including Screening activities) may be 
performed before a fully executed IRB approved current informed consent form (ICF) has been 
obtained, with a copy of the ICF given to the subject and another copy placed in the subject’s 
medical records.  
Information about the study, explaining the objectives, procedures, and potential risks versus 
benefits will be given to the subject in writing and verbally in a language that is understood by 
the subject.  The subject should have adequate time to read the information and to ask the 
Investigator any questions.  The Investigator must be satisfied that the subject has understood 
the information provided in the ICF before written consent is obtained. 
12.4. 
General Considerations 
12.4.1. 
Demographics 
The birth date, gender, race, and ethnicity of each subject will be documented.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 47 OF 78 
12.5. 
Study Periods 
This study will consist of the following periods:  
• Screening Period: Days -21 through Day 1 Pre-dose 
• Treatment Period: From Day 1 Dosing through Week 12 Visit (Day 1 Dosing - Day 85) 
• Post-Treatment Follow-Up Period: Between Week 13 and Week 16 Visits (Day 85 – Day 
113) 
12.6. 
Study Procedures per Period and Visit  
12.6.1. 
Screening Period 
The Screening Period begins immediately following the ICF signing (see Section 12.3 for a 
description of the informed consent procedures).   
✓ Screening Visit (Day -21 to Day -1) 
The following procedures are to be performed during the Screening Visit:   
• Site personnel confirm that the ICF: (a) is the most current ICF; (b) was signed and dated 
both by the subject and investigator or designee; and (d) was copied with one copy given 
to the subject for their personal records. The process of the informed consent should be 
documented in the subject's medical records.  
• Demographics recorded 
• Medical (and surgical) history recorded 
• Prior concomitant medications 
• Adverse events that occur following ICF signing will be recorded. 
• Height and weight recorded. 
• Vital Signs: oral temperature, peripheral blood pressure, heart rate, and respiratory rate will 
be recorded 
• Clinical laboratory tests including hematology, chemistry, coagulations, and urinalysis: 
Fasting status will be recorded. 
• Urine beta-HCG will be performed on all women  
• 12-lead ECG tracing recorded. An original duplicate copy of the recorded ECG is required 
for trial documentation. This ECG will also be transmitted electronically to the central ECG 
laboratory. 
• Scalp and face examination by PI (or designee) with selection of a Treatment Field that is 
anticipated to meet the criteria stated in Section 11.2 at the Day 1 Visit 
• AK lesion count (Section 11.1.1) 
• Supervised study drug measurement and application training (see Section 13.6.3). The 
Treatment Field Map and Template will be prepared as per the Investigator. Subject will 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 48 OF 78 
be trained to measure (using placebo ointment on the Dosing Card) and to accurately apply 
the study drug, without actually applying placebo ointment to their Treatment Field. 
• Subject instructions will be reviewed including appointment for the next visit 
• Inclusion and exclusion (enrollment) criteria applied by Investigator and recorded 
✓ Day 1 Pre-Dose Visit 
Subjects who have completed all screening procedures and continue to meet the study 
enrollment criteria will return to the investigative site on Day 1 Pre-Dose.  During this visit, 
the following procedures will be performed: 
• Vital signs: oral temperature, peripheral blood pressure, heart rate, and respiratory rate will 
be recorded 
• Adverse event(s): volunteered, elicited, and observed AEs will be recorded 
• Concomitant medications documented 
• Treatment Field selection/confirmation 
• The Treatment Field photograph, Map, and Template will be prepared. 
• Supervised study drug measurement and application training (see Section 13.6.3). Subject 
will be trained to measure (using placebo ointment on the Dosing Card) and to accurately 
apply the study drug, without actually applying placebo ointment to their Treatment Field. 
• Physical examination (Section 10.3.3) 
• Local Skin Reaction Score of the skin around the AK lesions in the Treatment Field 
(baseline) 
• AK Lesions in the Treatment Field: baseline count (Section 11.1.1) 
• Clinical Laboratory tests including hematology, chemistry, and urinalysis. Fasting status 
should be recorded. 
• Urine beta-HCG test will be performed on all women and results recorded. 
• 12-lead ECG tracing will be recorded. An original (duplicate) copy of the ECG is required 
for trial documentation. This ECG will also be transmitted to the central ECG laboratory  
• Repeat supervised study drug measurement and application training (see Section 13.6.3) 
will occur a 2nd time at the end of the Day 1 Pre-Dose Visit. Subject will be tested as to 
whether they can measure (using placebo ointment on the Dosing Card) and to accurately 
apply the study drug, without actually applying placebo ointment to their Treatment Field. 
Subjects (or their dosing partners) who fail to measure and/or apply the study drug properly 
will be screen failed.  
• Enrollment criteria and safety data (from Screening and all available data from the Day 1 
Pre-Dose Visit) will be reviewed and approved by the Investigator (or designee) 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 49 OF 78 
12.6.2. 
Treatment Period 
✓ Day 1 Dosing Visit 
The following procedures will be performed on subjects selected to proceed to the Treatment 
Period. 
• Study drug accountability and dosing compliance: Study drug tube will be designated and 
a Dosing Diary will be provided to the subjects.  
• Used and new study drug tubes will be weighed and the results recorded.  
• Study drug application and completion of the Dosing Diary by the subject under the 
supervision of the site personnel. 
• Subject instructions will be reviewed including appointment for the next visit.  Study drug 
and study tools will be given to the subject.  
✓ Day 1 Post-Dose through Week 4 Visit 
• Subjects will dose at home and record each application in the Dosing Diary.  
• Study drug application: 
– Subjects in Cohort 1 will apply study drug twice daily. On Day 1 subjects in Cohort 
1 will apply the second dose at home in the evening.  
– Subjects in Cohort 2 will apply study drug once daily. 
• Site personnel will communicate with the subjects approximately 2 weeks after Day 1 
(Section 12.7) to review the trial instructions and Dosing Diary as well as to remind each 
subject of their next site visit. Subjects will be reminded to bring all study drug with them 
to the next visit.    
✓ Week 4 Visit 
On Day 29 (±5 days) the following procedures will be performed: 
• Adverse event(s) AEs will be recorded 
• Concomitant medications documented 
• Vital signs: peripheral blood pressure, respiratory and heart rates, and oral temperature will 
be recorded 
• Physical examination 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (Section 11.1.1) 
• Study drug accountability and dosing compliance: Used study drug tube will be collected 
and new tubes designated. Dosing Diaries will be collected and reviewed with the subject, 
and a new diary will be provided to the subjects.  
• Used and new study drug tubes will be weighed and the results recorded.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 50 OF 78 
• Study drug application and completion of the Dosing Diary by the subject under the 
supervision of the site personnel. 
• Trial instruction review including an appointment for the next visit will be given. Study 
drug and study tools (as required) will be re-supplied to the subject, as needed. Subjects 
will be reminded to bring all study drug with them to the next visit.    
✓ Week 5 through Week 8 Visit 
• Subjects will dose at home and record each application in the Dosing Diary. 
• Study drug application: 
– Subjects in Cohort 1 will apply study drug twice daily.   
– Subjects in Cohort 2 will apply study drug once daily. 
• Site personnel will communicate with the subjects approximately 2 weeks after the Week 
4 Visit (Section 12.7) to review the trial instructions and Dosing Diary as well as to remind 
each subject of their next site visit. Subjects will be reminded to bring all study drug with 
them to the next visit.    
