Clinical trial NCT02844777
Conditions: Actinic Keratosis
Keywords: topical ointment skin hexokinase precancerous conditions carcinoma, squamous cell
Sponsor: Vidac Pharma
Start date: 2016-07-15; Completion date: 2017-05-26
Enrollment: 93 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 2 clinical trial is a multi-center, randomized, double-blind, placebo-controlled, multiple-dose, parallel-cohort study to assess the efficacy, safety and tolerability of VDA-1102 in the treatment of actinic keratosis (AK) on the head of male and female adult subjects.

Detailed description:
Approximately 84 subjects who meet the study's enrollment criteria at the completion of the Screening Period will be randomized to receive 5% or 10% VDA-1102, or matched-placebo. During the Treatment Period, study drug will be applied once-daily for 28 days to a 25 square centimeter area of skin containing 4-8 actinic keratosis lesions on the face or scalp. Subjects will be followed for an additional 28 days (Observation Period) wherein no study drug will be applied.

The purpose of the study is to determine whether once-daily application of VDA-1102 ointment for 28 days is effective and well-tolerated in the treatment of actinic keratosis of the face and scalp.

Arms: arm 1: Excipeint alone arm 2: Active study medication arm 3: Active study medication
Interventions: intervention 1: Placebo intervention 2: 5% VDA-1102 intervention 3: 10% VDA-1102
Intervention descriptions: intervention 1: 200 mg applied once-daily for 28 days intervention 2: 200 mg applied once-daily for 28 days intervention 3: 200 mg applied once-daily for 28 days

Protocol documents:
Prot_000.pdf: 
 
 
VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03 P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2; 31 OCTOBER 2016 
 
 
 
PAGE 1 OF 93 
 
CLINICAL STUDY PROTOCOL 
1. 
COVER AND SIGNATURE PAGES 
1.1 
Title Page 
Clinical Study Number: 
VDA-CP-03 
 
Original Clinical Protocol Date: 
09 June 2016 
Clinical Protocol Amendment 
2 
Clinical Protocol Amendment 2 Date 
 31 October 2016 
Study Drug Identification: 
VDA-1102 
Clinical Protocol Version 
1.0 
Clinical Protocol Title: 
A Phase 2 Randomized, Double-Blind, Placebo-
Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics 
of Once-Daily Application of Topical VDA-1102 
Ointment for 28 Days in Subjects with Actinic 
Keratosis 
Study Phase: 
Phase 2 
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.  
Vice-President for Clinical Affairs 
Study Principal Investigator: 
Mark Lebwohl, M.D. 
Mount Sinai Medical Center 
New York, NY 
 
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. 
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03 P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2; 31 OCTOBER 2016 
 
 
 
PAGE 3 OF 93 
 
1.2.2 Investigator Signature Page 
Clinical Study Number: 
VDA-CP-03 
Original Clinical Protocol Date: 
Clinical Protocol Version: 
09 June 2016 
1.0 
Clinical Protocol Amendment: 
2 
Clinical Protocol Amendment Date: 
31 October 2016 
Study Drug Identification: 
VDA-1102 
Clinical Protocol Title: 
A 
Phase 
2 
Randomized, 
Double-Blind, 
Placebo-
Controlled, Parallel-Cohort Study to Evaluate the Efficacy, 
Safety, Tolerability, and Pharmacokinetics of Once-Daily 
Application of Topical VDA-1102 Ointment for 28 Days
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 
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VDA-1102 topical ointment
CONFIDENTIAL
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 4 OF 93 
 
 
2.  PROTOCOL SYNOPSIS 
Title of Study:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort 
Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of  Once-Daily 
Application of Topical VDA-1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
Study Center(s):  Approximately 6 sites in the US and 3 in Israel 
Study Duration: 11 months 
Phases of Development: Phase 2 
Study Objectives:  
Primary Objective: To compare the reduction on Day 56 in the number of the actinic 
keratosis (AK) lesions in the Treatment Field of subjects receiving once-daily topical 5% or 
10% VDA-1102 ointment for 28 days to the reduction in the number of AK lesions in 
subjects receiving placebo. 
Secondary Objectives: 
• To evaluate the systemic and local (skin) safety and tolerability of once-daily topical 
application of 5% or 10% VDA-1102 ointment or placebo for 28 days in adult subjects 
with AK. 
• To assess the systemic exposure of VDA-1102 and jasmonic acid, its primary 
metabolite, at selected time points during topical application of 5% or 10% VDA-1102 
ointment or placebo for 28 days in adult subjects with AK. 
Exploratory Objectives: 
• To compare the proportion of subjects receiving 28 days of 5% or 10% VDA-1102 who 
on Day 56 had complete clearance of AK lesions to subjects receiving placebo. 
• To compare the reduction on Day 84 in the number of the actinic keratosis (AK) lesions 
in the Treatment Field of subjects receiving once-daily topical 5% or 10% VDA-1102 
ointment for 28 days to the reduction in the number of AK lesions in subjects receiving 
placebo. 
Study Design:  
This Phase 2 clinical trial is a multi-center, randomized, double-blind, placebo-controlled, 
multiple-dose, parallel-cohort study involving the once-daily non-occluded, topical dermal 
application of the study drug (5% or 10% VDA-1102 ointment, or placebo) for 28 days.   
Approximately 84 subjects will be enrolled in this study in order to obtain at least 75 evaluable 
subjects by the end of the trial. Fifteen (15) of these subjects will constitute a Nested Phase 1b 
Safety Study Sub-Cohort, and a maximum of 18 of the 84 subjects will be included in a PK 
Study Sub-Cohort. These 2 sub-cohorts may overlap and are described below. 
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 discrete Grade 1 or 2 AK 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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lesions within a 25 cm2 area on the scalp or face (“the Treatment Field”). Subjects will be 
randomly assigned in a double-blind fashion to 1 of 3 parallel treatment cohorts (5%, or 10% 
VDA-1102, or placebo, respectively) in a ratio of 1:1:1. Randomized subjects will apply a 
single thin application of the study drug to their Treatment Field for 28 days.  
This clinical trial will include 3 study periods.   
Screening Period (Day -21 through Day 1 Pre-Dose): 
During the Screening Visit (up to 21 days pre-dose) subjects who have given written informed 
consent will undergo safety assessments including medical and medication histories, adverse 
event (AE) documentation, vital signs, limited physical examination, clinical laboratory testing, 
12-lead electrocardiograms (ECGs), dermatologic examination, and Treatment Field 
identification, as well as 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. The 18 subjects enrolled in the PK Study Sub-
Cohort (described below) will have a baseline blood sampling for PK analysis.  Subjects who 
continue to meet the enrollment criteria will undergo randomization to 1 of 3 treatment groups: 
5% VDA-1102, 10% VDA-1102, or placebo.  
Three times during the Screening and Day 1 Pre-Dose Visits, subjects will be trained and tested 
in proper application of the study drug to the Treatment Field with the help of 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 evening.  
Treatment Period (Day 1 Dosing through Day 28): 
During the Day 1 Dosing Visit, randomized subjects (or their dosing partner) will apply the first 
dose of the study drug under the supervision of the site personnel in order to further assure 
proper application.  
From Day 1 through Day 27, subjects will continue dosing the study drug to their respective 
Treatment Fields each evening while at home. Subjects will visit their respective investigative 
sites on Day 7 and Day 14 for safety and efficacy assessments, drug accountability, and re-
training in proper application of the study drug.  In addition, subjects in the PK Study Sub-
Cohort will undergo a single blood sampling at approximately 12 h after the prior evening's 
dose. On the Day 28 Visit, subjects will return to the clinic for safety and efficacy assessments. 
Subjects in the PK Study Sub-Cohort will have timed blood samples taken at approximately 12, 
15, 18 and 21 hours after their Day 27 evening dose and a 24-hour Holter monitor will be 
attached.  
During the Treatment Period, site personnel will communicate once-weekly with each subject in 
order to assure study drug compliance, review dosing instructions, and remind subjects of their 
next study visit.   
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
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Observation Period (Day 29 through 84): 
Subjects will visit their respective investigative site on Days 35 and 56 for efficacy and safety 
assessments.  On Day 84 subjects will return to the sites for their final efficacy and safety 
assessments.  Subjects with continuing AEs will be scheduled for follow-up evaluation, as 
appropriate.  
Nested Phase 1b Safety Sub-Cohort:  The first 15 (PK and non-PK) subjects enrolled in the 
trial will undergo on Day 7 the safety examinations planned for all other subjects plus physical 
examination, clinical laboratory and ECG assessments. Once all 15 subjects in this Nested 
Phase 1b Safety Sub-Cohort have completed their Day 7 Visit, safety data (including AEs, LSR 
scores, clinical laboratory results, and ECG data) from Day 1 through Day 7 will be reviewed in 
a blinded fashion by a safety committee. During this blinded interim safety review, enrolled 
subjects will continue dosing the study drug and study enrollment will remain open. 
PK Study Sub-Cohort:  Of the approximate 84 subjects to be enrolled in this trial, a maximum 
of 18 subjects at select sites will undergo blood sampling for PK analysis on Day 1 Pre-Dose as 
well as on Days 7, 14, 28, and 35. In addition, the PK Study Sub-Cohort will undergo 24-hour 
cardiac Holter monitoring on Day 28. Subjects included in this Sub-Cohort may also be 
included in the Nested Phase 1b Safety Sub-Cohort if they are in one of the first 15 subjects to 
be enrolled into the study. 
Number of Randomized Subjects (planned):  Approximately 84 (3x28) subjects will be 
randomized in order to complete the study with at least 75 (3x25) subjects anticipated to be 
available for efficacy analysis.  
Maximum Time Subjects May Remain in the Study: Subjects may participate in this study 
for a maximum of approximately 117 days (21 Screening Period + 32 Treatment Period + 64 
Observation Period) 
Study Endpoints: 
Primary Efficacy Endpoint:  Change from baseline in the number of AK lesions in the 
Treatment Field of each subject on Day 56. 
Safety Endpoints:  Assessment of AEs, vital signs, physical examinations, clinical laboratory 
parameters, Local Skin Reaction (LSR) Scores, and electrocardiograms.   
Pharmacokinetic Endpoints:  Assessment of the systemic exposure of VDA-1102 and its 
primary metabolite jasmonic acid at selected time points during topical application of 5% or 
10% VDA-1102 ointment for 28 days in adult subjects with AK. 
Exploratory Endpoints:  The percentage of subjects achieving complete clearance of AK 
lesions within the Treatment Field on Day 56. 
Change from baseline in the number of AK lesions in the Treatment Field of each subject on 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
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Day 84. 
Statistical Analyses:  
Efficacy Analysis 
Efficacy analysis will be based on changes from baseline to Day 56 in AK lesions.  
Comparative analysis of the changes will be applied between each of the active groups versus 
the placebo group using the two-sample t-test or non-parametric Wilcoxon-Mann-Whitney rank 
sum test for independent samples or Median test (as is appropriate). In the event that the number 
of baseline lesions is different between the treatment groups, then relative changes (%) will be 
analyzed as well. 
The overall change and the trend of differences in the changes over time between the groups 
will be analyzed using mixed-effect model for repeated measures. The model will include 
changes at any time, the fixed effect time and the interaction of treatment and time. The model 
will be adjusted for baseline measures and for other relevant covariates. 
Interim Efficacy Analysis (IEA) 
A single interim efficacy analysis will be conducted as soon as 50% of the subjects have 
completed their Day 56 Visit. The objective of the IEA is to evaluate the probability of 
achieving the primary efficacy endpoint at the conclusion of the study. The unblinded data for 
the interim analysis sub-set will be analyzed by an independent statistician.  
The result of the IEA will be a calculated effect size and t-value, which will be based on the 
difference in the change from baseline in the number of AK lesions for each of the active 
groups as compared to the placebo group. If baseline measure differs between the groups, then 
relative change (%) will be tested. The total significance level of 5% was divided between the 
interim efficacy analysis (0.005) and the final analysis (0.045). The spending function 
calculation for alpha will be performed using the O'Brien-Fleming methods. In case the 
distribution of the outcome variable does not approximate normality, the appropriate non-
parametric methods will be considered for the interim analysis. 
Safety Analysis 
The safety end point 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 treatment group.  Safety will 
also be assessed by evaluating findings of physical examinations, vital signs, Local Skin 
Reaction Scores, clinical laboratory test results, 12-lead ECG tracings, drug exposure, 
concomitant medications, and withdrawals/terminations.  Clinical and laboratory data will be 
presented by dose group.  Continuous variables will be described as the mean, median, standard 
deviation, and minimum and maximum values of n observations. Categorical data will be 
described with contingency tables including frequency and percent. These findings will be 
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CONFIDENTIAL
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
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summarized and compared between treatments and within treatment groups compared to 
findings from baseline evaluations. 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
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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 ........................................................................................................9 
4. 
LIST OF ABBREVIATIONS ...............................................................................................14 
5. 
BACKGROUND AND RATIONALE .................................................................................17 
5.1 
Indication ..................................................................................................................17 
5.2 
Actinic Keratosis and Current Approaches to Treatment .........................................17 
5.3 
Unmet Medical Need ................................................................................................17 
5.4 
Nonclinical Summary ...............................................................................................18 
5.5 
VDA-1102 Clinical Summary ..................................................................................18 
5.6 
Study Rationale .........................................................................................................19 
5.6.1 Rationale for Study Design and Subject Population .................................................19 
5.6.2 Dose and Posology Justification ...............................................................................20 
6. 
STUDY OBJECTIVES .........................................................................................................23 
7. 
STUDY DESCRIPTION ......................................................................................................24 
7.1 
Study Design – Study Periods, Days, and Visits ......................................................24 
7.2 
Table of Study Assessments .....................................................................................26 
7.3 
Nested Phase 1b Safety Sub-Cohort .........................................................................28 
7.4 
PK Study Sub-Cohort ...............................................................................................28 
7.5 
Safety Reporting .......................................................................................................29 
7.5.1 
Expedited Reporting to Sponsor and CRO ................................................29 
7.6 
Dose Holidays and Adjustments ...............................................................................29 
7.7 
Study Endpoints ........................................................................................................30 
8. 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ...........................................31 
8.1 
Inclusion Criteria ......................................................................................................31 
8.2 
Exclusion Criteria .....................................................................................................31 
8.3 
Subjects Withdrawn, Terminated, or Lost to Follow-Up .........................................33 
8.4 
Subject Withdrawal...................................................................................................33 
8.5 
Subjects Leaving the Trial ........................................................................................33 
8.5.1 
Termination by the Investigator.................................................................33 
8.5.2 
Subjects Who Wish to Withdraw ..............................................................34 
8.5.3 
Subjects Lost to Follow-Up .......................................................................34 
9. 
PROCEDURES FOR SAFETY AND PHARMACOKINETIC 
EVALUATIONS ..................................................................................................................35 
9.1 
General Considerations .............................................................................................35 
9.2 
Pre-Screening ............................................................................................................35 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
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9.3 
Screening Period Evaluations ...................................................................................35 
9.3.1 
Demographics ............................................................................................35 
9.3.2 
Fitzpatrick Skin Types ...............................................................................35 
9.3.3 
Medical History .........................................................................................35 
9.4 
Safety Measures ........................................................................................................36 
9.4.1 
Adverse Events ..........................................................................................36 
9.4.2 
Vital Signs, Weight, Height, and BMI ......................................................36 
9.4.3 
Physical Examination ................................................................................36 
10. CLINICAL LABORATORY TESTS ...................................................................................37 
10.1.1 
Pregnancy Testing .....................................................................................38 
10.1.2 
Toxicology and Drug Screen (PK Study Sub-Cohort only) ......................38 
10.1.3 Electrocardiogram .....................................................................................................38 
10.1.4 Holter Monitoring (PK Study Sub-Cohort only) ......................................................39 
10.1.5 Local Skin Reaction Score ........................................................................................39 
10.1.6 Once-Weekly Subject Contact ..................................................................................39 
10.2 
Pharmacokinetic Measures (PK Study Sub-Cohort only) ........................................39 
11. PROCEDURES FOR EFFICACY EVALUATIONS ..........................................................41 
11.1 
AK Lesions ...............................................................................................................41 
11.1.1 AK Lesion Grading ...................................................................................................41 
11.1.2 AK Lesion Eligibility................................................................................................41 
11.1.3 Treatment Field Selection .........................................................................................41 
11.1.4 Study Tools ...............................................................................................................42 
11.1.5 AK Lesion Count ......................................................................................................43 
11.1.6 Photography ..............................................................................................................43 
12. CONDUCT OF THE STUDY ..............................................................................................44 
12.1 
Study Blinding and Randomization ..........................................................................44 
12.1.1 
Randomization ...........................................................................................44 
12.1.2 
Blinding .....................................................................................................44 
12.1.3 
Unblinding .................................................................................................44 
12.2 
Subject Informed Consent ........................................................................................44 
12.3 
Study Periods ............................................................................................................45 
12.4 
Study Procedures per Period and Visit .....................................................................45 
12.4.1 
Screening Period ........................................................................................45 
12.4.2 
Treatment Period .......................................................................................48 
12.4.3 
Observation Period ....................................................................................51 
12.5 
Unscheduled Visits ...................................................................................................53 
12.6 
General Restrictions ..................................................................................................54 
12.6.1 Medication and Other Therapeutic Restrictions .......................................................54 
12.6.1 Topical Product Restrictions .....................................................................................55 
12.6.2 Sun Protection and Tanning ......................................................................................55 
12.6.3 Dietary Restrictions ..................................................................................................55 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
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12.6.4 Special Restrictions for the PK Study Sub-Cohort ...................................................56 
12.6.5 Physical Exercise Restrictions ..................................................................................56 
12.7 
Childbearing Potential ..............................................................................................56 
12.7.1 
Definitions .................................................................................................56 
12.7.2 
Contraception .............................................................................................57 
13. STUDY MEDICATION .......................................................................................................58 
13.1 
Description of Study Medication ..............................................................................58 
13.2 
Drug Packaging.........................................................................................................58 
13.3 
Drug Labeling ...........................................................................................................58 
13.4 
Study Drug Distribution............................................................................................58 
13.5 
Study Drug Storage ...................................................................................................58 
13.6 
Study Drug Dispensing and Administration .............................................................59 
13.6.1 
Study Drug Dispensing ..............................................................................59 
13.6.2 
Study Drug Dosing Cards ..........................................................................59 
13.6.3 
Study Drug Measurement and Application Review ..................................59 
13.6.4 
Study Drug Administration at Home .........................................................60 
13.7 
Study Drug Accountability and Dosing Compliance ...............................................61 
14. CONCOMITANT MEDICATION .......................................................................................62 
15. ADVERSE EVENTS ............................................................................................................63 
15.1 
Adverse Event Definition .........................................................................................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 
Laboratory Test and Diagnostic Procedure Abnormalities.......................................64 
15.6 
Follow-up of Adverse Events ...................................................................................65 
15.7 
Documentation and Reporting of Adverse Events by Investigator ..........................65 
16. SERIOUS ADVERSE EVENTS ..........................................................................................66 
16.1 
Definition ..................................................................................................................66 
16.2 
Reporting of Serious Adverse Events .......................................................................66 
16.2.1 Reporting of Serious Adverse Events by Investigators ............................................66 
17. STATISTICAL PLAN ..........................................................................................................69 
17.1 
Sample Size Rationale and Justification ...................................................................69 
17.2 
Statistical analysis .....................................................................................................69 
17.2.1 
Efficacy Analysis .......................................................................................69 
17.2.2 
Safety Assessments ....................................................................................70 
17.2.3 
Pharmacokinetic Parameters ......................................................................70 
17.2.4 
Exploratory Endpoints Assessment ...........................................................70 
17.3 
Missing Data .............................................................................................................71 
17.4 
Interim Efficacy Analysis .........................................................................................71 
17.5 
Data Sets ...................................................................................................................71 
17.5.1 
Intent-to-Treat Population .........................................................................71 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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17.5.2 Modified ITT (mITT) Population .............................................................................72 
17.5.3 Per-Protocol Population ............................................................................................72 
17.5.4 Pharmacokinetic Population .....................................................................................72 
17.5.5 Definitions of the Terms Violation and Deviation ...................................................72 
17.5.6 Subject Compliance Definitions ...............................................................................72 
17.6 
Demographic and Baseline Characteristics ..............................................................73 
18. STUDY MANAGEMENT AND DATA COLLECTION ...................................................74 
18.1 
Data Collection Methods ..........................................................................................74 
18.2 
Monitoring ................................................................................................................74 
18.3 
Data Retention ..........................................................................................................74 
19. CLINICAL STUDY ADMINISTRATION, ETHICS, AND CONDUCT ...........................76 
19.1 
Good Clinical Practice ..............................................................................................76 
19.2 
Confidentiality ..........................................................................................................76 
19.2.1 Study Confidentiality ................................................................................................76 
19.2.2 Subject Anonymity ...................................................................................................76 
19.3 
Subject Information and Informed Consent..............................................................76 
19.4 
Study Closure ............................................................................................................77 
19.5 
Early Termination of the Clinical Trial ....................................................................77 
20. INVESTIGATOR'S OBLIGATIONS ..................................................................................78 
20.1 
General ......................................................................................................................78 
20.2 
Institutional Review Board .......................................................................................78 
20.3 
Investigator Protocol Adherence ..............................................................................78 
20.4 
Protocol Amendments...............................................................................................79 
20.5 
Audits and Inspections ..............................................................................................79 
21. REFERENCES .....................................................................................................................80 
22. APPENDICES ......................................................................................................................82 
22.1 
Local Skin Reaction Score ........................................................................................82 
22.2 
Treatment Field Map ................................................................................................83 
22.3 
Treatment Field Map Instructions.............................................................................84 
22.4 
Treatment Field Template .........................................................................................85 
22.5 
Treatment Field Template Instructions .....................................................................86 
22.6 
Subject Dosing Card .................................................................................................87 
22.7 
Subject Instruction Packet ........................................................................................88 
22.8 
Dosing Diary .............................................................................................................92 
 