✓ Week 8 Visit 
On Day 57 (±5 days) the following procedures will be performed: 
• Adverse event(s) AEs will be recorded 
• Concomitant medications documented 
• Vital signs: peripheral blood pressure, respiratory and heart rates, and oral temperature will 
be recorded 
• Physical examination 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (Section 11.1.1) 
• Study drug accountability and dosing compliance: Used study drug tube will be collected 
and new tubes designated. Dosing Diaries will be collected and reviewed with the subject, 
and a new diary will be provided to the subjects.  
• Used and new study drug tubes will be weighed and the results recorded.  
• Study drug application and completion of the Dosing Diary by the subject under the 
supervision of the site personnel. 
• Trial instruction review including an appointment for the next visit will be given. Study 
drug and study tools (as required) will be re-supplied to the subject, as needed. Subjects 
will be reminded to bring all study drug with them to the next visit.    
✓ Week 9 through Week 12 Visit 
• Subjects will dose at home and record each application in the Dosing Diary. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 51 OF 78 
• Study drug application: 
– Subjects in Cohort 1 will apply study drug twice daily.  
– Subjects in Cohort 2 will apply study drug once daily. 
• Site personnel will communicate with the subjects approximately 2 weeks after the Week 
8 Visit (Section 12.7) to review the trial instructions and Dosing Diary as well as to remind 
each subject of their next site visit. Subjects will be reminded to bring all study drug with 
them to the next visit.    
✓ Week 12 Visit 
On Day 85 (±5 days) the following procedures will be performed: 
• Adverse event(s) AEs will be recorded 
• Concomitant medications documented 
• Vital signs: peripheral blood pressure, respiratory and heart rates, and oral temperature will 
be recorded 
• Physical examination 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (11.1.1) 
• 12-lead ECG tracing recorded pre-dose. An original (duplicate) copy of each ECG is 
required. This ECG will also be transmitted to the central ECG laboratory 
• Clinical laboratory tests including hematology, chemistry, coagulations, and urinalysis: 
Fasting status to be recorded 
• Study drug accountability and dosing compliance: Used study drug tube will be collected. 
Dosing Diaries will be collected and reviewed with the subject. Neither study drug nor 
Dosing Diaries will be returned to the subject.   
• Used study drug tubes will be weighed and the results recorded.  
• Trial instructions will be reviewed including an appointment for the next visit will be given.  
12.6.3. 
Post-Treatment Follow-Up Period 
✓  Week 12 through Week 13 Visit 
• No procedures will be performed on these days. 
✓ Week 13 Visit 
Note: Despite the overlap between the windows for the Week 12 and Week 13 Visits, the Week 
13 Visit should occur at least 5 days after the Week 12 Visit.  
On Day 92 (±5 days) the following procedures will be performed on all subjects: 
• Adverse event(s) will be recorded 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 52 OF 78 
• Concomitant medications documented 
• Urine Pregnancy Test will be performed on all women and results recorded. 
• Local Skin Reaction Score in the Treatment Field 
• AK lesion in the Treatment Field: count (11.1.1) 
• Trial instruction review including an appointment for the next visit will be given.  
✓ Week 14 through Week 16 Visit 
• Site personnel will communicate with the subjects on Week 15 (Section 12.7) to review the 
trial instructions and to remind each subject of their next site visit. Subjects will be 
reminded to bring all unreturned study drug with them to the next visit.    
✓ Week 16 Visit 
On Day 113 (±5) the following procedures will be performed on all subjects: 
• Adverse event(s) will be recorded 
• Concomitant medications documented 
• Vital signs: peripheral blood pressure, respiratory and heart rates, and oral temperature will 
be recorded 
• Physical examination 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesion in the Treatment Field: count (11.1.1) 
Subjects will be thanked for their participation in the trial and exit the study.  
12.6.4. 
Early Termination Visit 
Subjects exiting the study before completion of the Treatment Period should undergo Early 
Termination Visit assessments. The following assessments will be performed during such a 
visit.  
• Adverse event(s) AEs will be recorded 
• Concomitant medications documented 
• Vital signs: peripheral blood pressure, respiratory and heart rates, and oral temperature will 
be recorded 
• Physical examination 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (11.1.1) 
• 12-lead ECG tracing recorded pre-dose. An original (duplicate) copy of each ECG is 
required. This ECG will also be transmitted to the central ECG laboratory 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 53 OF 78 
• Clinical laboratory tests including hematology, chemistry, coagulations, and urinalysis: 
Fasting status to be recorded 
• Study drug accountability and dosing compliance: study drug tubes will be weighed and 
the results recorded. Dosing Diaries will be collected. Neither study drug nor Dosing 
Diaries will be returned to the subject.  
• Urine Pregnancy Testing will be performed on all women and results recorded. 
12.7. 
Once-Monthly Subject Contact 
Site personnel will contact each subject between study visits. These phone calls should be 
made, whenever possible, approximately 2 weeks after the Day 1, Week 4, Week 8, and Week 
13 Visits. The goals of this contact are: (a) to review the dosing instructions and Dosing Diary 
with each subject; (b) to answer any questions raised by the study participants; (c) to remind 
subjects of their upcoming site visit and any related activities; (d) to remind subjects to bring 
their study drug to each site visit; and/or (e) to ask subjects not to take their dose on site visit 
days since the study drug dose on those days will be applied under the supervision of site 
personnel.  
12.8. 
Unscheduled Visits 
Investigators will invite subjects to attend an unscheduled visit to the investigative site (a) if 
during the trial a subject’s medical condition warrants more frequent observations than 
prescribed by the clinical protocol and/or (b) if a subject has an AE that has not stabilized or 
resolved and requires additional visits or follow-up beyond the standard study days. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 54 OF 78 
12.9. 
General Restrictions 
12.9.1. 
Medication and Other Therapeutic Restrictions 
Prohibited Products and Procedures 
All prescription medications, vitamins, medicinal products, and AK therapies (including 
chemical peels and photodynamic therapy) are prohibited from Day 1 through the subject’s 
exit from the study unless explicitly permitted below or approved in writing by the Investigator 
and Study Medical Monitor.  
Topical creams, lotions, makeup, or gels of any kind are prohibited within the selected 
Treatment Field and the 3-inch area around the border of this field from Day 1 through the 
subject’s exit from the study unless prescribed by the site Investigator and documented in the 
subject’s file. 
 
Permitted Products and Procedures 
Allowed medications or therapies during the study must be documented and include: 
• Daily medications: Subjects taking vitamins, prescription medications, or medical 
products daily may continue taking those products as long as the subject has been taking 
them continually for at least 2 months prior to Screening with no significant change in 
dose or dosing interval. These medicinal products must be recorded on the appropriate 
Concomitant Medication pages. All other prescription medications, medicinal products, 
and vitamins (with exceptions noted in the bullets below) are prohibited without prior 
approval of the Investigator and the Medical Monitor.  
• Non-prescription prn medications: The following non-prescription medications are 
allowed without prior consultation: ≤ 1500 mg acetaminophen, ≤ 1650 mg naproxen, 
or ≤ 1200 mg ibuprofen within a 24-hour period for not more than 2 consecutive days. 
• Prescription prn medications: Prescribed medications taken prn including 
antihistamines, bronchodilators, sleep medications, and intranasal, inhaled, and 
ophthalmic corticosteroids that are listed as concomitant medications at Screening 
and/or Day 1 Pre-Dose Visits are permitted. PRN medication taken daily are to be 
considered “daily medications.”  