 
 
 
 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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LIST OF TABLES 
Table 1: VDA-1102 doses tested in the pivotal 28-day non-clinical studies compared to 
the proposed clinical doses ................................................................................................ 21 
Table 2:  Comparison of the proposed clinical doses to the non-clinical HED NOAELs in 
mg/kg/day .......................................................................................................................... 22 
Table 3:  Comparison of the proposed clinical doses to the non-clinical NOAELs in 
mg/m2/day ......................................................................................................................... 22 
Table 4:  Periods, Study Day, and Visits .............................................................................................. 26 
Table 5:  Schedule of Assessments for all Subjects .............................................................................. 27 
Table 6:  Table of Assessments for PK Study Sub-Cohort ................................................................... 28 
 
 
 
LIST OF FIGURES 
Figure 1. Study Design Schematic ........................................................................................................ 25 
 
 
 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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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 
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 
D5W 
5% Dextrose 
dL 
Deciliter 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediamine tetraacetic acid  
eg 
Exempli gratia, for example 
EP 
eRT 
Electrophysiology 
eResearch Technology, Inc. 
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 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IEA 
Interim Efficacy Analysis 
I.e. 
IID 
Id est, in other words 
FDA’s database on Inactive Ingredients 
IND 
Investigational New Drug 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Responsive Technology 
ITT 
Intent-to-Treat 
IU 
International Units 
IV 
Intravenous 
IWRS 
Interactive Web Randomization System 
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 
NSAID 
Nanomoles 
Non-steroidal anti-inflammatory drugs 
OD 
Right eye 
Oz / ozs 
Ounce / ounces 
PBS 
Phosphate buffered saline 
pg 
Picogram 
PI 
Primary Investigator 
pH 
hydrogen ion concentration 
PK 
Pharmacokinetic 
PM 
Evening 
prn 
Pro re nata (as needed) 
PSA 
Prostate-Specific Antigen 
PT 
Preferred Term 
QAM 
Each morning 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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Abbreviation 
Definition 
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 
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 
US 
UVB 
Upper limit of normal 
United States 
Ultraviolet B light 
Vss 
Volume of distribution at steady state 
 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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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 AKs (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. 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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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. .  
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 two GLP toxicology studies were: 1) a 28-day repeated dose oral toxicity study in rats 
with a recovery phase and toxico-kinetics, and 2) a 28-day topical dermal toxicity study in 
male and female minipigs with a recovery phase and toxico-kinetics.  
An MTD for the local application of VDA-1102 was not reached at the highest feasible 
concentration tested (20%). As discussed below in Section 5.6.2, the relative doses of VDA-
1102 fed to rats and applied to the skin of minipigs were much higher than the exposures in 
the proposed 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 
Study VDA-CP-01 (titled, “A Phase 1 Randomized, Double-Blinded, Placebo-Controlled, 
Dose-Escalation Study in Healthy Older-Adult Volunteers to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of a Single Topical Dermal Application of VDA-1102 
Ointment”) was recently completed and preliminary blinded data are available. Healthy 
female volunteers without reproductive potential and male volunteers, aged 35-70, were 
sequentially assigned to 1 of 3 consecutive treatment cohorts (5%, 10% or 20% VDA-1102 
ointment, respectively). Five subjects were randomized in a double-blind fashion in each dose 
cohort with 4 subjects to receive active VDA-1102 ointment and 1 subject to receive matched 
placebo (0% VDA-1102; vehicle control).  A total of 15 subjects were randomized: 12 
subjects received active VDA-1102 and 3 received placebo.   
There were no deaths, serious adverse events, or early study discontinuations in this study.  
There were a total of 11 adverse events reported (whose treatment assignment is still 
unknown). All the AEs were mild, short-lived, and reversible.  There were no clinically 
significant changes in study drug application sites, vital signs, physical examinations, clinical 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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laboratory results, ECGs, or Holter monitors for any individual subject at any time point 
regardless of treatment. 
Plasma concentrations of VDA-1102 and its main metabolite, jasmonic acid were below the 
level of quantification of the LC/MS/MS bioanalytical assay (1 ng/mL and 50 ng/mL, 
respectively). 
Further details of the results of this trial are provided in the VDA-1102 Investigator’s 
brochure. 
There are currently no ongoing clinical trials in which VDA-1102 is being administered. 
5.6 
Study Rationale 
5.6.1 Rationale for Study Design and Subject Population 
(i) 
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 a week 
or two of treatment initiation, although full clinical benefit was observed after 3-4 weeks.  
In this clinical protocol, study drug will be applied once-daily for 28 days to the Treatment 
Field on the scalp or face subjects with AK. Approximately 84 male and female subjects aged 
18 or older with 4-8 discrete Grade 1 and/or 2 AK lesions who sign informed consent and 
meet the study enrollment criteria will be randomly assigned in a double-blinded fashion to 1 
of 3 parallel treatment cohorts (5% or 10% VDA-1102 ointment, or placebo) at a ratio of 
1:1:1. The primary endpoint of this study is reduction in the number of AK lesions in the 
Treatment Field on Day 56. 
(ii) 
Safety 
The results from the toxicology studies and the estimated safety margins indicate that daily 
dermal application of 250 mg of VDA-1102 ointment for 28 days at doses as high as 20% to 
an area of 25 cm2 do not pose an untoward risk for evaluation in the target patient population. 
Specifically, topical application once-daily for 28 days of 5% or 10% VDA-1102 ointment to 
10% of the minipigs body surface area in the nonclinical toxicology program resulted in no 
significant systemic safety findings and only mild, reversible skin findings.  
In the completed Phase 1a clinical trial (Section 5.5 above), 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 
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demonstrated that there were no detectable concentrations of VDA-1102 or its primary 
metabolite, jasmonic acid.  
In this study a lower dose of 200 mg of 5% or 10% VDA-1102 ointment will be applied for 
28 days to an area of 25 cm2. Safety assessments will be performed throughout the Phase 2a 
study. In addition, the first 15 subjects enrolled in the trial will be defined as a Nested Phase 
1b Safety Sub-Cohort. Available safety data (including AEs, LSR scores, clinical laboratory 
results, and ECG data) from Day 1 through Day 7 from these 15 subjects will be reviewed in 
a blinded fashion by a safety committee consisting of 2 independent investigators (not 
involved in the evaluation of subjects in the study) and the Study Safety Monitor.  
(iii) 
Pharmacokinetics 
In preclinical PK studies, VDA-1102 was rapidly metabolized, forming jasmonic acid 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 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 completed Phase 1a clinical trial (Section 5.5 above), there were no detectable 
concentrations of VDA-1102 or its primary metabolite, jasmonic acid following a single-dose 
of approximately 250 mg of 5%, 10%, or 20% VDA-1102 that was applied once to a 25 cm2 
area on the forehead of healthy older-adult volunteers.   
In the current study, approximately 84 subjects will be dosed once each evening for 28 days 
with approximately 200 mg of study drug. Eighteen subjects will be enrolled into a PK Study 
Sub-Cohort and will undergo plasma sampling on Days 7, 14, 28, and 35 for PK assessment. 
Holter monitoring will be performed for 24 hours on Day 28 in all  subjects enrolled in the 
PK Study Sub-Cohort so that relevant ECGs tracings corresponding to peak levels (if 
detected) of VDA-1102 and/or jasmonic acid may be extracted once the PK/exposure data are 
available.  
5.6.2 Dose and Posology Justification 
The doses to be evaluated in this clinical trial are approximately 200 mg of 0%, 5%, and 10% 
VDA-1102 topical ointment, spread evenly (unoccluded) over a 25 cm2 area of skin on the 
face or scalp of subjects with actinic keratosis.  
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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Table 1 lists the mg/kg/day exposures in non-clinical toxicology studies as compared to the 
exposure planned in the proposed human trial. Data is presented as dose ratios rather than 
exposure ratios, because in vivo, trans-dermal absorption of VDA-1102 and its primary 
metabolite, jasmonic acid, appears to be minimal (minipig and human single doses) as 
determined with a sensitive bioanalytical assay. 
The relative doses of VDA-1102 fed to rats and applied to the skin of minipigs were much 
higher than the highest dose (10% VDA-1102) to be applied in this study (Table 1). 
Table 1: VDA-1102 doses tested in the pivotal 28-day non-clinical studies compared to 
the proposed clinical doses 
  