• Physical treatments or procedures such as cryo-destruction, surgical excision, curettage, 
dermabrasion, or laser resurfacing more than 3 inches from the border of the Treatment 
Field are permitted. 
• Topical creams, lotions, makeup, or gels applied outside the 3-inch border area of the 
selected Treatment Field is permissible. Subjects, however, should not change such 
products between and screening and their exit from the trial.   
• Light bodied bland moisturizer (e.g., Cetaphil or Lubriderm without alpha-hydroxy 
acid) may be applied to the selected Treatment Field as an aid to managing AEs with 
the approval of the site Investigator. Moisturizers must not be applied within six hours 
of the last study drug application and the Treatment Field must be washed with soap 
prior to the next dosing. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 55 OF 78 
12.9.2. 
Topical Non-Medicinal Product Restrictions 
Subjects should be instructed not to change their cosmetics, soaps, shampoos, laundry 
detergents, deodorants, moisturizers, sunscreens, etc. from Day 1 through their exit from the 
trial.  
12.9.3. 
Sun Protection and Tanning 
Purposeful tanning and application of tanning agents are prohibited at any time during the trial. 
Subjects must avoid purposeful direct exposure to the sun or ultra-violet light from Day 1 
through their trial exit. Subjects who go outdoors should wear proper clothing and hats that 
protect their skin from sunlight.  
NOTE: Subjects should be encouraged to apply sunscreens that the subject has applied 
previously without untoward effects. Sunscreen products that have not been used previously 
by the subject must be avoided.  
No topical sunscreens, creams, lotions, or gels of any kind may be applied within the selected 
Treatment Field or within the surrounding 3-inch border area from Day 1 through the subject’s 
exit from the trial unless prescribed by the site Investigator and documented in the subject’s 
file. Therefore, at Screening, subjects should be carefully instructed regarding this restriction 
as well as use of proper headwear to protect the Treatment Field and the surrounding skin.  
12.9.4. 
Dietary Restrictions 
Since this study does not include PK, subjects have no food restrictions.  
12.9.5. 
Nicotine and Alcohol Restrictions 
Subjects enrolled in the study have no smoking restrictions. Social drinking of alcoholic 
beverages is also not restricted. 
12.9.6. 
Physical Exercise Restrictions 
There are no restrictions placed upon physical exercise. However, subjects should not swim or 
perform strenuous activities within 6 hours after applying the study drug. If the subject would 
like to perform such activities, the study drug application should be postponed until after the 
activity has been completed.  
12.10. Childbearing Potential 
12.10.1. 
Definitions 
Childbearing Potential:  Female subjects with at least one of the following medical conditions 
will be considered lacking childbearing potential:  
a) aged ≥ 50 years and last normal menstrual period was at least 12 months prior to 
Screening; 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 56 OF 78 
b) undergone removal of her entire uterus (total hysterectomy); bilateral tubal ligation at 
least 6 months prior to Screening and/or bilateral oophorectomy 
Females who do not meet at least 1 of the above criteria or do not have at least 1 criterion 
documented in the Medical History will be considered capable of childbearing and must be 
willing and able to use an acceptable form of contraception. Any subject meets this definition 
for childbearing and who cannot use an acceptable form of contraception, must be excluded 
from the study under Exclusion Criterion #3 (Section 9.2).  
Acceptable forms of contraception are: a) hormonal contraceptives [e.g., oral, transdermal, 
injectable, or intravaginal], b) barrier methods [condom and spermicidal or diaphragm/cervical 
cap and spermicidal], c) partner vasectomy (performed at least six months prior to study entry), 
or d) total abstinence. Subjects who become sexually active or begin to have relations with a 
partner who is not sterile during the study must agree to use an effective form of birth control 
for the duration of the study. 
Urine Pregnancy Test (UPT):  All women enrolled in the trial must have a negative UPT at 
Screening and on Day 1 Pre-Dose before first study drug dosing. In addition, all women must 
also undergo a UPT testing approximately one week after the final study drug application. 
12.10.2. 
Contraception 
Women with childbearing potential (as defined in Section 12.10.1) must be able and willing to 
use a contraceptive method describes in that section, from Screening until 1 month following 
the final study drug application. 
Non-vasectomized male subjects with female partners without childbearing potential (as 
defined in Section 12.10.1) are not required to use contraception.  
Non-vasectomized male subjects with female partners with childbearing potential (as defined 
in Section 12.10.1) must agree to use an acceptable form of contraception (as defined in Section 
12.10.1) from Screening until 3 months after the last dose of study drug and must refrain from 
sperm donation for 3 months after the last dose of study drug.  
Vasectomized males ≥ 6 month post the vasectomy procedure, require no contraception. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 57 OF 78 
13. 
STUDY MEDICATION 
13.1. 
Description of Study Medication 
The study drug will be manufactured, packaged, and labeled under GMP. 
VDA-1102 is formulated as a milky-white ointment, with the drug substance being dissolved 
in a water-free ointment base.  
– 10% VDA-1102 topical ointment is supplied in 15 grams (gm) aluminum tubes with plastic 
caps and stored refrigerated at 2-8 °C (36-46°F).  
– 20% VDA-1102 is supplied in 10 grams (gm) aluminum tubes with plastic caps and stored 
refrigerated at 2-8 °C (36-46°F). 
13.2. 
Drug Packaging 
The study drug tubes are enclosed in an aluminum pouch with an enclosed desiccant. The pouch 
is packaged in a protective cardboard container. 
13.3. 
Drug Labeling 
Each tube will be labeled with the following information: 
1. Study number 
2. Name of the Sponsor 
3. Drug name 
4. Lot numbers 
5. Directions for use 
6. The statement, “Caution: New drug - limited by United States law to investigational use” 
7. Storage conditions (degrees C and F) 
8.   Quantity 
13.4. 
Study Drug Distribution 
Study drug will be shipped under refrigerated conditions with temperature loggers from the 
drug depot to the site pharmacy.  
13.5. 
Study Drug Storage 
Site Pharmacy 
All study drug will be stored at the investigative site or their institutional pharmacy at 2-8 °C 
(36-46°F) in a secured area with access limited by coded keypads and/or locks. The aluminum 
pouch and desiccant may be discarded once the pouch is opened at the site for the first study 
drug application.  
 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 58 OF 78 
Home Storage 
Subjects will be instructed to keep the study drug tube in the accompanying cardboard 
container and to keep this unit in their home refrigerator.   
Travel 
If a subject must transport the study drug (for example, while travelling on vacation, on 
business, or to the site) they will be instructed to protect the study drug from heat in the supplied 
cooler pack. The drug should not be placed in the trunk of a car or in checked luggage on a 
plane.  
Subjects planning to travel away from home should contact their site in order to receive 
instructions how to properly care for the study drug. 
13.6. 
Study Drug Dispensing and Administration 
13.6.1. 
Study Drug Dispensing  
Following conclusion of the Day 1 Pre-Dose procedures, the Investigator (or designee) will 
assure that the subject still meets all the study enrollment criteria. The investigator may then 
approve subject enrolment.  
Site personnel (or institutional pharmacist) will allocate the appropriate study drug for each 
subject. The tube with its aluminum envelope will be removed from the cardboard container in 
which it was stored while refrigerated. The aluminum envelope will be opened by site 
personnel and the tube removed.  The aluminum envelope will be retained at the site for 
monitoring purposes and the tube will be returned to the container until dosing time.   
Subjects will receive a new tube of the study drug at Day 1 Dosing, Week 4, and Week 8 Visits 
and tubes will be returned by the subjects at Week 4, Week 8, and Week 12 Visits.  
13.6.2. 
Study Drug Dosing Cards 
Study Drug Dosing Cards will be distributed to the site.  These cards will be used: (a) by site 
personnel to train and to test subjects in the proper length of the study drug ointment strip to 
be expressed and applied to the Treatment Field, and (b) by enrolled subjects to measure the 
appropriate length of study drug ointment to be applied to their Treatment Field.   
13.6.3. 
Study Drug Measurement and Application Review 
All sites will receive tubes of placebo with which to train all subjects to measure the appropriate 
quantity of study drug to be applied. These training tubes will be clearly marked.  
Using the Treatment Field photograph and Template, placebo training ointment, and a Study 
Drug Dosing Card, the subject will be trained and tested in proper and precise dosing 
techniques.  
Note: Training tubes containing placebo ointment will only be used to practice 
measurement of the proper study drug dose on the Dosing Card and not for application 
to the face during training and testing.   


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 59 OF 78 
Screening Visit 
Subjects will be trained and tested by site personnel at the Screening Visit. The subject will be 
taught to measure the study drug using placebo tubes supplied by the Sponsor. The subjects 
will also be taught how to apply the study drug, but they will not use the placebo for this part 
of the training. In other words, placebo should not be applied to their skin during the training.  
Subjects who have difficulty measuring the dose or applying the study drug to the precisely 
may be asked to bring a dosing partner with them to the Day 1 Pre-Dose Visit. This dosing 
partner must be willing and able to assist the subject with study drug application once every 
evening for 84 days.  
If the subject (or their dosing partner) is unlikely to apply the study drug appropriately, the 
subject should be terminated from the study based on Inclusion #3 (Section 9.1).  
Day 1 Pre-Dose Visit 
Subjects who continue to meet the study enrollment criteria following Screening will be trained 
and tested twice by site personnel during the Day 1 Pre-Dose Visit: once at the beginning of 
the visit and once again at the end of the visit before randomization. If the subject (or dosing 
partner) is unlikely to apply the study drug appropriately, the subject should be excluded from 
the study based on Inclusion #3 (Section 9.1). 
Day 1 Dosing Visit 
Dosing at this visit will occur under the supervision of the site personnel.  If at this visit the 
subject (or their dosing partner) is unable to precisely prepare the study drug or is unable to 
properly locate the Treatment Field, they should be withdrawn before the study drug is 
applied and considered a screening failure. Application of the study drug during this visit 
will be the same as described in Section 13.6.4, below.  
13.6.4. 
Study Drug Administration at Home  
The study drug will be applied to the Treatment Field by the subject or their dosing partner. 
Subjects in Cohort 1 will apply approximately 200 mg of 10%VDA-1102 each morning before 
10:00 am and each evening at least 3 hours prior to bedtime. Subjects in Cohort 2 will apply 
approximately 200 mg of 20%VDA-1102 each morning before 10:00 am. 
Cohorts 1 and 2: The morning dose should be applied before 10 am. If a subject knows that 
they will perspire, shower, vigorously exercise, etc. before 10 am, application of the study 
drug should be delayed until completion of those activities.  
Cohort 1 only: The evening dose should be applied each day at least 3 hours before bedtime.  
If the subject would like to shower, wash their face, shampoo their hair, etc., these should 
be performed prior to study drug application. 
At the dosing time, the subject should check the Treatment Field in the mirror to assure it is 
clean and dry.  
The study drug tube will be removed from the container, the tube cover unscrewed, and the 
study drug ointment expressed as a strip into the rectangle printed on the supplied Dosing Card.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 60 OF 78 
Using a mirror, Treatment Field photograph, and/or the landmarks drawn on the Treatment 
Field Template, the template will be appropriately positioned on the subject’s face or scalp. 
The subject (or dosing partner) will apply the study drug to the Treatment Field on their skin 
that corresponds to the 25 cm2 area cut out of the template. Subjects (or their dosing partners) 
will apply the study drug with one finger to the center of the Treatment Field and spread the 
ointment evenly over the entire field. The Treatment Field will not be occluded. The subject 
will remove the Treatment Field Template from their face.  With the same finger, the subject 
will spread ointment at the periphery of the Treatment Field approximately ¼ inch beyond the 
Treatment Field perimeter to ensure that the whole Treatment Field was covered with study 
drug.  
After each study drug application, the subject’s hands should be very carefully washed 
with warm water and soap.  
The subject will be instructed not to wet or touch the Treatment Field. Subjects should not 
perform activities that might cause wetting or excessive sweating of the Treatment Field, for 
approximately 6 hours after dosing.  
After each dosing, the Dosing Diary must be completed.  
13.7. 
Study Drug Accountability and Dosing Compliance 
13.7.1. 
Study Drug Site Accountability  
Study sites will be asked to acknowledge receipt of the study drugs on the day of arrival at the 
site.  The site pharmacist and/or the assigned site personnel will be responsible for drug 
inventory. A drug inventory record should be maintained by the person responsible for 
dispensing the study drug to the subject.  This should record which supplies arrived at the site 
and which container(s) is issued to each subject. The Sponsor should be notified of details of 
any supplies which are inadvertently damaged.  Details of any supplies which are inadvertently 
damaged or unaccountable for any reason should be documented on the drug inventory record, 
which will be collected at the end of the study.   
All study drug will be inventoried by the monitor during and at the conclusion of the study.  
Secure disposal or return of unused supplies to the Sponsor at the end of the study will be 
arranged. Sufficient study drug will be given to each subject to allow for proper dosing between 
site visits.  
13.7.2. 
Study Drug Accountability and Dosing Compliance 
Study drug distributed to each subject and returned by each subject will be documented in the 
Drug Accountability Log.  
Dosing cards will be distributed and collected with study drug. Subjects will complete a Dosing 
Diary with the date and time of each dosing. Missed doses will be recorded. Dosing cards will 
be used to assess subject compliance.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 61 OF 78 
13.7.3. 
Study Drug Weighing 
Each new (unused) study drug tube will be weighed before the first dose is dispensed. As part 
of study drug accountability, study tubes returned by the subjects at Weeks 4, 8, and 12 will be 
weighed. Study drug weights will be recorded and these data will be used to assess subject 
compliance.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 62 OF 78 
14. 
CONCOMITANT MEDICATION 
Any prescription or non-prescription medication, alternative medication, herbal product, 
homeopathic substance, etc. that the subject receives while they are enrolled in the trial or that 
was taken within 2 months of Screening will be referred to as a Concomitant Medication. The 
Investigator is to record the use of all concomitant medications, both prescribed and over-the-
counter, in the subject medical record.   
Subjects should be advised against taking any new medication, both prescribed and over-the-
counter, without consulting the Investigator, unless the new medication is urgently required for 
emergency use.  Subjects taking medication other than those listed as prohibited in Section 
12.9.1 may continue taking their routine medications and vitamins so long as they have been 
taking them for at least 2 months prior to Screening with no change in dose or dosing interval. 
At Screening and Day 1 Pre-Dose Visits, the study site personnel will review each subject’s 
concomitant medications to ensure that subjects are not taking any prohibited medications 
listed in Section 12.9.1. 