Exposure   
VDA-1102 
(mg/kg/day) 
Exposure HED 
(mg/kg/day)  
Exposure  
(mg/m2/day) 
Remarks 
Dose Group 
Proposed Phase 2a Clinical Study 
Ointment 5% 
0.166 
  
6.2 
Assuming body weight of 60 kg 
Ointment 10% 
0.333 
  
12.3 
Exposure Levels in Completed Non-Clinical Studies: 
28-Day Oral Toxicity Study in Rats 
Low dose 
100 
17 
 
  
Intermediate 
dose 
300 
48 
 
NOAEL 
High dose 
800 
129 
 
Mild and at least partially reversible 
adverse effects  
28-Day Dermal Toxicity Study in Minipigs  
Ointment 5% 
15 
10.7 
405 1 
NOAEL for local toxicity  
Ointment 10% 
30 
21.4 
810 
Minimal local effects  
 Ointment 20% 
60 
42.9 
1620 
NOAEL for systemic toxicity 
1 Minipigs weighed <25 kg, therefore a converting factor of 27 was used.  
 
Tables 2 and Table 3 compare the proposed clinical doses to the systemic HED NOEALs in 
mg/kg/day, and to the systemic NOAEL in mg/m2/day, respectively, determined in the two 
toxicology studies performed in minipig and rat. As can be seen from these tables, the highest 
planned dose in early clinical studies, 200 mg of 10% VDA-1102 ointment, is approximately 
135-fold below the non-clinical systemic HED NOEAL levels determined in both species, rat 
and minipig. 
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Table 2:  Comparison of the proposed clinical doses to the non-clinical HED NOAELs 
in mg/kg/day 
Dose Group 
Exposure VDA-1102  (mg/kg/day) 
  
Early Clinical Studies 
NOAEL 28-Day  
Oral Rat (HED) 
NOAEL 28-Day  
Dermal Minipig  (HED) 
Ointment 5% 
0.166 
48 
42.9 
Ointment 10% 
0.333 
 Ointment 20% 
0.666 
Table 3:  Comparison of the proposed clinical doses to the non-clinical NOAELs in 
mg/m2/day 
Dose Group 
Exposure VDA-1102  (mg/m2/day) 
  
Early Clinical Studies 
NOAEL 28-Day Dermal Minipig 
Ointment 5% 
6.2 
1620 
Ointment 10% 
12.3 
 
Based upon the non-clinical toxicology data and the safety findings from the Phase 1 clinical 
trial, VDA-1102 will be advanced to Phase 2 development. The doses in this clinical trial 
(200 mg of 5% or 10% VDA-1102 once daily for 28 days) are well below the nonclinical 
systemic HED NOEAL levels determined in both rats and minipigs. Furthermore, the daily 
dose proposed (~200 mg) is below the ~250 mg single dose administered in the Phase 1 
clinical trial in healthy older-adult volunteers in order to more closely approximate the 200 
mg dose administered in the non-clinical toxicology studies and to reduce the local and 
systemic exposures in humans.  
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6. STUDY OBJECTIVES 
Study Objectives:  
Primary Objective: To compare the reduction on Day 56 in the number of the actinic 
keratosis (AK) lesions in the Treatment Field of subjects receiving once-daily topical 5% 
or 10% VDA-1102 ointment for 28 days to the reduction in the number of AK lesions in 
subjects receiving placebo. 
Secondary Objectives: 
• To evaluate the systemic and local (skin) safety and tolerability of once-daily topical 
application of 5% or 10% VDA-1102 ointment or placebo for 28 days in adult 
subjects with AK. 
• To assess the systemic exposure of VDA-1102 and jasmonic acid, its primary 
metabolite, at selected time points during topical application of 5% or 10% VDA-1102 
ointment or placebo for 28 days in adult subjects with AK. 
Exploratory Objectives: 
• To compare the proportion of subjects receiving 28 days of 5% or 10% VDA-1102 
who on Day 56 had complete clearance of AK lesions to subjects receiving placebo. 
• To compare the reduction on Day 84 in the number of the actinic keratosis (AK) 
lesions in the Treatment Field of subjects receiving once-daily topical 5% or 10% 
VDA-1102 ointment for 28 days to the reduction in the number of AK lesions in 
subjects receiving placebo. 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 23
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 24 OF 93 
  
 
 
 
 
 
 
7. STUDY DESCRIPTION 
7.1 
Study Design – Study Periods, Days, and Visits 
Approximately 84 subjects, aged 18 or older, who sign informed consent and meet the study 
enrollment criteria, will be randomized to 1 of 3 parallel treatment cohorts (5% or 10% VDA-
1102 ointment, or placebo) in a 1:1:1 ratio. The clinical trial will include 3 study periods 
(Figure 1 and Table 4). 
Screening Period – Subjects who have given written consent to participate in the trial will 
undergo safety and qualifying procedures between Day -21 and Day -1 (Screening Visit). At 
this visit, the subject’s Treatment Field will be identified and the subject will be trained to 
precisely measure and apply the study drug without actually applying ointment to their 
Treatment Field. Subjects unable to express the proper dose from the study drug tube and/or 
unable to identify their Treatment Field will be required to bring a dosing partner to the next 
study visit in order to proceed in the study.  
Subjects who meet all the study’s inclusion criteria and none of the exclusion criteria will 
return on Day 1 for baseline assessments to ensure they still meet the study enrollment 
criteria (Day 1 Pre-Dose Visit). During this visit, the Treatment Field selected at the 
Screening Visit will be requalified.  If the field previously chosen fails to requalify, a new 
Treatment Field must be found or the subject must be excluded for failure to meet Inclusion 
Criterion #3 (Section 8.1). Subjects will be trained and tested twice during this visit for 
proper dose measurement (using the Dosing Cards 13.6.2), proper identification of the 
Treatment Field (using the Treatment Field Template 22.4), and precise dosing of that field 
using the template (stencil). Subjects (or their dosing partner) who are unable to express the 
proper dose from the study drug tube and/or are unable to precisely identify their Treatment 
Field will also be considered ineligible for the study (Inclusion Criterion #4, Section 8.1). 
Subjects who continue to meet all the study enrollment criteria following the Day 1 Pre-Dose 
Visit will be randomized in a double-blinded fashion and proceed to the Day 1 Dosing Visit. 
Subjects enrolled in the PK Study Sub-Cohort will have a pre-dose blood sample drawn.    
Treatment Period – At the Day 1 Dosing Visit, subjects will apply the assigned study drug 
(i.e., active VDA-1102 or placebo) under the supervision of site personnel. Details of the 
study drug application are found in Section 13.6. 
From Day 1 through Day 27 subjects will apply the study each evening approximately 2 
hours before bedtime. Site personnel will communicate with the subject once-weekly.  
On Day 7 and Day 14 all subjects will return to the investigative site for safety and efficacy 
assessments. At each site visit, the subject’s study drug will be weighed and the result will be 
recorded. At each visit, the subject will be re-trained in proper dose application to their 
Treatment Field. Subjects in the PK Study Sub-Cohort will have a blood sample taken 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 24
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 25 OF 93 
  
 
 
 
 
 
 
approximately 12 hours after their evening respective Day 6 and Day 13 evening doses. 
Subjects in the Nested Phase 1b Safety Sub-Cohort will undergo an additional physical 
examination, 12-lead ECG, and clinical laboratory assessment on Day 7.  
Subjects will return to the site on Day 28 for safety and efficacy assessments. Subjects in the 
PK Study Sub-Cohort will undergo blood sampling for analysis at approximately 12, 15, 18, 
and 21 hours after their Day 27 study drug application. Remaining study drug will be 
collected from all subjects at this visit.  
Observation Period – On Day 35 subjects will return to the site for efficacy and safety 
assessments. Subjects in the PK Study Sub-Cohort will undergo a single untimed blood 
sampling. Subjects in the PK Study Sub-Cohort will have a PK sample drawn at the time of 
their visit. Subjects will return to the sites on Day 56 for efficacy and safety assessments. At 
the End-of-Study visit on Day 84, final efficacy and safety assessments will be performed 
followed by discharge from the study. Any subject with active TEAE(s) will be followed 
beyond this scheduled visit until resolution. 
 
 
Figure 1. Study Design Schematic 
 
 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 25
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 26 OF 93 
  
 
 
 
 
 
 
Table 4:  Periods, Study Day, and Visits 
PERIODS 
SCREENING 
TREATMENT 
OBSERVATION 
STUDY 
DAYS 
Day -21 to Day -1 
Day 1 
Day 
7±2 
Day 
14±2 
Day 
28±4 
Day 
35 
±2 
Day 
56  
±4 
Day 
84  
±4 
VISITS 
Screening Visit(s) 
Day 1   
Pre-Dose 
Visit 
Day 1 
Dosing 
Visit 
Day 7 
Visit 
Day 14 
Visit 
Day 28 
Visit 
Day 
35 
Visit 
Day 
56 
Visit 
Day 
84 
Visit 
PURPOSE 
• Screening Procedures 
• Baseline Assessments 
• Study drug application testing/ training 
• Randomization 
• PK sampling (PK Study Sub-Cohort) 
• Dosing Study Drug  
• Safety & Efficacy Assessments 
• PK sampling (PK Study Sub-Cohort) 
• Drug accountability 
• Safety & Efficacy 
Assessments 
• Day 35 PK sampling 
(PK Study Sub-
Cohort) 
 
7.2 
Table of Study Assessments 
Tables 5 and 6 are the Schedule of Assessments for all subjects enrolled in the trial. Table 6 
is the Schedule of Assessments for subjects enrolled in the PK Study Sub-Cohort.  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 26
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 27 OF 93 
  
 
 
 
 
 
 
Table 5:  Schedule of Assessments for all Subjects 
Table 6, below, indicates the additional assessments to be performed on subjects enrolled in the PK 
sub-cohort. 
Period 
SCREENING 
PERIOD 
TREATMENT PERIOD 
OBSERVATION 
PERIOD 
Study Day 
Day -21 to 
Day -1 
Day 1 
Day 
7±2 
Day 
14±2 
Day 
28±4 
Day   
35±2 
Day  
56±4 
Day  
84±4 
Procedure\Visit 
Screening 
Day 1   
Pre-Dose 
Day 1 
Dosing 
Day 7 
Day 14 
Day 28 
Day  
35 
Day 
56 
Day 
84 
ICF procedures, signature, dating confirmed 
√ 
 
 
 
 
 
 
 
 
Enrollment criteria and/or safety data review 
√ 
√ 
 
 
 
 
 
 
 
Demographics and Medical History 
√ 
 
 
 
 
 
 
 
 
Adverse events reporting 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Concomitant medications recorded 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Vital signs 
√ 
√ 
 
√ 
√ 
√ 
√ 
 
 
Physical examination 
√ 
√ 
 
√ 1 
√ 
√ 
√ 
 
 
Height / Weight / BMI calculated 
√ 
 
 
 
 
 
 
 
 
12-Lead ECG 
√ 
√ 
 
√ 1 
√ 
√ 
 
 
 
Clinical laboratory testing 
√ 
√ 
 
√ 1 
√ 
√ 
 
 
 
Fitzpatrick skin type 
 
√ 
 
 
 
 
 
 
 
Treatment Field Selection 
√ 
√ 
 
 
 
 
 
 
 
AK lesions in the Treatment Field count and 
grade 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Local Skin Reaction Score 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Study drug measurement & application review 
√ 
√ twice 
 
√ 
√ 
 
 
 
 
Pregnancy test (urine) at the site 
√ 
√ 
 
 
 
√ 
 
√ 
 
Subject randomization 
 
√ 
 
 
 
 
 
 
 
Application of the study drug each evening 
 
 
√ Day 1 through Day 27 
 
 
 
Supervised study drug application at the site 
 
 
√ 
 
 
 
 
 
 
Trial instruction review / Closure procedure 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Telephone contact by study staff 
 
Once-weekly communication between site visits 
 
 
 
Photographs of Treatment Field (at selected 
sites only) 
 
√ 
 
 
 
 
 
√ 
√ 
Study drug & tools given subject, as needed 
 
 
√ 
√ 
√ 
 
 
 
 
Study drug accountability/dosing compliance 2 
 
√ 
 
√ 
√ 
√ 
 
 
 
1 Only subjects enrolled in the Phase 1b Safety Cohort will undergo these assessments. 
2 Weigh study tube / record dates of any doses missed between Days 1 and 28 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 27
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 28 OF 93 
  
 
 
 
 
 
 
Table 6:  Table of Assessments for PK Study Sub-Cohort 
The following table indicates additional evaluations to those listed in Table 6 to be performed 
only in subjects enrolled in the PK Study Sub-Cohort. 
 