The Investigator and his designees are obligated to ensure the well-being of all subjects during 
this study. Consequently, no medication or treatment should be withheld from a subject 
requiring medical intervention.  This may include treatments received by the subject prior to 
enrollment as well as in response to any new medical conditions that developed during the 
study.  The Investigator (or designee) must inform a subject when concomitant medical 
intervention or treatment is indicated and report this in the appropriate section of the CRF.  


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 63 OF 78 
15. 
ADVERSE EVENTS 
15.1. 
Adverse Event Definitions 
15.1.1. 
General 
An AE is any untoward medical occurrence which does not necessarily have to have a causal 
relationship with the pharmaceutical product treatment.  Any worsening of the subject’s disease 
under study or other medical conditions will also be considered to be an AE, unless it is within 
the normal range of disease fluctuation for that subject. 
Abnormal clinically significant changes in physical examination or vital signs should be 
recorded as AEs.   
15.1.2. 
Local Skin Reactions 
In this trial Local Skin Reactions (LSRs) will not be recorded as AEs unless they (a) 
require treatment with a prescribed medication; (b) extend >2 centimeters beyond the 
border of the Treatment Field; or (c) require a study drug dose adjustment. 
15.1.3. 
Laboratory and ECG Data 
Abnormal clinical laboratory or ECG findings should be reported as an AE are as follows: 
1. Test result is associated with accompanying symptoms; 
2. Test result requires additional diagnostic testing or medical/surgical intervention; 
3. Test result leads to a change in study dosing, discontinuation from the study, initiation of a 
prescription medication, or surgical intervention; and 
4. Test result leads to any of the outcomes included in the definition of a SAE. 
If such an event occurs, the test should be repeated within approximately 7 days to confirm 
the finding and appropriately monitored.  The mere repetition of an abnormal test, in the 
absence of any of the above conditions, does not fulfil Condition 2 above for reporting as an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
15.1.4. 
Miscellaneous Definitions 
Treatment Emergent Adverse Events (TEAEs) are AEs that occur de novo or worsen 
following the initiation of study treatment.  
Surgical procedures themselves are not AEs; they are therapeutic measures taken due to an 
AE and they should be documented as such.   
Planned hospital admissions documented in the subject’s medical record prior to enrolment 
and study-related procedures are also not to be reported as AEs. 
Overdoses of the study drug will not be reported as an AE. However, any AEs or SAEs, as 
defined in Section 15, associated with an overdose will be reported as such. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 64 OF 78 
15.2. 
Clarification of the Difference between “Severe” and “Serious” 
Severity describes the intensity of an event, irrespective of its medical significance (such as 
severe headache).  This is not the same as seriousness, which is based on regulatory definitions. 
Seriousness (not severity) defines SAE reporting obligations.  The severity of all AEs will be 
graded on a 3-point scale (mild, moderate, severe) and reported in detail on the CRF.  
• Mild: Discomfort noticed but no disruption of normal daily activity. 
• Moderate: Discomfort sufficient to reduce or affect daily activity. 
• Severe: Inability to work or perform normal daily activity. 
15.3. 
AE Reporting 
Specific instructions regarding the reporting of AEs, including start and stop dates, relationship 
to study drug, outcomes, expectedness, etc. will be detailed in the Safety Monitoring Plan.  
15.4. 
Relationship to Study Treatments 
“Causality” refers to the relationship of the AE to the study drug. The investigator must include 
assessment of causality (whether there is a reasonable possibility the drug caused the event) for 
each AE. Causality will be categorized according to the following criteria: 
 
• Not Related: There is no medical evidence to suggest that the AE may be related to 
study drug usage and other causes are much more likely.  
• Unlikely Related: There is no medical evidence to suggest that the AE may be related 
to study drug usage, but a relationship cannot be completely ruled out. There are other 
more likely causes.  
• Possibly Related: There is weak medical evidence to suggest that the AE may be 
related to study drug usage and a relationship cannot be completely ruled out. 
• Likely Related: There is good medical evidence to suggest that the AE may be related 
to study drug usage but other causes cannot be ruled out completely.  
• Related: There is a strong and convincing medical evidence to suggest that the AE is 
related to study drug usage and other possible causes are highly unlikely. 
15.5. 
Follow-up of Adverse Events 
All AE related symptoms and/or signs will be followed until there is a return to the baseline 
status, all associated parameters have returned to normal (or are no longer considered clinically 
significant), stabilized, or no further improvement is anticipated.  Follow-up is mandatory, 
irrespective of causal relationship to the study drug(s).  SAEs will be monitored until resolution 
or stabilized as medically indicated.  Any subject who has received at least 1 dose of the study 
drug and has experienced an AE that has not resolved or stabilized, may be invited to attend 
and unscheduled visits. Subjects with AEs that have not resolved or stabilized should be 
followed until resolution of the AE or for a minimum of 30 days after the subject’s last 
application of the study medication. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 65 OF 78 
16. 
SERIOUS ADVERSE EVENTS 
16.1. 
Definition 
An SAE is any AE that, at any dose, results in at least one of the following outcomes: 
1. Death.  Death is an outcome, not an event.  Where the cause of death is uncertain, the 
reported SAE should be the same as the term on the subject’s death certificate. 
2. Life-threatening.  Life-threatening means that the subject was at immediate risk of death at 
the time of the SAE; it does not refer to an SAE that hypothetically might have caused 
death if it were more severe. 
3. Requires or prolongs inpatient hospitalization. 
4. Persistent or significant disability or incapacity. “Persistent or significant disability or 
incapacity” means that there is a substantial disruption of a person’s ability to carry out 
normal life functions. 
5. Congenital anomaly or birth defect. 
6. Medically serious event based upon appropriate medical judgment.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
16.2. 
Reporting of Serious Adverse Events 
Full details of SAE reporting will be based on the ICH guidelines for reporting SAEs and 
will appear in the study Safety Monitoring Plan.  
If the AE is serious, the Investigator must complete an SAE Report form, in addition to the AE 
page in the CRF. In addition, when a non-serious event becomes serious, details must be 
forwarded, within 24 hours of Investigator awareness that an AE has become serious, to the 
Sponsor or designee on an SAE Report form, with the date of the seriousness upgrade as the 
SAE start date. 
The SAE Report Form must be completed in accordance with instructions provided by the 
Sponsor or designee.  The completed form must be emailed to Dr. Chaim Brickman, the Study 
Safety Monitor, within 24 hours of discovery of the SAE.  
The initial report must be as complete as possible, including details of the current illness and 
the SAE, and an assessment of the causal relationship between the event and the investigational 
product(s) or the study procedures. 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented as a follow-up on the SAE 
Report form. 
Any SAE, whether or not related to the study treatment, must be reported within 24 hours to 
the Study Medical Monitor and the CRO responsible for the site.  The following contact and 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 66 OF 78 
communication methods may be used. The Medical Monitor and CRO will confirm receipt 
upon receiving the notification.   
Chaim M. Brickman, Study Medical Monitor (Sponsor) 
Telephone (mobile): 1-646-757-1062 
E-mail: cbrickman@vidacpharma.com 
Marietta Radona, Project Manager (Therapeutics, Inc.) 