Period 
SCREENING PERIOD 
TREATMENT PERIOD 
OBSERVATION 
PERIOD 
Study Day 
Day -21 to Day -1 
Day 1 
Day 
7±2 
Day 
14±2 
Day 
28±4 
Day 
35±2 
Day 
56±4 
Day  
84±4 
Procedure\Visit 
Screening 
Day 1   
Pre-Dose 
Day 1 
Dosing 
Day 7 Day 14 Day 28 Day 35 Day 56 Day 84 
Additional Exclusion Criteria 
√ 
 
 
 
 
 
 
 
 
24-hour Holter monitor attached 
 
 
 
 
 
√ 
 
 
 
Toxicology screen 
√ 
 
 
 
 
 
 
 
 
Blood sampling for PK1 
 
√ 
 
√ 
√ 
4 √ 
√ 
 
 
1 One pre dose PK sample will be collected at the Day 1 pre-dose Visit, At the Day 7, Day 14 and Day 28 Visits, a sample 
will be collected when the subject arrives at the site (or approximately 12 hours after the last study drug application the 
previous evening). At the Day 28 Visit, three additional PK samples will be collected at 15, 18 and 21 hours (±30 mins) after 
the Day 27 evening dose.  A final sample will be collected at the Day 35 Visit, at any time during that visit with the time 
noted.  
7.3 
Nested Phase 1b Safety Sub-Cohort  
The first 15 (PK and non-PK) subjects enrolled in the trial will undergo on Day 7 the safety 
examinations planned for all other subjects plus a physical examination, clinical laboratory 
tests, and an ECG assessment. Once all 15 subjects in this Nested Phase 1b Safety Sub-
Cohort have completed their Day 7 Visit, available blinded safety data (including AEs, LSR 
scores, clinical laboratory results, and ECG data) from Day 1 through Day 7 will be reviewed 
within 10 business days by a safety committee consisting of 2 Board-certified physicians not 
involved in the trial and the Study Medical Monitor (a Board-certified Allergist and 
Internist). During this blinded interim safety review, enrolled subjects will continue dosing 
the study drug and study enrollment will remain open.  
7.4 
PK Study Sub-Cohort 
Of the approximate 84 subjects to be enrolled in this trial, a maximum of 18 subjects (who 
meet more stringent enrollment criteria than the other subjects enrolled) at select sites, will 
undergo blood sampling for PK analysis on Day 1 Pre-Dose as well as on Days 7, 14, 28, and 
35 (Table 6). In addition, these subjects will undergo 24-hour cardiac Holter monitoring on 
Day 28 so that ECGs may be extracted based upon the other safety findings and the plasma 
PK data.  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 28
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 29 OF 93 
  
 
 
 
 
 
 
Subjects included in this sub-cohort may also be included in the Nested Phase 1b Safety Sub-
Cohort if they are one of the first 15 subjects to be enrolled into the study. 
7.5 
Safety Reporting 
7.5.1 Expedited Reporting to Sponsor and CRO 
In addition to the reporting requirements for serious adverse events (SAEs) described in 
Section 16, all severe AEs must be reported to the Study Medical Monitor and the site’s CRO 
contact within 24 hours.  
All dose holidays and adjustments (described in Section 7.6 below) must be reported to the 
Study Safety Monitor (Sponsor) and the site’s CRO contact within 24 hours. Such 
occurrences must be documented in the eCRF along with the reason for their occurrence.  
In addition, if at any time during the course of the trial a potentially serious safety finding is 
noted by an Investigator, the Sponsor’s Study Medical Monitor and the site’s CRO contact 
must be notified within 24 hours. 
7.6 
Dose Holidays and Adjustments 
Subject may be offered the following options at the Investigator’s discretion:  
a) To temporarily stop the study drug for up to 7 days and to re-assess within that period;  
b) To temporarily stop the study drug for up to 7 days and instruct the subject to re-start 
the study drug application every other evening. The study drug may even be advanced 
to once-daily application as tolerated; or  
c) To stop the study drug for the duration of the trial but follow the subject otherwise as 
planned. 
Bland moisturizers may be recommended at any time to any subject to manage LSRs. 
However, the 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.     
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 29
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 30 OF 93 
  
 
 
 
 
 
 
7.7 
Study Endpoints 
Primary Efficacy Endpoint:  Change from baseline in the number of AK lesions within the 
Treatment Field of each subject on Day 56.  
Safety Endpoints:  Assessment of AEs, vital signs, physical examinations, clinical laboratory 
parameters, Local Skin Reaction (LSR) Scores, and electrocardiograms.   
Pharmacokinetic Endpoint: Assessment of the systemic exposure of VDA-1102 and its 
primary metabolite jasmonic acid at selected time points during topical application of 5% or 
10% VDA-1102 ointment for 28 days in adult subjects with AK. 
Exploratory Endpoints: The percentage of subjects achieving complete clearance of AK 
lesions within the Treatment Field on Day 56. 
Change from baseline in the number of AK lesions within the Treatment Field of each subject 
on Day 84.  
 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 30
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 31 OF 93 
  
 
 
 
 
 
 
8. SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
8.1 
Inclusion Criteria 
Subjects fulfilling all of 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. Subject is aged 18 years or older and is able and willing to comply with the 
contraception requirements described in Section 12.7.2; 
3. Subject at the Screening and Day 1 Pre-Dose Visits has a minimum of 4 and a 
maximum of 8 discrete Grade 1-2 AK (see AK Grades, Section 11.1.1) lesions within a 
single 25 cm2 area of skin on their scalp or face that meet the criteria for the AK 
Lesions and Treatment Field listed in Sections 11.1.2 and 11.1.3, respectively. 
4. Subject (or their dosing partner) has demonstrated adequate precision applying the study 
drug to the Treatment Field during the Screening and Day 1 Pre-Dose Visits.  
8.2 
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 results that (a) are clinically significant and have not been 
approved in writing by the Safety Monitor; (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.  
3. Subject is: (a) pregnant; (b) lactating; (c) planning to become pregnant during the study, 
or (d) fertile (as defined in Section 12.7.1) and they or their fertile partner is unable or 
unwilling to use the contraceptive methods discussed in Section 12.7.2; 
4. 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 an 
interfering topical or systemic therapy; 
5. Subject is immunosuppressed (e.g., organ transplant recipients, HIV, systemic 
chemotherapy, graft vs. host disease, receiving dialysis, etc.); 
6. Subject is currently enrolled in a clinical trial or has received an investigational drug or 
been treated with an investigational device within 21 days prior to Screening. 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 32 OF 93 
  
 
 
 
 
 
 
7. Subject is unable to comply with the sun protection techniques or the limitations placed 
on tanning, medicinal products, activities, or foods listed in Section 12.6;  
8. Subject has (a) an unstable medical, psychiatric, or social problem; (b) self-reported 
alcohol or illicit drug dependency; (c) communication or motor deficit; or (d) any 
similar condition that could place the subject at a safety risk or might interfere with the 
performance of the trial activities, completion of the trial, and/or interpretation of the 
subject’s data or risk the safety of the subject.  
9. Subject may be unreliable for the study including subjects who engage in excessive 
alcohol intake or drug abuse, or subjects who are unable to return for scheduled follow-
up visits. 
10. Subject has a known sensitivity to propylene glycol, caprylic acid, dimethyl sulfoxide 
(DMSO), petrolatum, or paraffin wax.  
11. Subject is unwilling to avoid any form of therapy, emollients, moisturizers, makeup, 
sunscreens, etc. to the Treatment Field from Screening through Day 84 except for bland 
emollients prescribed by the site Investigator. 
12. Subject has used any of the following topical treatments in the Treatment Field: 
• Topical retinoids (e.g. tazarotene, adapalene, tretinoin) within 8 weeks of Screening, 
or 
• Microdermabrasion, laser ablative treatments, ALA-PDT, chemical peels, 5-FU, 
diclofenac, imiquimod, ingenol, or other topical treatments for AK or that might 
impact AK within 12 weeks of Screening. 
13. Subject has used systemic retinoid therapy within 6 months of Screening Visit.  
14. Subject has a history of malignancy within 5 years of Screening other than adequately-
treated carcinoma in-situ of the cervix and non-metastatic basal cell or squamous cell 
carcinoma of the skin. 
15. Subject had major surgery within 60 days of Day 1 or plans to have major surgery 
during the study; or 
16. Subject has any reason that will preclude repeated venipuncture. 
Additional Exclusion Criteria for Subjects in the PK Study Sub-Cohort: 
17. Subject has a Body Mass Index (BMI) of ≤18 and ≥35; 
18. Subject within 4 weeks of Screening had major blood loss or donated blood or a blood 
component;  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 32
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
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19. Subject has any clinically significant medical abnormality or chronic disease that may 
interfere with the absorption, metabolism, or excretion of the investigational product. 
This includes such conditions as hepatic, renal, cardiac, or pulmonary disease or an 
estimated glomerular filtration rate <60 milliliters per minute; 
20. Subject (self-reported) abused drugs or alcohol within 3 years of screening or used 
tobacco, smoking cessation products, or products containing nicotine within three 
months of Screening;  
21. Subject has positive toxicology or drug, at Screening other than a benzodiazepine for 
sleep that the subject is willing to avoid during the trial and is negative upon re-test 
during Screening;  
22. Subject is unable or unwilling avoid alcoholic beverages, smoking, nicotine products, 
and any medications unapproved by the Investigator from Screening through Day 35; or 
23. Subject was exposed to any paint solvents or pesticides within 4 weeks of Screening. 
8.3 
Subjects Withdrawn, Terminated, or Lost to Follow-Up 
Subjects who are terminated by the PI, who withdraw from the study, or who are lost to 
follow-up and who received at least one dose of the study drug will not be replaced. 
8.4 
Subject Withdrawal 
Subjects may withdraw their consent at any time and for any reason.  
Subjects who have applied at least 1 study drug dose and would like to withdraw from the 
study will be offered to attend all of the scheduled study visits and to undergo the planned 
safety and efficacy assessments. 
8.5 
Subjects Leaving the Trial 
8.5.1 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.  
Subjects who have applied at least 1 dose of the study drug and are terminated from the study 
will be asked to attend all of the scheduled study visits through Day 84, as appropriate.  
If an Investigator (or designee) is of the opinion that continued daily dosing may be 
detrimental to a subject’s well-being, that subject may be offered the options discussed in 
Section 7.6 (Dose Holidays and Adjustments) following consultation with the Safety Medical 
Monitor.  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 33
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 34 OF 93 
  
 
 
 
 
 
 
8.5.2 Subjects Who Wish to Withdraw  
If a subject who received at least 1 dose of the study drug wishes to withdraw from the trial, 
study staff should ask the subject to complete as many as possible of the planned evaluations 
scheduled through Day 84, as appropriate. If the subject declines, the subject should be asked 
to undergo the Day 28 safety and efficacy procedures.  
Subjects may also be offered the options listed in Section 7.6. 
8.5.3 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.  
Subjects who received at least 1 dose of the study drug, were lost to follow-up, and re-
contacted, will be encouraged to rejoin the trial. 
− If the subject missed ≤ 7 consecutive days of study drug, the subject will be 
encouraged to continue in the trial as usual.  
− If the subject missed >7 consecutive days of treatment, the subject will be encouraged 
to continue in the trial as usual but will be considered a major deviator.    
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 34
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 35 OF 93 
  
 
 
 
 
 
 
9. PROCEDURES FOR SAFETY AND PHARMACOKINETIC EVALUATIONS 
9.1 
General Considerations 
No procedures (including Screening activities) may be performed before informed consent 
has been obtained, with a copy of the ICF given to the subject and another copy placed in the 
subject’s medical records.  
The Investigator will use their judgment when determining the clinical significance of any 
findings.  
9.2 
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.  
9.3 
Screening Period Evaluations 
9.3.1 Demographics 
The birth date, gender, race, and ethnicity of each subject will be documented in the eCRF. 
9.3.2 Fitzpatrick Skin Types 
Fitzpatrick skin types will be classified as follows: 
Type I: 
Pale white skin, always burns, and never tans. 
Type II: 
White skin, usually burns easily, tans minimally. 
Type III: 
Light brown skin, burns moderately, tans uniformly. 
Type IV: 
Moderate brown skin, burns minimally, always tans well. 
Type V: 
Dark brown, rarely burns, tans very easily. 
Type VI: 
Deeply pigmented dark brown to black skin, never burns deeply. 
9.3.3 Medical History 
Medical history, including any diseases, all past surgeries including skin procedures, and 
psychiatric illnesses will be documented in the CRF of enrolled subjects.  
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.   
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9.4 
Safety Measures 
9.4.1 Adverse Events 
The investigator will determine during the course of all study periods whether any AEs have 
occurred.  Sections 15 and 16 , respectively, contain additional information with regard to 
AEs and SAEs. 
9.4.2 Vital Signs, Weight, Height, and BMI 
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 in the CRF during the Screening visit. 
BMI calculations will be performed as per the BMI calculator on the National Heart, Lung, 
and Blood Institute web site: 
http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm. This site offers the 
option to enter either standard or metric data.  
9.4.3 Physical Examination 
The physical examinations performed during the trial will include skin, external eyes, oral 
cavity, nodes, lungs, heart, abdomen, extremities, and gross motor neurologic examination.  
All abnormal acute and chronic findings must be recorded whether they are new or were 
recorded previously in the CRF. For example, a surgical scar should be recorded on every 
scheduled physical examination.  
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10. CLINICAL LABORATORY TESTS 
Blood and urine sampling will occur as listed in Section 12.4 and the Table of Study 
Assessments (Section 7.2).  All blood samples will be drawn, prepared, maintained, and 
shipped as per the study Clinical/PK Laboratory Manual. Blood sampling for all clinical 
laboratory tests should be performed following the fasting period prescribed in the manual.  
The following tests will be performed at 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 
• Hemoglobin 
• Hematocrit 
• Mean Corpuscular Volume 
• Mean Corpuscular Hemoglobin Concentration 
• Red Blood Cell Count 
• Platelet Count 
b) Coagulation Profile:  The coagulation parameter analysis consists of the following tests: 
• Prothrombin Time (PT) and/or International Normalized Ratio (INR) 
• Activate Partial Thromboplastin (aPTT) 
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* 
 
 
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*Estimated glomerular filtration rate will be calculated using the SOPs of CRL, the central 
clinical laboratory.  
d) Urinalysis:  The urinalysis consists of the following tests: 
• Glucose 
• Erythrocytes 
• Protein 
• Leucocytes 
• pH 
• Nitrites 
• Ketones 
 
Note: Urine with abnormal protein, erythrocyte, leucocyte, or nitrite results will undergo a 
reflex automated examination.  
10.1.1 Pregnancy Testing 
The pregnancy testing will be performed on urine samples to be processed, assayed, and 
reported by site personnel as per the study Clinical/PK Laboratory Manual. The urine test 
must have a minimum sensitivity of 25 mIU for β-hCG per mL. 
All women enrolled in the trial must have a negative urine pregnancy test at Screening and 
Day 1 Pre-Dose.  
10.1.2 Toxicology and Drug Screen (PK Study Sub-Cohort only) 
The toxicology, drug, and alcohol testing will be performed on urine samples to be processed, 
assayed, and reported by site personnel as per the study Clinical/PK Laboratory Manual. 
10.1.3 Electrocardiogram 
A standard, surface 12-lead ECG will be obtained as per the ERT manual at the time points 
listed in the Schedule of Assessments (Section 7.2).  
ECGs will be interpreted by a Board-Certified cardiologist at ERT (Philadelphia, PA, USA).  
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). 
All ECGs will be electronically transmitted to the central ECG laboratory for interpretation.   
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10.1.4 Holter Monitoring (PK Study Sub-Cohort only) 
Subjects in the PK Study Sub-Cohort will undergo approximately 24-hours of continuous 
multi-lead cardiac telemetric monitoring from Day 28 (approximately 12 hours after the Day 
27 dosing) through Day 29. Subjects will remove the monitors on Day 29, approximately 24 
hours after they are attached, and return the Holter recorder at the Day 35 Visit.  
ERT’s instruction manual describes proper use and placement of these monitors. Site 
personnel will be trained regarding proper placement of the electrodes and recorders.  
The purpose of the 24-hour cardiac Holter monitor recording is to allow ECGs to be extracted 
based upon the plasma PK findings.  
10.1.5 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, itching, or pain)  in the 
Treatment Field on a 5-point scale, from 0 (none) to 4 (severe).  This assessment will be 
performed on Day 1 Pre-Dose (baseline) and repeated at each subsequent visit. The 
individual scores for each potential finding will be recorded in the respective cells by the 
assessor.  
In this trial LSRs will be collected independently of AEs. Details regarding reporting are 
included in Section 15.1. 
10.1.6 Once-Weekly Subject Contact 
Site personnel will contact each subject once-weekly during the Treatment Period. The goals 
of this contact are: (a) to review the Dosing Instruction Packet 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; and (d) to remind subjects to bring their 
study drug to each site visit.  
10.2  Pharmacokinetic Measures (PK Study Sub-Cohort only) 
A maximum of eighteen subjects will participate in the PK Study Sub-Cohort. Blood samples 
for measurement of plasma VDA-1102 and its primary metabolite jasmonic acid (JA) will be 
taken at Day 1 Pre-dose. Post-dose blood sampling will occur at the Days 7, Day 14, and Day 
28 Visits at approximately 12 hours after the Day 6, Day 13, and Day 27 evening doses, 
respectively. On Day 28, the sample should be drawn as close to 12 hours after the previous 
evening’s dose as possible, and additional samples should be drawn at approximately 15, 18, 
and 21 hours (±30 mins) after the Day 27 evening dose. A final sample will be collected on 
Day 35. The exact time of each blood sampling will be recorded in the EDC.   
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Further details regarding the PK blood sampling as well as PK sample handling, processing, 
storage, and shipping are included in the study Clinical/PK Laboratory Manual.  
Non-compartmental PK parameters (e.g., AUC, Cmax, Tmax, t1/2) will be calculated, if possible. 
  
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11. PROCEDURES FOR EFFICACY EVALUATIONS 
11.1 AK Lesions 
11.1.1 AK Lesion Grading 
This trial will use the AK lesion clinical grading established by Olsen et al and as 
recommended by the International League of Dermatologic Societies and the European 
Dermatology Forum:  
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 and/or obvious AK). Treatment Fields selected for this trial must 
not contain any Grade 3 AK lesions (see Section 11.1.2, below). 
11.1.2 AK Lesion Eligibility 
In order to be eligible for this trial, the AK lesions must meet each of the following criteria: 
a. Grade 1 or Grade 2 AK lesions (Section 11.1.1); 
b. located on the subject’s forehead, cheeks, or scalp but not on the lips, submandibular 
area, or neck; 
c. discrete (i.e., no borders are clearly touching one another);  
d. a maximum diameter 10 mm (inclusive) in any direction; 
e. non-hypertrophic and non-hyperkeratotic (i.e., no thick scale, horn, or > 1 mm raised 
above background skin); and 
f. not atrophic, acantholytic, pigmented, or Bowenoid.  
11.1.3 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 11.1.2) 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 may be selected on Day 1 Pre-Dose.  
It is recommended that the Treatment Field be a square or rectangle and that is visible to the 
subject when looking in the mirror. Treatment Fields not visible to the subject when looking 
in the mirror are best managed by having a dosing partner help with the dosing. Dosing 
partners must accompany the subject on Day 1 so as to undergo training and testing like all 
the subjects who self-dose.   
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The Treatment Field or its outer border must not be: 
a) Within 2.5 cm (~1 inch) of either labial commissure of the mouth, lip vermilion 
border, palpebral fissure or a suspected or proven malignancy; 
b) 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; or 
c) 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. 
11.1.4 Study Tools 
The following 3 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.   
Examples of the 3 study tools appear in Section 22.2 (Treatment Field Map), Section 22.4 
(Treatment Field Template), and Section 22.6 (Subject Dosing Card).  
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 appear in the Treatment Field Map Instructions (Section 22.3).  
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. 
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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 appear in the Treatment Field Template Instructions (Section 22.5). 
3. Dosing Card – a clear, thin, flexible plastic transparency with a rectangle printed on the 
back side. 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 each evening 
by the subject to measure their proper study drug dose, and will be discarded after use. 
A sample of the Dosing Card is included in Section 22.6. Instructions regarding use of 
the Dosing Card are included in the Subject Instruction Packet.  
11.1.5 AK Lesion Count 
At the Screening and Day -1 Pre-Dose Visits, the selected Treatment Field must include at 
least four (4) and no more than eight (8) visible and discrete non-hyperkeratotic, non-
hypertrophic AK lesions.  
All AK lesions in the selected contiguous 25 cm2 Treatment Field will be identified, counted, 
graded, and recorded at each visit. 
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 unable to be obtained due to a LSR. 
11.1.6 Photography 
Photography will be performed at designated study visit(s) at selected sites participating in 
this study as specified per protocol. The selected study sites will be provided with suggested 
guidelines to assist them in taking standardized photographs. However, it should be noted 
that all study sites, at the discretion of the investigator, may elect to photograph the subject 
under various magnification and lighting conditions to document the effects of treatment, 
adverse events or other findings during the trial. All photographs taken as part of this study 
are for informational purposes only and are not to assist in grading or for any other 
assessment.  
Note: Subjects may decline to have photographs taken during the conduct of the study. If a 
subject initially consents to photographs, then declines further photography, the Sponsor may 
use the photographs taken under consent for the purposes noted. 
. 
 
 
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12. CONDUCT OF THE STUDY 
12.1 Study Blinding and Randomization 
12.1.1 Randomization 
Assignment of study drug will be performed using a web-based Interactive Responsive 
Technology (IRT)-based randomization system. On Day 1 Pre-Dose, after confirming the 
subject’s eligibility, the Investigator (or his designee) may approve the subject’s blinded 
randomization.  
The web-based IRT will randomize subjects in a fashion that will maintain a balance among 
the 3 treatment groups (5% and 10% VDA-1102, and placebo) across all subjects enrolled 
(not per site) and within the PK Study Sub-Cohort.  
Subjects who withdraw or are terminated after 1 study dose has been applied will not be 
replaced in the trial.  
Should a subject lose or destroy a tube, the IRT is capable of assigning additional study drug 
to each subject with the appropriate treatment assignment.  
12.1.2 Blinding 
All site staff at the investigative sites, Sponsor, CROs, and vendors as well as all enrolled 
subjects will be masked to the study drug assignments throughout the trial. One pre-
designated statistician will have access to the blinded treatment assignments and be 
responsible for all activities that require unblinding, including the per protocol Interim 
Efficacy Analysis (Section 17.4).  
12.1.3 Unblinding 
In the event of an emergency, the Investigator (or designee) should contact the Study Medical 
Monitor to discuss the case before unblinding of an individual subject’s treatment code is 
broken by the site. If the medical condition of the subject warrants immediate unblinding, the 
treatment assignment of the subject may be obtained from the IRT without first consulting the 
Study Medical Monitor. However, the site must contact the Study Medical Monitor as soon 
as possible after the unblinding.  
An interim efficacy analysis will performed after approximately 50% of the enrolled subjects 
have completed their Day 56 Visit and their data have been recorded. The single pre-
designated unblinded statistician described above in Section 12.1.2 will perform this analysis. 
The specifics of this interim analysis will be included in the Statistical Analysis Plan.  
12.2 Subject Informed Consent 
Written consent will be obtained from the subject prior to any study-specific procedure or 
investigation. 
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Information about the study, explaining the objectives and potential risks and 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 before written consent is obtained. 
If a subject agrees to participate, he/she will be asked to sign and date an informed consent 
form (ICF), the original copy of which will be kept by the Investigator.  A copy of the signed 
ICF will be given to the subject. 
12.3 Study Periods 
The clinical trial will consist of the following periods:  
• Screening: Days -21 through Day 1 Pre-dose 
• Treatment: Day 1 Dosing through Day 28 
• Observation: Day 29 through Day 84 
 
12.4 Study Procedures per Period and Visit  
 Procedures that relate only to the PK Study Sub-Cohort will be denoted by a diamond 
similar to the one at the beginning of this paragraph. 
12.4.1 Screening Period 
The Screening Period begins immediately following the ICF signing (see Section 12.2 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 
by the subject, (c) was witnessed; and (d) was copied with one copy given to the subject 
for their personal records  
• Demographics recorded 
• Medical history recorded 
• Concomitant medications documented 
• Adverse events that occur following ICF signing will be recorded 
• Height and weight recorded 
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• Vital Signs: oral temperature, peripheral blood pressure, heart rate, and respiratory rate 
will be recorded 
• Physical examination 
• Clinical laboratory tests: Fasting status will be recorded  
• Urine pregnancy test will be performed in all females and the results will be recorded 
• 12-lead ECG tracing recorded as per the ERT manual. An original (duplicate) copy of the 
ECG is required for trial documentation. This ECG will also be transmitted to the central 
ECG laboratory. 
• Scalp and face examination by PI (or designee) with selection of a Treatment Field that 
meets the criteria stated in Section 11.1. The Treatment Field Map and Template will be 
prepared as per the Investigator  
• AK lesions count (11.1.5) and grading (11.1.1) 
• Study Drug Measurement and Application review (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 
• Subject instructions review will be reviewed including appointment for the next visit 
• Inclusion and exclusion (enrollment) criteria applied by Investigator and recorded 
• Investigator may declare of subject’s potential eligibility for PK Study Sub-Cohort 
 
Subjects who are eligible for the PK Study Sub-Cohort will undergo the following 
additional safety assessments: 
 Review additional Exclusion Criteria for PK subjects 
 Toxicology and drug screen 
 Alcohol level 
 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 
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• Concomitant medications documented 
• Study Drug Measurement and Application review (see Section 13.6.3) should be one of 
the first procedures performed upon arrival at the site. The Treatment Field Map and 
Template will be prepared as per the Investigator instruction sheet.  
• 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 
• Fitzpatrick skin typing (Section 9.3.2) 
• Local Skin Reaction Score (baseline) 
• AK Lesions in the Treatment Field: baseline count (11.1.5) and grading (11.1.1) 
• Urine pregnancy test will be performed in all females and results recorded. 
• 12-lead ECG tracing will be recorded as per the ERT manual. An original (duplicate) 
copy of the ECG is required for trial documentation. This ECG will also be transmitted to 
the central ECG laboratory  
• Study Drug Application: Training and Testing (see Section 13.6.3) should be repeated 
after all the above activities have been completed. 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. 
• Safety data from Screening, all available data from the Day 1 Pre-Dose Visit, as well as 
the Enrollment Criteria will be reviewed and approved by the Investigator (or designee) 
Subjects who meet the study enrollment criteria will undergo the following procedures: 
• Randomization of subjects 
• Clinical laboratory tests: Fasting status will be recorded.  
• Photographs of Treatment Field at designated sites 
• Study drug weighed and recorded 
 
Subjects enrolled in the PK Study Sub-Cohort will undergo the following additional 
procedure: 
 Notify IWRS that the subject was enrolled in the PK Study Sub-Cohort to enable proper 
randomization and treatment assignment 
 Blood sampling for (baseline) PK  
 
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 48 OF 93 
  
 
 
 
 
 
 
12.4.2 Treatment Period 
 Day 1 Dosing Visit 
The following procedures will be performed on subjects selected to proceed to the Treatment 
Period. 
• Study drug application and completion of the Dosing Diary by the subject under the 
supervision of the site personnel. 
• Subject Instruction Packet 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 Day 6 
• Subjects will dose at home each evening, beginning with Day 1 and record the application 
in the Dosing Diary.   
Note: Subjects will receive 2 doses of the study drug on Day 1: once at the site after 
randomization and once in the evening at home.  
• Site personnel will communicate with the subjects once a week (Section 10.1.6) in order 
to review the Subject Instruction Packet and Dosing Diary as well as to remind each 
subject of their next site visit.   
 Day 7 Visit 
On Day 7 (±2) the following procedures will be performed: 
• Adverse event(s) recorded 
• Concomitant medications documented 
• Study drug accountability and dosing compliance: study drug tubes will be weighed, the 
results recorded, and diaries reviewed and photocopied.  Study drug and/or tools will be 
replenished, as needed. 
• Vital signs: oral temperature, peripheral blood pressure, heart rate, and respiratory rate 
will be recorded. 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (11.1.5) and grading (11.1.1) 
• Study Drug Measurement and Application review (see Section 13.6.3) 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 48
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 49 OF 93 
  
 
 
 
 
 
 
• The first 15 subjects randomized (Nested Phase 1b Safety Cohort) will undergo: 
− 12-lead ECG tracing will be recorded as per the ERT manual. An original 
(duplicate) copy of the ECG is required for trial documentation. This ECG will 
also be transmitted to the central ECG laboratory 
− Clinical laboratory tests: fasting status will be recorded 
− Physical examination 
 
The following additional procedures will only be performed on the Day 7 Visit only in 
subjects enrolled in the subjects enrolled in the PK Study Sub-Cohort: 
 PK blood sampling approximately 12 hours after the Day 6 dose 
 