Telephone (mobile): 1-973-979-3307  
E-mail: mradona@therapeuticsinc.com 
Office: 1-858-571-1800 x171 
Fax:     1- 858-571-1234 
If, for any reason, the Investigator cannot notify the Study Safety Monitor via the appropriate 
form or if the Investigator suspects that using this method will delay the notification (e.g., 
during a holiday period), the Investigator must verbally notify the Sponsor Medical Monitor 
(or designee) via telephone.  The SAE Report form must still be relayed at the earliest possible 
opportunity.  SAEs must be reported to the IRB according to IRB guidelines.  
All ancillary documentation (e.g. discharge letters, laboratory reports and consultations) must 
be sent to the Sponsor or designee.  In the event of an SAE resulting in death, post-mortem 
reports should be routinely sent to the Sponsor or designee. 
All subjects with SAEs must be followed-up for outcome. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 67 OF 78 
17. 
STATISTICAL PLAN 
17.1. 
Sample Size Rationale and Justification 
The study is designed to evaluate the efficacy, safety, and tolerability of topical VDA-1102 
ointment in subjects with actinic keratosis. Approximately 150 subjects will be enrolled in this 
2-cohort clinical trial. In each cohort, approximately 75 subjects will be enrolled in order to 
complete each cohort with safety and efficacy data from at least 70 subjects who received study 
drug. Considering the results from a previous Phase 2 parallel, randomized, placebo-controlled 
study with a sample size of 29 to 32 subjects per treatment group, this sample size is considered 
adequate to evaluate the stated objectives.  A formal sample size calculation was not performed. 
17.2. 
Statistical analysis 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. Data will be summarized by cohort and visit, if appropriate.  
Unless stated otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, 
median, standard deviation (SD), minimum, and maximum for continuous data and frequencies 
and percentages for categorical data. The data will be analyzed using the SAS® version 9.4 or 
higher (SAS Institute, Cary North Carolina). Details of all statistical analyses to be performed 
will be included in the Statistical Analysis Plan (SAP). 
17.3. 
Secondary Efficacy Analyses 
17.3.1. 
Primary Efficacy Analyses 
The proportion of subjects achieving complete clearance of AK lesions within their Treatment 
Field will be summarized by cohort and visit. The 95% confidence interval for the percentage 
will be calculated using the Clopper-Pearson method for binomial proportions. The analysis 
will be conducted on the modified Intent-to-Treat (mITT) population, mITT Face (mITT-Face) 
subpopulation, Per Protocol population (PP), and PP Face (PP-Face) subpopulation. 
17.3.2. 
Secondary Efficacy Analyses 
The proportion of subjects achieving partial (≥75%) clearance of AK lesions within their 
Treatment Field will be summarized by cohort and visit. The 95% confidence interval for the 
percentage will be calculated using the Clopper-Pearson method for binomial proportions. 
The number of facial AK lesions in the Treatment Field, change from baseline values, and 
percent change from baseline values will be summarized by cohort and visit. 
These analyses will be conducted on the modified Intent-to-Treat (mITT) population, mITT 
Face (mITT-Face) subpopulation, Per Protocol population (PP), and PP Face (PP-Face) 
subpopulation. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 68 OF 78 
17.4. 
Safety Assessments 
The safety endpoint data will be summarized for the ITT population.  AEs will be categorized 
by System Organ Class (SOC) and Preferred Terms (PT) using the Medical Dictionary for 
Regulatory Activities (MedDRA version 19.1 or higher).  The incidence of AEs, as well as the 
intensity and relationship to study drug will be summarized by cohort.  Safety will also be 
assessed by evaluating findings of physical examinations, vital signs, clinical laboratory test 
results, 12-lead ECG tracings, Local Skin Reaction Score, drug exposure, concomitant 
medications, Urine Pregnancy Test results, withdrawals/terminations, and dose adjustments.  
These findings will be summarized and compared to findings from baseline evaluations.   
Local Skin Reaction (LSR) Scores will be summarized.     
17.5. 
Pharmacokinetic Parameters 
Not applicable. 
17.6. 
Missing Data 
Every effort will be made to obtain required data at each scheduled visit from all subjects who 
have been enrolled. Details regarding the handling of missing data will be presented in the 
SAP. 
17.7. 
Data Sets 
17.7.1. 
Safety Population 
The Safety population will be defined as all subjects who are randomized and who receive 
study drug.  Safety analyses will be performed on the Safety population.  
17.7.2. 
Modified ITT (mITT) Population 
The modified Intent-to-Treat (mITT) population will be defined as all subjects who are enrolled 
into the study, received any study drug, and did not fail Exclusion Criterion #2.  Subjects in 
this population will be analyzed according to the cohort to which they were allocated. All 
efficacy analyses will be performed on the mITT population.  
17.7.3. 
Per Protocol Population 
Subjects without violations or major deviations will be included in the Per Protocol Population. 
All efficacy analyses will be repeated on this population.  
17.7.4. 
Face Subpopulation 
Subjects whose Treatment Fields are located on their face (i.e., cheeks or forehead) will 
constitute the ITT-Face, mITT-Face, and PP-Face populations. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 69 OF 78 
17.7.5. 
Pharmacokinetic Population 
Not applicable. 
17.8. 
Definitions of the Terms Violation and Deviation 
Violation – Any enrolled subject who does not meet the study enrollment criteria (see Inclusion 
and Exclusion Criteria in Section 9) will be considered a violation.  
Deviation – Any activity that diverges from the procedures defined by this clinical protocol 
will be considered a deviation.  
A major deviation is one that will definitely, probably, or possibly significantly impact the 
subject safety or the quality of the trial data. An example of a major deviation is a subject who 
missed dosing >7 consecutive days of study drug.  
A minor deviation is one that does not, or is unlikely to, significantly impact subject safety or 
the quality of the trial data. 
All violations and deviations must be recorded in the study site’s electronic system and signed 
by the Investigator (or designee).  
A Violation and Deviation Review Meeting that includes members of the study team from the 
Sponsor and the Statistical Management CRO will determine which subjects meet the above 
definitions. Details of this meeting will be included in the Statistical Analysis Plan. It is the 
Sponsor’s responsibility to determine whether the event will be considered a violation, major 
deviation, or minor deviation.   
17.9. 
Subject Compliance  
Subjects will record administered and missed doses in their Dosing Diaries. Study drug tubes 
will also be weighed at each site visit.  
17.10. Demographic and Baseline Characteristics 
The comparability of the cohorts will be summarized by the evaluation of the demographic 
information, including age, gender, and country.   


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 70 OF 78 
18. 
STUDY MANAGEMENT AND DATA COLLECTION 
18.1. 
Data Collection Methods 
Trained investigational site staff will enter the data required by the protocol into the eCRFs 
from source documents.  All information on the eCRFs must be traceable to these source 
documents.  Instances of missing or uninterpretable data will be discussed with the study site 
for resolution.  The study site is responsible for providing missing data and resolutions to the 
data queries and for correcting the eCRFs as appropriate.  eCRFs must be reviewed, signed, 
and dated by the Investigator.  All original laboratory and ECG reports will be kept with the 
subject source documentation and a copy will be transmitted to the Sponsor (or designee), if 
required. 
ECGs should be transmitted to the central laboratory the same day the data are obtained, if 
possible.  
18.2. 
Monitoring 
Vidac Pharma (or their designee) will conduct site visits to the investigation facilities for the 
purpose of monitoring all aspects of the study.   
18.3. 
Data Retention 
All relevant correspondence (e.g. with the Sponsor, CRO, IRB, etc.) relating to this clinical 
study conduct should be maintained in the appropriate file at the site. 