• Subject Instruction Packet will be reviewed including appointment for the next visit. 
• Study drug and study tools will be given to the subject, as needed. 
 Day 7 through Day 13 
• Subjects will dose at home each evening approximately 2 hours before bedtime and 
record the application in the dosing diary. 
• Site personnel will communicate with the subjects once a week (Section 10.1.6) in order 
to review the Subject Instruction Packet and Dosing Diary as well as to remind each 
subject of their next site visit.  
 Day 14 Visit 
On Day 14 (±2) the following procedures will be performed: 
• 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 
• Clinical laboratory tests: Fasting status should be recorded  
• 12-lead ECG tracing will be recorded as per the ERT manual. An original (duplicate) 
copy of the ECG is required for trial documentation. This ECG will also be transmitted to 
the central ECG laboratory  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 49
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 50 OF 93 
  
 
 
 
 
 
 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (11.1.5)  and grading (11.1.1) 
• Study Drug Measurement and Application review (see Section 13.6.3) 
• Study drug accountability and dosing compliance: study drug tubes will be weighed, the 
results recorded, and diaries reviewed and photocopied 
• Study drug and study tools will be given to the subject, as needed 
 
The following additional procedures will be performed on the Day 14 Visit only in subjects 
enrolled in the subjects enrolled in the PK Study Sub-Cohorts: 
 PK blood sampling approximately 12 hours after the Day 13 dose 
 
• Subject Instruction Packet will be reviewed including an appointment for the next visit 
will be given 
 Day 14 through Day 27 
• Subjects will dose at home each evening approximately 2 hours before bedtime and 
record the application in the Dosing Diary. 
• Site personnel will communicate with the subjects once a week (Section 10.1.6) in order 
to review the Subject Instruction Packet and Dosing Diary as well as to remind each 
subject of their next site visit   
 Day 28 Visit 
On Day 28 (±4) 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 (11.1.5) and grading (11.1.1) 
• Study drug accountability and dosing compliance: study drug tubes will be weighed and 
the results recorded. Dosing Diaries will be collected and not returned  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 50
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 51 OF 93 
  
 
 
 
 
 
 
• 12-lead ECG tracing recorded as per the ERT manual. An original (duplicate) copy of 
each ECG is required. This ECG will also be transmitted to the central ECG laboratory 
• Complete clinical laboratory tests: Fasting status to be recorded 
• Urine pregnancy test will be performed at the investigative site in all females and the 
results will be recorded 
 
 
The following Procedure will only be performed on the Day 28 Visit in subjects enrolled in 
the PK Study Sub-Cohort: 
 PK blood sampling approximately 12 hours after the Day 27 dose. Additional blood 
samples will be collected at approximately 15, 18, and 21 hours post dose 
 24-hour ambulatory cardiac Holter monitor will be connected to the subject 
 
• Trial instruction review including an appointment for the next visit will be given.  
12.4.3 Observation Period 
 Day 29 through Day 34 
• No procedures will be performed on these days. 
 Subjects in the PK Study Sub-Cohort will remove the Holter on Day 29 approximately 
24 hours after it was attached and will be returned by the subject to the site on Day 35.   
 Day 35 Visit 
On Day 35 (±2) the following procedures will be performed: 
• 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 (11.1.5) and grading (11.1.1) 
• Trial instruction review including appointment for the next visit will be given  
 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 51
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 52 OF 93 
  
 
 
 
 
 
 
The following Procedure will only be performed on the Day 35 Visit in subjects enrolled in 
the PK Study Sub-Cohort: 
 PK blood sampling  
 Day 36 through Day 55 
From Day 36 through Day 55 no procedures will be performed.  
 Day 56 Visit 
On Day 56 (±4) the following procedures will be performed: 
• Adverse event(s): volunteered, elicited, and observed AEs will be recorded 
• Concomitant medications documented 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (11.1.5) and grading (11.1.1) 
• Urine pregnancy test will be performed in all females and the results will be recorded 
• Photographs of Treatment Field at selected sites 
• Trial instruction review including appointment for the next visit will be given  
 
 Day 57 through Day 83 
From Day 57 through Day 83 no procedures will be performed  
 Day 84 Visit 
On Day 84 (±4) the following procedures will be performed: 
• Adverse event(s): volunteered, elicited, and observed AEs will be recorded 
• Concomitant medications documented 
• Local Skin Reaction Score in the Treatment Field 
• AK Lesions in the Treatment Field: count (11.1.5) and grading (11.1.1) 
• Photographs of Treatment Field at selected sites 
• Visit Closure Procedures: Subjects will be thanked for their participation and completion 
of the study will be noted in the subject’s record  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 52
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 53 OF 93 
  
 
 
 
 
 
 
12.5 
Unscheduled Visits 
Investigators will invite subjects to attend an unscheduled visit to the investigative site (a) if 
during the course of 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 Day 84. 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 53
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 54 OF 93 
  
 
 
 
 
 
 
12.6 General Restrictions 
12.6.1 Medication and Other Therapeutic Restrictions 
• Topical creams, lotions, makeup or gels of any kind within the selected Treatment Field 
and the surrounding 2 cm border area from Screening through Day 84 are prohibited 
unless prescribed by the site Investigator and documented in the subject’s file. 
• Topical medications within the region of the head that contains the selected Treatment 
Field (i.e., left face, right face or scalp) are prohibited from Screening through Day 84: 
− Topical skin corticosteroids; 
− Keratolytic-containing therapeutic products or medicated or irritant topical salves, 
including, but not limited to, alpha-hydroxy acids (e.g., glycolic acid, lactic acid 
etc. >5%), beta-hydroxy acid (salicylic acid >2%), and urea >5%; 
− Topical retinoids (e.g., tazarotene, adapalene, tretinoin). 
• Topical AK treatments including, but not limited to, 5-fluorouracil, diclofenac, 
imiquimod, or ingenol mebutate, and other at-home AK treatments at any body site are 
prohibited from Screening through Day 84. 
• Any AK therapy including, but not limited to, topical medications, cryo-destruction or 
chemo-destruction, surgical excision, curettage, photodynamic therapy, dermabrasion, 
chemical peel, or laser resurfacing on the head are prohibited from Screening through 
Day 84.  
• Systemic medications: 
o Immuno-modulatory 
medications 
including 
corticosteroids, 
interferon or 
interferon inducers, cytotoxic drugs, or immunosuppressive therapies 
o Retinoid therapy 
• Investigation drug or devices. 
• Any prescription medications or medicinal products that might obscure, impact, or 
interfere with proper evaluation of the test product and the Treatment Field are prohibited 
during the study. 
• Starting any new systemic therapy during the trial is prohibited without prior approval of 
the Study Medical Monitor.  
Allowed medications or therapies during the study must be documented and include: 
• Subjects taking prescription medication, vitamins, or medical product not specifically 
prohibited above, 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 change in 
dose, manufacturer, or dosing interval. These medicinal products must be recorded on 
the appropriate Concomitant Medication pages. All other prescription medications, 
medicinal products, and vitamins are prohibited without prior approval of the 
Investigator and the Medical Monitor. The only exceptions to this rule are ≤ 1000 mg 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 54
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 55 OF 93 
  
 
 
 
 
 
 
acetaminophen, ≤ 550 mg naproxen, ≤ 400 mg ibuprofen or aspirin 325 mg once daily 
without prior consultation.  
• Intranasal, inhaled, and ophthalmic corticosteroids used in the past for the 
management of allergies, pulmonary disorders, or other conditions. 
• Light bodied bland moisturizer (e.g., Cetaphil, Lubriderm [without alpha-hydroxy 
acid]) in 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 test article 
application and the Treatment Field must be washed with soap prior to the next 
dosing. 
• Medications used as prn (e.g. bronchodilators, antihistamines, sleep medications) 
listed as concomitant medications at Screening and/or Day 1 Pre-Dose Visits are 
permitted. 
• Physical AK therapies including, but not limited to, topical cryo-destruction, surgical 
excision, curettage, dermabrasion, or laser resurfacing on areas other than the head 
are permitted at any time during the trial.  
 
12.6.2 Topical Product Restrictions 
Subjects should be instructed not to change their soaps, shampoos, laundry detergents, 
deodorants, etc. from Screening Visit through completion of the Day 84 Visit.  
12.6.3 Sun Protection and Tanning 
Subjects must avoid purposeful direct exposure to the sun or ultra-violet light from Screening 
Visit through completion of the Day 84 Visit activities. Subjects who go outdoors should 
wear proper clothing and hats that protect their skin from sunlight.  
Purposeful tanning and application of tanning agents are prohibited at any time during the 
trial. 
NOTE: Subjects should be encouraged to apply sunscreens that the subject has applied 
previously without developing a reaction. However, no topical sunscreens, creams, lotions, or 
gels of any kind may be applied within the selected Treatment Field or the surrounding 2 cm 
border area from Screening through Day 84 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.  
12.6.4 Dietary Restrictions 
Subjects may not ingest any product containing jasmine (e.g. jasmine tea).  
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 55
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 56 OF 93 
  
 
 
 
 
 
 
Subjects may not drink any spiced, herbal, scented, or flavored teas from Screening until 
completion of all Day 35 procedures since these often contain jasmine without necessarily 
appearing on the label.  
Subjects not included in the PK Study must limit their daily alcohol consumption to ≤ 24 ozs 
(ounces) of beer; ≤ 8 ozs of wine; or ≤ 2 ozs of any distilled alcoholic beverage from Day 1 
through completion of the Day 35 Visit. 
Dietary restrictions for the subjects in the PK Study are discussed in Section 12.6.5. 
12.6.5 Special Restrictions for the PK Study Sub-Cohort 
Subjects enrolled in the PK Study Sub-Cohort may not smoke, use nicotine products, or 
drink any alcohol from the Screening Visit until they complete Day 35 Visit. All medications 
taken between Screening and Day 84 must be pre-approved by their site Investigator.  
12.6.6 Physical Exercise Restrictions 
There are no restrictions placed upon physical exercise.  
12.7 Childbearing Potential 
12.7.1 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; 
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 and have that 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 who considered childbearing 
and who cannot use an acceptable form of contraception, must be excluded from the study 
under Exclusion Criterion #3 (Section 8.2).  
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. 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 56
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 57 OF 93 
  
 
 
 
 
 
 
Urine Pregnancy test:  All women enrolled in the trial must have a negative urine pregnancy 
test at Screening and Day 1 Pre-Dose. The urine dipstick test must have a minimum 
sensitivity of 25 mIU for β-hCG/mL. 
12.7.2 Contraception 
Nursing mothers, pregnant females, and women with childbearing potential (as defined in 
Section 12.7.1) must be able and willing to use a contraceptive method describes in that 
section, until 1 month following the final study drug application (i.e., until the Day 56 
Visit). 
Non-vasectomized male subjects with female partners without childbearing potential (as 
defined in Section 12.7.1) are not required to use contraception.  
Non-vasectomized male subjects with female partners with childbearing potential (as defined 
in Section 12.7.1) must agree to use an acceptable form of contraception (as defined in 
Section 12.7.1) 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 require no contraception. 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 57
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 58 OF 93 
  
 
 
 
 
 
 
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. There are no discernable differences in color between VDA-
1102 ointment and placebo. 
5% and 10% VDA-1102 topical ointments and placebo ointment are supplied in 10 gm 
aluminum tubes with plastic caps, and stored refrigerated at 2-8 °C (36-46°F). Placebo will 
be identical to VDA-1102 minus the API (Active Pharmaceutical Ingredient). 
13.2 Drug Packaging 
The study drug tubes are enclosed in an aluminum envelope with an enclosed desiccant. The 
pouch is packaged in a protective 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 (or placebo) 
4. Lot numbers for placebo, 5% VDA-1102, and 10% VDA-1102 
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: 10 grams 
13.4 Study Drug Distribution 
Sites in the U.S. will receive their drug from a depot located in the United States, while sites 
located in Israel will receive their drug from an Israeli depot. Study drug will be shipped 
under refrigerated conditions with temperature loggers.  
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. 
Home Storage 
Subjects will be instructed to keep the study drug tube in the accompanying container and to 
keep this unit in their home refrigerator.   
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 58
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 59 OF 93 
  
 
 
 
 
 
 
Travel 
If a subject needs to transport the study drug (while travelling on vacation or 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 randomization.  
Based on the randomization number generated by the IVRS, the site personnel (or 
institutional pharmacist) will allocate the appropriate study drug for each subject. The tube 
with its aluminum envelope will be removed from its container in the refrigerator. The 
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 placed in the 
container until dosing time.   
13.6.2 Study Drug Dosing Cards 
Study Drug Dosing Cards will be distributed to all the sites.  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 each evening to their Treatment 
Field.   
A sample of the Dosing Card is included in Section 22.6. Instructions regarding proper use of 
the Dosing Card are included in the Subject Instruction Sheet.  
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 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.   
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 59
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 60 OF 93 
  
 
 
 
 
 
 
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 28 days.  
If the subject (or dosing partner) is unlikely to apply the study drug appropriately, the subject 
should be terminated from the study based on Inclusion#4 (Section 8.1).  
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 #4 (Section 8.1). 
Day 1 Dosing Visit 
Dosing at this visit will occur under the supervision of the site personnel.  If at this visit the 
subject 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. 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 dosing partner) each 
evening approximately 2 hours before bedtime. If the subject would like to shower, wash 
their face, shampoo their hair, etc. before bedtime, 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.  
Using a mirror, photographs, 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 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 60
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
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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 in order to insure that the whole Treatment Field was covered with 
study drug.  
The subject will be instructed not to wet or touch the Treatment Field from the time of dosing 
until the following morning.  
13.7 Study Drug Accountability and Dosing Compliance 
The CRO will request the Investigator or their designee to sign a receipt for 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 accountability. A drug accountability 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 Medical 
Monitor 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 given on this drug accountability record, which will be collected at the end of the 
study.   
All drugs 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. 
A single 10 mL tube of study drug will be assigned to each subject. Each tube will be 
weighed prior to the first dosing and at Day 7, 14, and 28 Visits. Subjects will also be asked 
during the once-weekly communication with the site and at each site visit whether they 
missed any doses and responses will be appropriately documented in the subject’s medical 
record. In addition, subjects will complete a Dosing Diary, following each evening dose, with 
the date and time of dosing.  
 
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14. CONCOMITANT MEDICATION 
Any prescription or non-prescription medication, alternative medication, herbal product, 
homeopathic substance, etc. used by the subject from 30 days prior to Screening until the 
subjects leaves the trial 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 
CRF.   
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 12.6.1 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, 
manufacturer, or dosing interval. 
At Screening and Day -1 Pre-Dose Visits, the study site personnel will check each subject’s 
concomitant medications to ensure that subjects are not taking any prohibited medications 
listed in Section 12.6.1. 
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.  
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15. ADVERSE EVENTS 
15.1 Adverse Event Definition 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product, 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. 
In this trial LSRs will be collected independently of AEs. Any LSR that occurs within 
the selected Treatment Field and extends to adjacent surrounding skin (defined as 
within a 2 cm border around the Treatment Area) will be considered LSRs and will not 
be recorded as AEs.  LSRs that require medical intervention (prescription medication) 
or extend beyond the 2 cm surrounding skin should be documented as an AE. 
Clinically meaningful (for a given subject) changes in physical examination and test findings 
should also be recorded as AEs.  The criteria for determining whether an abnormal objective 
test finding should be reported as an AE are as follows: 
1. Test result is associated with accompanying symptoms, and/or 
2. Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
3. Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or 
4. Test result leads to any of the outcomes included in the definition of a SAE. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
meet 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. 
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 for the AE, 
and should be documented as such.   
Planned hospital admissions documented in the subject’s CRF prior to randomization and 
study-related procedures are also not 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. 
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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 Laboratory Test and Diagnostic Procedure Abnormalities 
An abnormal result will not be recorded as an AE unless one or more of the below occurs: 
• The abnormal test is accompanied by symptoms. 
• The test result leads to an alteration or interruption in study medication. 
• The test result requires medical or surgical intervention 
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• The test result is considered clinically significant by an Investigator. 
If such an event occurs, the test should be repeated within 10 days to confirm the finding and 
appropriately monitored.   
15.6 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), 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, 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. 
15.7 Documentation and Reporting of Adverse Events by Investigator 
Instructions for the completion of AE reports in a clinical study are provided by the Sponsor 
in the Safety Monitoring Plan.   
 
 
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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. Is 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. A congenital anomaly or birth defect. 
6. A 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 appear in the Safety Monitoring Plan.  
16.2.1 Reporting of Serious Adverse Events by Investigators 
If the AE is serious, the Investigator must complete an SAE Report form, in addition to the 
AE page in the CRF. 
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 
communication methods may be used. The Medical Monitor and CRO will confirm receipt 
upon receiving the notification.   
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Chaim M. Brickman, Study Medical Monitor (Sponsor) 
Telephone (mobile): 1-646-757-1062 
E-mail: cbrickman@vidacpharma.com 
Office Fax:  011-972-2-595-2091 from US 
Home fax:   011-972-9-743-7061 from US 
 
Chris Jones, Project Manager (U.S. CRO; Therapeutics, Inc.) 
Telephone (mobile): 1-858-232-6969  
E-mail: cjones@therapeuticsinc.com 
Office: 1-858-571-1800 x169 
Fax:     1- 858-571-1234 
 
Samuel Kalderon, Monitor (Israel CRO; CTA Clinical Research Ltd.) 
Telephone (mobile): +972-504233110 
E-mail: samuelk@tca.co.il 
Office: +972-9-966-2857 
Fax:     +972-9-894-3445 
The SAE Report Form must be completed in accordance with instructions provided by the 
Sponsor or designee.  The completed form must be faxed or emailed to the Study Safety 
Monitor within 24 hours of discovery of the SAE.  
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.  
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. 
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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. 
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. 
Any serious adverse events (SAEs) including death due to any cause, which occurs in any 
subject through Day 84, whether or not related to the investigational product, must be 
reported to the Sponsor within 24 hours.  All subjects with SAEs must be followed-up for 
outcome. 
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17. STATISTICAL PLAN 
17.1 Sample Size Rationale and Justification 
The primary objective of the trial is to compare the reduction on Day 56 in the number of the 
AK lesions (or % reduction if baseline measure will be found different between the groups) 
in the Treatment Field of subjects receiving 5% or 10% VDA-1102 ointment to the reduction 
in the number of AK lesions in subjects receiving placebo. The sample size calculation was 
based on demonstrating an effect size of 0.83 using a two group t-test with a 0.045 two-sided 
significance level. The total significance level of 5% was divided between the interim 
analysis 0.5% (0.005) and the final analysis 4.5% (0.045). The sample size calculation was 
based on the final significance. The spending function calculation for alpha will be performed 
using the O'Brien-Fleming approach. Assuming a drop-out rate of 10%, approximately 84 
subjects will be recruited in order to complete the study with a sample of approximately 75 
evaluable subjects. 
A sample size of 25 in each group will have 80% power to detect an effect size of 0.83 using 
a two group T-test with a 0.045 two-sided significance level. 
17.2 Statistical analysis 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. For categorical variables summary tables will be provided 
giving sample size, absolute and relative frequency and 95% CI (Confidence Interval) for 
proportions by treatment group. For continuous variables summary tables will be provided 
giving sample size, arithmetic mean, standard deviation, coefficient of variation (CV%), 
median, minimum and maximum and 95% CI (Confidence Interval) for means of variables 
by treatment group. The data will be analyzed using the SAS ® version 9.3 or higher (SAS 
Institute, Cary North Carolina). 
17.2.1 Efficacy Analysis 
The efficacy analysis will be performed with the ITT, mITT, and PP populations (see Section 
17.5.2).  The primary efficacy endpoint is the change from baseline in number of AK lesions. 
If the baseline lesions number will be found different between the treatment groups, then 
relative change (%) will be analyzed as well. The within-group absolute changes (decrease) 
in AK number of lesions from baseline to each visit will be analyzed using paired t-test or 
signed rank test for two means (paired observations, as is appropriate). 
Comparative analysis of the above changes will be applied between each of the active groups 
versus the placebo group using the two-sample t-test, the non-parametric Wilcoxon-Mann-
Whitney rank sum test for independent samples, or the Median test (as appropriate). 
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If no statistically significant differences are observed between the two active VDA-1102 
groups then these two groups will be pooled and compared to the placebo group in order to 
achieve higher statistical power. 
The overall effect and trend of differences in the changes over time between the groups will 
be analyzed using a mixed-effect model for repeated measures. The model will include 
changes from baseline at any time, the fixed effect time, and the interaction of treatment and 
time. Contrast will be calculated for each time point (Days 7, 14, 28, 35 and 56) versus 
baseline and the overall effect. The model will be adjusted for baseline measure and for other 
covariates suspected as affecting the outcome and which will be found different between the 
treatment groups.  
In case the baseline number of lesions differs between the groups, analysis of relative change 
(%) will be applied as well.  
Chi-square test or Fisher’s exact test (as is appropriate) will be used for analyzing the 
difference in percent of subjects with complete clearance of study AK lesions at the end of 
the treatment. Logistic regression will be applied for analyzing the difference in proportions 
with adjustment for baseline measure and for other covariates suspected as affecting the 
outcome and which will be found different between the treatment groups.  
17.2.2 Safety Assessments 
The safety end point 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 treatment 
group.  Safety will also be assessed by evaluating findings of physical examinations, vital 
signs, dermatologic assessments, clinical laboratory test results, 12-lead ECG tracings, Local 
Skin Reaction Score, drug exposure, concomitant medications, and withdrawals/terminations.  
These findings will be summarized and compared between treatments and within treatment 
group compared to findings from baseline evaluations.   
Local Skin Reaction scores (LRS) will be summarized by treatment.     
17.2.3 Pharmacokinetic Parameters 
Non-compartmental PK parameters (e.g., AUC, Cmax, Tmax, t1/2) will be calculated, if possible. 
17.2.4 Exploratory Endpoints Assessment 
Chi-square test or Fisher’s exact test (as is appropriate) will be used for analyzing the 
difference in percent of subjects with complete clearance of study AK lesions at the end of 
the treatment. Logistic regression will be applied for analyzing the difference in proportions 
with adjustment for baseline measure and for other covariates suspected as affecting the 
outcome and which will be found different between the treatment groups.  
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Sensitivity analysis will be applied for identifying the cut-off of the change (or relative 
change) from baseline in number of lesions on Day 56. Analysis of the difference in the 
binary change will be applied using Chi-square test or Fisher’s exact test. Logistic regression 
will be applied for analyzing these differences with adjustment for baseline measure and for 
other covariates suspected of affecting the outcome and which will be found different 
between the treatment groups.  
Additional exploratory endpoint assessments will be described in the Statistical Analysis 
Plan.  
17.3 Missing Data 
Assuming the scope of missing data of the primary efficacy endpoint will be significant, data 
imputation will be applied. Missing data at random imputation (MAR) will be performed for 
those subjects with missing data. Multiple imputation will be applied using SAS PROC MI to 
perform the imputations. Sensitivity analysis will be used for detecting differences between 
the analyses with and without data imputation. 
17.4 Interim Efficacy Analysis 
An interim efficacy analysis will be conducted as soon as approximately 50% of the subjects 
have completed the study. The objective of the interim analysis is to evaluate the probability 
to achieve the primary efficacy endpoint. 
The data for the interim analysis sub-set will be collected and analyzed for effect size and t-
value. Effect size will be calculated based on the difference in the change from baseline in 
AK lesions for each of the active groups as compared to the placebo group. Relative change 
(%) will be used if baseline measure will be found different between the groups.  
Futility will be based on O'Brien-Fleming boundaries. If the t-value with 22 degrees of 
freedom is below 0.34, then the study is unlikely to succeed when taken to completion. In 
case the distribution of the outcome variable will not be found with approximation to 
normality, then appropriate non-parametric methods will be considered for the interim 
analysis. 
17.5 Data Sets 
17.5.1 Intent-to-Treat Population 
The ITT population will be defined as all subjects who are randomized and who receive study 
drug.  This is an appropriate population for the primary analysis because this is a blinded trial 
and the dose will be applied in the clinic by the research clinic staff.   
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All safety analyses will be performed on the ITT population.  Subjects will be analyzed 
according to the treatment actually received, not the treatment they were supposed to have 
received.  
17.5.2 Modified ITT (mITT) Population 
The mITT population includes all ITT patients who completed the study and have protocol 
deviations that do not significantly impact efficacy. The mITT population will also be used 
for the primary efficacy endpoint analysis. 
17.5.3  Per-Protocol Population 
The PP population includes all ITT patients who have no major protocol deviations. The PP 
population will also be used for the primary efficacy endpoint analysis. 
17.5.4 Pharmacokinetic Population 
A maximum of 18 subjects enrolled in the PK Study Sub-Cohort will constitute the PK 
population. 
17.5.5 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 8) 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).  
It is the Sponsor’s responsibility to determine whether the event will be considered a 
violation, major deviation, or minor deviation.   
17.5.6 Subject Compliance Definitions 
Subjects in the Treatment Period will be contacted by site personnel once-weekly.  During 
that telephone conversation, subject compliance with the study drug dosing will be obtained 
and recorded.  
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17.6 Demographic and Baseline Characteristics 
The comparability of the dose groups will be summarized by the evaluation of the 
demographic information, including age, gender, and country.   
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18. STUDY MANAGEMENT AND DATA COLLECTION 
18.1 Data Collection Methods 
An Electronic Data Capture (EDC) system will be utilized in this trial. The EDC system is 
fully validated and conforms to Title 21 Code of Federal Regulations (CFR) Part 11 and the 
Guidance for Industry on Computerized Systems Used in Clinical Trials requirements.  The 
system has capabilities such as on-line data review via the browser, tracking review status of 
eCRFs with built-in flagging, issuance and tracking of electronic Data Clarification Forms 
(queries), and real-time viewing of entered subject’s data.  If the EDC is not ready to accept 
data by the time the trial begins enrollment, data may be entered on paper CRFs and 
transferred to the EDC as soon as it is ready to accept data. 
The trained Investigational site staff will enter the data required by the protocol into the 
eCRFs from source documents into the EDC system.  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.  
Electronic CRFs 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. 
Cardiac data should be transferred to eRT (eResearch Technology, Inc., Philadelphia, PA) the 
same day the data are obtained, if possible. Central Laboratory samples should be shipped on 
a daily basis, if possible, unless specific holiday or weekend schedules are in effect. 
Data should be entered into the EDC (or paper CRF) within 5 business days of the study visit; 
queries should be appropriately addressed within 3 business days of receipt. During data 
cleaning and preparations for data lock, queries must be appropriately addressed by the site in 
a timely manner (2-3 business days).   
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, central 
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 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 74
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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. 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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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 eCRFs and other documents submitted to the Sponsor.  
Documents not submitted to the Sponsor include those that identify the subject (eg, 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.  
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The Sponsor (or designee) may submit ICFs to a central IRB for review and approval or 
favorable opinion contingent upon the prior Investigator permission and review.   
The Investigator will not undertake any measures or procedures specifically required of a 
subject for the clinical study until valid consent has been obtained. 
The Investigator should inform the subject’s primary physician about the subject’s 
participation in the study if the subject has a primary physician and if the subject agrees to the 
primary physician being informed, as per the site’s standard operating procedures. 
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 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 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 the Investigator, the clinical observations in the study suggest that it may 
be unwise to continue, the Investigator may terminate the study after consultation with the 
Sponsor.  A written statement fully documenting the reasons for such a termination will be 
provided to the Sponsor.  In addition, the Sponsor may terminate the study at any time.   
If it becomes apparent that subject enrollment 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 the study and remove all study materials from the investigational 
site.  A written statement will be provided to the Investigator, the IRB, and regulatory 
authorities, if required.  In the event any SAEs or non-SAEs are reported, all documentation 
relating to the event(s) must be obtained. 
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20. INVESTIGATOR'S OBLIGATIONS 
20.1 General 
The Investigator agrees that the study will be conducted in accordance with the clinical 
protocol, FDA’s GCP guidelines, ICH 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 PI or designee 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.  While 
deviations from the protocol are discouraged, they may be necessary in order to eliminate an 
immediate hazard to subjects or to facilitate adherence to protocol procedures.  
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.  The Investigator or other attending physician will contact 
the Sponsor as soon as possible in the case of such a deviation.  These deviations do not 
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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 eCRF 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 quality assurance offices. 
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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. 
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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. 
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. 
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CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
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22. APPENDICES 
22.1 Local Skin Reaction Score  
This score has been modified from a score published in Lebwohl M et al (2012), “Ingenol 
Mebutate Gel for Actinic Keratosis”, N Engl J Med 2012;366:1010-9).  
The Local Skin Reaction Score is an assessment of all the skin in the Treatment Field (not of 
the AK lesions). At each study visit the Investigator (or designee) will assign a severity score 
to each of the objective and subjective findings listed in the table. For example, if the 
Treatment Field contains vesicles of moderate severity, the number 3 would be placed under 
the field labelled “Vesicles”. 
The Investigator will assess the selected Treatment Field and rate the findings on a 5 point 
scale. The LSR score will consist of the sum of all the individual severity scores.  
 