The Investigator must retain all records, including the source documents, ICFs, laboratory 
reports including ECGs, and all other study-related documentation for a period of at least 2 
years following the date the last marketing application is approved for the study drug for the 
indication for which it is being investigated, or 2 years after the date that the FDA has been 
notified that all clinical investigation of the drug has been discontinued, whichever is greater, 
unless notified otherwise in writing by the Sponsor.  These documents should, however, be 
retained for a longer period if required by the applicable regulations or if requested by the 
Sponsor. The Investigator must contact the Sponsor and gain written approval prior to 
destroying any records.  No study documents will be destroyed or moved to a new location 
without prior written approval of the Sponsor.  If the Investigator relocates, retires, or 
withdraws from a clinical study for any reason, all records required for the study should be 
transferred to an agreed-upon designee, e.g. another Investigator. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 71 OF 78 
19. 
CLINICAL STUDY ADMINISTRATION, ETHICS, AND 
CONDUCT 
19.1. 
Good Clinical Practice 
GCP is an important ethical and scientific quality standard for designing, conducting, 
recording and reporting studies that involve the participation of human subjects.  Compliance 
with this standard provides public assurance that the rights, safety and well-being of study 
subjects are protected.  
19.2. 
Confidentiality 
19.2.1. 
Study Confidentiality 
All information regarding the nature of the investigation provided by the Sponsor or its 
designee to the Investigator and his / her staff or designees (except for information required by 
law or regulations to be disclosed to the IRB, the subject, and/or the appropriate regulatory 
authorities) must be maintained in confidence by the Investigator and his / her staff or 
designees. 
19.2.2. 
Subject Anonymity 
The anonymity of participating subjects must be maintained.  Subjects will be identified by 
their initials and subject number on CRFs and other documents submitted to the Sponsor.  
Documents not submitted to the Sponsor include those that identify the subject (e.g., the signed 
ICF), and must be maintained in strict confidence by the Investigator, except as necessary to 
allow auditing by the IRB, Sponsor or its designee, FDA, and/or equivalent authorities. 
19.3. 
Subject Information and Informed Consent 
Before being enrolled in the clinical study, subjects must consent to participate after the nature, 
scope, and possible consequences of the clinical study have been explained in a form 
understandable to them. 
An informed consent document that includes information about the study will be prepared and 
given to the subject.  This document will contain all the elements required by the ICH E6 
Guideline for GCP and any additional elements required by local regulations.  The document 
must be in a language understandable to the subject and must specify who informed the subject.  
Where required by local law, the person who informs the subject must be a physician. 
All ICFs must contain the minimum elements as mandated by the FDA and ICH guidelines and 
will be subject to the Sponsor’s (or designee’s) approval as well as the IRB’s approval. 
The Investigator will not undertake any measures or procedures specifically required of a 
subject for the clinical study until valid consent has been obtained. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or increases the potential risk to the subject, the ICF must be revised, submitted to the IRB for 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 72 OF 78 
review and approval or favorable opinion.  The revised ICF must be used to obtain consent 
from a subject currently enrolled in the study only if he or she is affected by the amendment.  
The revised ICF must be used to obtain consent from any new subjects who are enrolled into 
the study after the date of the approval or favorable opinion of the amendment. 
19.4. 
Study Closure 
Completion or premature termination of the study will be reported by the Sponsor to the 
regulatory agency and by the Sponsor or by the Investigator to the IRB as required by local 
regulations or by the IRB. 
Once the database is locked, and all efforts are made to settle all outstanding queries, site 
closeout will occur.  Study materials (including used and unused study drug) must be returned, 
disposed of, or retained, as directed by the Sponsor.  
19.5. 
Early Termination of the Clinical Trial 
If, in the opinion of an Investigator, the clinical observations in the study suggest that it may 
be unwise to continue, that Investigator may terminate their site’s participation after 
consultation with the Sponsor.  A written statement fully documenting the reasons for such a 
termination will be provided to the Sponsor.     
The Sponsor may terminate the study at any time for any reason.  
If it becomes apparent that subject enrollment at a particular site is unsatisfactory with respect 
to quality or quantity, or that data recording is inaccurate or incomplete on a chronic basis, the 
Sponsor has the right to terminate participation of that site and remove all study materials from 
that investigational site.  A written statement will be provided to the Investigator, the IRB, and 
regulatory authorities, if required. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 73 OF 78 
20. 
INVESTIGATOR’S OBLIGATIONS 
20.1. 
General 
The Investigator agrees that the study will be conducted in accordance with the clinical 
protocol, ICH-GCP guidelines, and the Declaration of Helsinki. The Investigator will conduct 
all aspects of this study in accordance with all governmental, state and local laws. 
20.2. 
Institutional Review Board 
Before initiation of the study at any site, the Investigator must obtain approval of the clinical 
protocol and ICF from the IRB complying with the provisions specified in FDA CFR, Title 21, 
Part 56, ICH Guidelines, and all governmental, state and local laws. 
A copy of the written IRB approval of the protocol, ICF and any other documentation (such as 
advertising) as appropriate must be provided to the Sponsor or its designee prior to initiation 
of the study.  The approval letter must identify the IRB name and address, the clinical protocol 
by title and/or protocol number, and the date approval was granted. Furthermore, the approval 
letter must contain a statement that the IRB complies with the FDA CFR, Title 21, Part 56, and 
ICH Guidelines for a study conducted under an IND, or other applicable government 
regulations for studies not conducted under an IND. 
The Investigator is responsible for supplying the IRB with the data required for continued 
review of this study at intervals not exceeding one year, or at intervals otherwise specified by 
the IRB.  The Investigator shall supply the Sponsor with written documentation of this 
continued review.  When necessary, an extension or renewal of the IRB approval must be 
obtained and this shall also be forwarded to the Sponsor. A list of the IRB members should be 
forwarded to the Sponsor in accordance with local regulations. 
The IRB and the regulatory authorities will be provided with any amendments for their review 
and/or approval.  A yearly status report on the progress of the study will be submitted by the 
Investigator to the IRB per their regulations. 
20.3. 
Investigator Protocol Adherence 
The Investigator and his/her designees are required to adhere to the protocol.   
In general, protocol deviations will not be granted. However, if a minor protocol deviation is 
necessary in order to eliminate an immediate hazard to a subject or to facilitate a subject’s 
adherence to protocol procedures, such a deviation request may be communicated to the Study 
Medical Monitor in writing for their consideration. Such a request should include a clear, 
complete, and compelling written description and justification. A copy of this request and the 
written response of the Study Medical Monitor must also be placed in the appropriate file at 
the site.  
Emergency deviations from the protocol that eliminate an apparent immediate hazard to a 
subject and that are deemed crucial for the safety and well-being of a particular subject may be 
instituted for that subject only.  If time allows, the Investigator must consult with the Study 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 74 OF 78 
Medical Monitor. If time does not allow, the Investigator may approve the deviation without 
prior consultation with the Study Medical Monitor. The Investigator will contact the Sponsor 
as soon as possible in the case of such a deviation.  These deviations do not require pre-approval 
by the IRB; however, the Sponsor and the IRB must be notified in writing as soon as possible 
after the departure has been made.  In addition, the Investigator will document in the subject’s 
CRF the reasons for protocol deviation and the ensuing events. 
20.4. 
Protocol Amendments 
Any additions or changes to the clinical protocol will require a protocol amendment. The 
Amended Clinical Protocol Signature Page will be signed by the protocol signatories.  Protocol 
amendments must undergo IRB approval prior to implementation.  Should the ICF require 
changes, the revised ICF must be approved also according to the same procedure. 
20.5. 
Audits and Inspections 
The Investigator will permit study-related monitoring, audits and inspections by the IRB, the 
Sponsor or its designee, government regulatory bodies, and quality assurance groups of all 
study-related documents.  This includes direct access to source documents, regulatory 
documents, data collection instruments, study data, etc.  The Investigator will ensure that all 
study-related facilities (e.g., pharmacy, laboratories, etc.) are maintained in accordance with 
GCP guidelines. 
Participation as an Investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable Sponsor (or designee) quality assurance 
personnel. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 75 OF 78 
21. 
REFERENCES 
Chetty C, Choi F, and Mitchell T (2015), “Primary care review of actinic keratosis and its 
therapeutic options: a global perspective”, Dermatol Ther (Heidelb) 5:19-25.  
Cohen J.L. et al. (2010), “Actinic keratosis as a key component of preventive strategies for 
nonmelanoma skin cancer”, Journal of Clinical and Aesthetic Dermatology 3(6):39-44. 
Heaphy M.R. Jr. and A.B. Ackerman (2000), "The nature of solar keratosis: a critical review 
in historical perspective", Journal of the American Academy of Dermatology 43(1):138-150. 
Hurwitz R.M. and L.E. Monger (1995), "Solar keratosis: an evolving squamous cell carcinoma. 
Benign or malignant?”, Dermatologic Surgery 21(2):184. 
Kanellou P. et al. (2008), "Genomic instability, mutations and expression analysis of the 
tumour suppressor genes p14 ARF, p15 INK4b, p16 INK4a and p53 in actinic keratosis", 
Cancer letters 264(1): 145-161. 
Kanjilal S. et al. (1995), "p53 mutations in nonmelanoma skin cancer of the head and neck: 
molecular evidence for field cancerization", Cancer research 55(16): 3604-3609. 
Krawtchenko N. et al. (2007), " 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", British Journal of 
Dermatology 157(s2): 34-40. 
Mittelbronn et al. (1998), "Frequency of pre‐existing actinic keratosis in cutaneous squamous 
cell carcinoma", International Journal of Dermatology 37(9): 677-681. 
Olsen et al. (1991), “A double-blind, vehicle-controlled study evaluating masoprocol cream in 
the treatment of actinic keratosis on the head and neck: A double-blind, vehicle-controlled 
study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck”, 
J Am Acad Dermatol 24(5 Pt 1): 738-43. 
Oppel T. and H.C Korting (2004), "Actinic keratosis: the key event in the evolution from 
photoaged skin to squamous cell carcinoma. Therapy based on pathogenetic and clinical 
aspects", Skin Pharmacol Physiol. 17:67–76. 
Ortonne J.P. (2002), "From actinic keratosis to squamous cell carcinoma", British Journal of 
Dermatology 146(s61): 20–23. 
Padilla R. S. et al. (2010), "Gene expression patterns of normal human skin, actinic keratosis, 
and squamous cell carcinoma: a spectrum of disease progression", Archives of Dermatology 
146 (3): 288-293. 
Röwert-Huber J. et al. (2007)," Actinic keratosis is an early in situ squamous cell carcinoma: a 
proposal for reclassification", British Journal of Dermatology 156(s3): 8–12. 
Shergill B, Zokaie S, and Carr AJ (2014), “Non-adherence to topical treatment for actinic 
keratosis”, Patient Prefer Adherence 8:35-41. 
Stockfleth, E. (2012), “The paradigm shift in treating actinic keratosis: a comprehensive 
strategy”, Journal of Drugs in Dermatology: JDD 11(12):1462-1467. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 76 OF 78 
Warino L. et al. (2006), "Frequency and cost of actinic keratosis treatment", Dermatologic 
Surgery 32(8):1045–1049. 
Werner R.N. et al (2015), “Evidence- and consensus-based (S3) guidelines for the treatment of 
actinic keratosis – International League of Dermatological Societies in cooperation with the 
European Dermatology Forum - Short–Version", Journal of the European Academy of 
Dermatology and Venerology 29: 2069-2079.  
Ziegler A. et al. (1994), "Sunburn and p53 in the onset of skin cancer", Nature 372(6508): 773-
776. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 77 OF 78 
22. 
APPENDICES 
22.1. 
Local Skin Reaction Score  
The Local Skin Reaction Score is an assessment of the skin in the Treatment Field. At each 
study visit the Investigator (or designee) will assign a severity score to each of the objective 
findings listed in the table. Whenever possible, the same investigator should perform all 
the LSR assessments.  
The Investigator will assess the selected Treatment Field and rate the findings on a 5-point 
scale (0-4). The composite LSR score will consist of the sum of all the individual LSR scores.  
Local 
Skin 
Reaction 
0 
NONE  
1 
MILD 
2 
MODERATE 
3 
SEVERE 
4 
EXTREME 
Erythema 
None 
or  
Pinkish-red over 
isolated portions of 
the Treatment Field 
Pinkish-red over 
most of the 
Treatment Field 
Red  
Intense redness 
(beet red)  
Very intense 
redness that extends 
>2 cm beyond the 
Treatment Field 
Edema / 
Swelling 
None  
or  
Trace edema 
Slightly 
palpable or 
barely visible 
edema 
Visible and easily 
palpable edema 
Gross edema 
Gross edema that 
extends >2 cm 
beyond the 
Treatment Field 
Weeping / 
Exudate / 
Crust 
None 
Mild weeping or 
exudate  
Moderate 
weeping, exudate 
or crust  
Thick exudate    
or crust over 
>50% of the 
Treatment Field 
Heavy exudate or 
crust that extends 
>2 cm beyond the 
Treatment Field 
Vesicles / 
Pustules 
None 
Vesicles with 
limited 
coalescing 
Vesicles over 
>50% of the 
Treatment Field 
with majority 
coalescing 
Pustulation 
Coalesced pustules 
Flaking / 
Scaling 
None  
or  
Trace flaking/scale 
Mild flaking or 
light scale 
Moderate flaking 
and/or scaling 
over >50% of 
Treatment Field 
Severe, thick 
scale  
Severe, thick scale 
that extends >2 cm 
beyond the 
Treatment Field 
Erosion / 
Ulceration 
None 
Scattered 
shallow erosions 
Deep erosions 
over >50% of the 
Treatment Field 
or limited areas of 
ulcerations 
Small eschar or 
extensive 
ulcerations 
Eschar that covers 
the entire 
Treatment Field 
The 5-point LSR Score is: 0 = No or Trace Reaction, 1=Mild Reaction, 2=Moderate 
Reaction, 3=Severe Reaction, and 4=Extreme Reaction.  
In this trial Local Skin Reactions (LSRs) will not be recorded as AEs unless they (a) require 
treatment with a prescribed medication; (b) extend >2 centimeters beyond the border of the 
Treatment Field; or (c) require a study drug dose adjustment. 


CLINICAL PROTOCOL VDA-CP-05 P2B; 30APRIL2018 
PAGE 78 OF 78 
22.2. 
Subjective Local Skin Reaction Score 
Itching and pain will be reported as a Subjective LSR Score. The same 5-point (0-4) scale listed 
above for the LSR Score will be used for these parameters.