Treatment 
Field 
Findings 
Erythema 
Edema 
Weeping 
or 
Exudate 
Vesicles 
Erosion or 
Ulceration 
Scaling 
or 
Dryness 
Scabbing 
or 
Crusting 
Itching 
Pain 
Severity 
Score 1 
 
 
 
 
 
 
 
 
 
 
The 5 point LSR Score is: 0 = No reaction, 1=Trace reaction, 2= Mild reaction, 
3=Moderate reaction, and 4=Severe reaction. 
 
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22.2 Treatment Field Map 
 
Below is a picture of the Treatment Field Map on a white piece of paper on a brown platform.  
 
 
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22.3 Treatment Field Map Instructions 
This thin, flexible, plastic transparency sheet (Section 22.2), with a grid of 1cm x 1cm 
squares printed on the surface, will be used by the Investigator (or designee) to outline the 
Treatment Field, enabling consistent counting the AK lesions within the Treatment Field. It is 
also used to prepare the Treatment Field Template (see Treatment Field Template instructions 
Section 22.5). 
This tool should be used in the following manner: 
1. Affix a label that includes the subject’s identifier(s) and the visit date near the top of the 
sheet.      
2. Place this transparency over the Treatment Field selected on the subject’s face or scalp.  
3. With a supplied marker, draw the outline of several facial landmarks (e.g. eyebrows, ear 
helix and/or lobule, moles, scars) on this map. These landmarks will be transferred  
4. Write at the top of the map any additional information that helps orient placement of the 
map. For example, “Left Face” or “Center Scalp”.    
5. Identify the 25 squares that make up the 25 cm2 contingent area (that includes 4 to 8 
discrete non-hyperkeratotic and non-hyperkeratotic AK lesions) 
6. With the supplied marker, outline the outer border of the 25 squares that defines the 
chosen Treatment Field. 
 
 
 
 
 
 
 
 
 
 
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22.4 Treatment Field Template 
Below is a picture of the Treatment Field Template on a white piece of paper on a brown 
background. 
 
 
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22.5 Treatment Field Template Instructions 
This thin, flexible, plastic blank transparency (Section 22.4) will be used by the Investigator 
(or designee) to prepare a template (stencil) outlining the Treatment Field. This template will 
be used by the subject to precisely locate the Treatment Field and to properly apply the study 
drug. This tool should be prepared in the following manner by the Investigator (or designee): 
1. Take one of the supplied clear Treatment Field Templates and affix a label to the top 
that includes the subject’s identifiers and the date of the visit.  
2. Lay the template on top of the Treatment Field Map of this subject.  
3. Trace all the identifying landmarks from the Treatment Field map onto the clear 
template using the supplied marker. 
4. After the template is removed from the map, the Treatment Field should be precisely 
cut out of the Treatment Field Template using the supplied safety blade.  
5. At least 4 templates should be made by repeating steps 1-4.  
6. The map and the templates should each be checked for accuracy on the subject’s 
Treatment Field. Make sure the template delineates the Treatment Field precisely and 
doesn’t include a wider area (and different AK lesions) when it is laid flat.  
7. Use this opportunity to demonstrate to the subject the proper positioning of the 
template on the Treatment Field. If possible, let the subject use a mirror to observe 
the position of the template over the Treatment Filed.  
8. The Treatment Field Map and one copy of the template should be stored at the site in 
a protective envelope. The template should be used at each visit for counting AK 
lesions, not the map since the grip marks on the map might obscure or distort the AK 
lesions.  
9. At each visit, at least 2 copies of the Treatment Field Template should be given to the 
subject for practicing and dosing purposes.   
 
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22.6 Subject Dosing Card 
Below is a picture of the Dosing Card on a white piece of paper on a brown background.  
 
 
 
 
 
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22.7 Subject Instruction Packet 
Below is a copy of the Subject Instruction Packet.  
 
 
 
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CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 92 OF 93 
  
 
 
 
 
 
 
22.8 Dosing Diary 
 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 92
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VDA-1102 topical ointment
CONFIDENTIAL
 
CLINICAL PROTOCOL VDA-CP-03   P2A  09JUNE2016 
VDA-CP-03 P2A AMENDMENT 1;  07 JULY2016 
VDA-CP-03 P2A AMENDMENT 2;  31 OCTOBER 2016 
PAGE 93 OF 93 
  
 
 
 
 
 
 
 
2.5.1.7.2.1.1.1.1.1.2 vda-cp-03-protocol-1.pdf - Page 93
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SAP_001.pdf: 
 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 1 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
 
Statistical Analysis Plan 
 
Study Title: 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-1102 Ointment for 28 Days in Subjects with 
Actinic Keratosis 
 
 
 
 
 
 
 
 
 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 2 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 3 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Revision History 
 
Revision 
Revision Date 
Reason for Revision/Change Request 
Revised By 
1.0 
28-DEC-2016 
Original Release 
David Israel, BST 
2.0 
21-MAY-2017 
Comments from VidacPharma 
David Israel, BST 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 4 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
TABLE OF CONTENTS 
1. 
DEFINITIONS AND/OR ABBREVIATIONS ...................................................................... 5 
2. 
PURPOSE ............................................................................................................................... 7 
3. 
SCOPE .................................................................................................................................... 7 
4. 
RESPONSIBILITIES ............................................................................................................. 8 
4.1 
Medistat Responsibilities ................................................................................................. 8 
4.2 
Vidac Pharma's Responsibilities ...................................................................................... 8 
5. 
PROCEDURE ......................................................................................................................... 9 
5.1 
Study Objectives and Endpoints ...................................................................................... 9 
5.2 
Overall study design and plan ........................................................................................ 11 
5.3 
Selection of study population ......................................................................................... 21 
5.4 
Statistical Analysis Software .......................................................................................... 22 
5.5 
Subject Population for analyses ..................................................................................... 26 
5.6 
Statistical Analysis ......................................................................................................... 28 
6. 
RELATED DOCUMENTS .................................................................................................. 38 
6.1 
Internal Documents ........................................................................................................ 38 
6.2 
External documents ........................................................................................................ 38 
7. 
RELATED FORMS .............................................................................................................. 39 
8. 
REFERENCES ..................................................................................................................... 40 
9. 
APPENDICES ........................................................................................................................ 41 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 5 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
1. DEFINITIONS AND/OR ABBREVIATIONS 
 
AE  
Adverse event  
AK 
Actinic keratosis 
AUC  
Area under the plasma concentration-time curve from time zero (t0) to the time of the last measured sample (tlast) 
BL  
Baseline  
BLQ 
Below Level of Quantification 
BMI 
Body Mass Index 
Cmax 
Peak plasma concentration  
CRF 
Case Report Form (may be paper or electronic representation of the data collection tool) 
CRO  
Contract Research Organization  
ECG  
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA  
Food and Drug Administration 
Hr(s)   
Hour(s)  
ICF  
Informed Consent Form  
I.e.  
Id est, in other words  
ITT  
Intent-to-Treat  
MedDRA 
Medical Dictionary of Regulatory Affairs.   
mITT  
Modified ITT  


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 6 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
NA  
Not applicable  
PI  
Primary Investigator  
PK  
Pharmacokinetic  
PT  
Preferred Term 
QTcB  
QTc interval corrected using Bazett’s formula  
QTcF  
QTc interval corrected using Fridericia’s formula  
SD  
Standard Deviation  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC  
System Organ Class  
SOP  
Standard Operating Procedure  
TEAE 
Treatment-emergent adverse event 
t½  
Terminal plasma half-life  
Tmax  
Time of the peak plasma concentration  
ULN  
Upper limit of normal  
WHODRUG 
World Health Organization coding system for medications 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 7 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
2. PURPOSE 
2.1 The purpose of this document is to describe in detail the Statistical Plan Analysis of clinical trials 
procedure carried out by Medistat Ltd.  
2.2 This procedure serves Medistat Ltd. as a guiding document for all statistical analyses performed at 
the end of each clinical study. 
2.3 This SAP is adjusted for Vidac Pharma, VDA-CP-03, phase II.  
2.4 This SAP aims to provide details on: sample size calculation, efficacy analyses, safety analyses, 
exploratory analyses and PK analysis. 
  
3. SCOPE 
3.1 This document applies to all members of the statistical & data management units in Medistat Ltd.  
3.2 This document includes both the main study trial analysis and interim analyses when applicable. 
  
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 8 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
4. RESPONSIBILITIES 
4.1 Medistat Responsibilities  
The following personnel are responsible for these activities: 
 
Activities 
Responsible and 
accountable 
Title 
Statistical Analysis Plan 
(SAP) 
David Israel 
Senior Biostatistician, 
SAS & EDC 
Programmer 
Statistical Report and listing 
appendix 
David Israel 
Senior Biostatistician, 
SAS & EDC 
Programmer 
Quality Assurance (QA)  of 
SAP and programs 
Daphna Goffer 
Senior Biostatistician 
& SAS Programmer 
Quality Assurance (QA)  of 
final report 
Nia Hen 
Quality & Data 
Assurance Manager 
 
4.2 Vidac Pharma's Responsibilities 
4.2.1 
To review and approve the SAP and related documents prior to database lock. 
4.2.2 
To review and approve the draft and final statistical report and listing appendix 
 
 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 9 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5. PROCEDURE 
5.1 Study Objectives and Endpoints 
5.1.1 
Study Objectives  
5.1.1.1 
Primary Objectives: 
5.1.1.1.1 
To compare the reduction on Day 56 in the number of the actinic keratosis (AK) lesions in 
the Treatment Field of subjects receiving once-daily topical 5% or 10% VDA-1102 
ointment for 28 days to the reduction in the number of AK lesions in subjects receiving 
placebo. 
5.1.1.2 
Secondary Objectives: 
5.1.1.2.1 
To evaluate the systemic and local (skin) safety and tolerability of once-daily topical 
application of 5% or 10% VDA-1102 ointment or placebo for 28 days in adult subjects 
with AK. 
5.1.1.2.2 
To assess the systemic exposure of VDA-1102 and jasmonic acid, its primary metabolite, 
at selected time points during topical application of 5% or 10% VDA-1102 ointment or 
placebo for 28 days in adult subjects with AK. 
 
5.1.1.3 
Exploratory Objectives: 
5.1.1.3.1 To compare the proportion of subjects receiving 28 days of 5% or 10% VDA-
1102 who on Day 56 had complete clearance of AK lesions to subjects receiving 
placebo. 
5.1.1.3.2 To compare the reduction on Day 84 in the number of the actinic keratosis (AK) 
lesions in the Treatment Field of subjects receiving once-daily topical 5% or 10% 
VDA-1102 ointment for 28 days to the reduction in the number of AK lesions in 
subjects receiving placebo. 
 
5.1.2 
Study Endpoints  
5.1.2.1 
Primary Efficacy Endpoints: 
5.1.2.1.1 Change from baseline in the number of AK lesions within the Treatment Field of 
each subject on Day 56.  
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 10 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.1.2.2 
Safety Endpoints: 
 
5.1.2.2.1 
Assessment of: 
5.1.2.2.1.1 
AEs 
5.1.2.2.1.2 
Vital signs 
5.1.2.2.1.3 
Physical examinations 
5.1.2.2.1.4 
Clinical laboratory parameters 
5.1.2.2.1.5 
Local Skin Reaction (LSR) Scores (individual and total) 
5.1.2.2.1.6 
Electrocardiograms   
5.1.2.3 
Pharmacokinetic Endpoints:  
5.1.2.3.1 
Assessment of the systemic exposure of VDA-1102 and its primary metabolite jasmonic 
acid at selected time points during topical application of 5% or 10% VDA-1102 ointment for 
28 days in adult subjects with AK 
5.1.2.4 
Exploratory Endpoints: 
5.1.2.4.1 
The percentage of subjects achieving complete clearance of AK lesions within the Treatment 
Field on Day 56 
5.1.2.4.2 
Change from baseline in the number of AK lesions within the Treatment Field of each 
subject on Day 84.  
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 11 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.2 Overall study design and plan 
5.2.1 
Study Design 
5.2.1.1 
This Phase 2 clinical trial is a multi-center, randomized, double-blind, placebo-
controlled, multiple-dose, parallel-cohort study involving the once-daily non-
occluded, topical dermal application of the study drug (5% or 10% VDA-1102 
ointment, or placebo) for 28 days. 
5.2.1.2 
Approximately 84 subjects will be enrolled in this study in order to obtain at least 75 
evaluable subjects by the end of the trial. Fifteen (15) of these subjects will constitute 
a Nested Phase 1b Safety Study Sub-Cohort, and 18 of these subjects will be included 
in a PK Study Sub-Cohort. These 2 sub-cohorts may overlap and are described 
below. 
5.2.1.3 
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 
discrete Grade 1 or 2 AK lesions within a contiguous 25 cm2 area on the scalp or face 
(“the Treatment Field”). Subjects will be randomly assigned in a double-blind fashion 
to 1 of 3 parallel treatment cohorts (5%, or 10% VDA-1102, or placebo, respectively) 
in a ratio of 1:1:1. Randomized subjects will apply a single thin application of the 
study drug to their Treatment Field for 28 days. 
5.2.1.4 
This clinical trial will include 3 study periods: 
5.2.1.4.1 
Screening Period (Day -21 through Day 1 Pre-Dose): 
5.2.1.4.1.1 
During the Screening Visit (up to 21 days pre-dose) subjects who have given written 
informed consent will undergo safety assessments including medical and medication 
histories, adverse event (AE) documentation, vital signs, limited physical examination, 
clinical laboratory testing, 12-lead electrocardiograms (ECGs), dermatologic 
examination, and Treatment Field identification, as well as other qualifying procedures. 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 12 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.2.1.4.1.2 
At the Day 1 Pre-Dose Visit, eligible subjects will return to the investigative site for 
baseline assessments as well as final eligibility screening. The 18 subjects enrolled in the 
PK Study Sub-Cohort (described below) will have a baseline blood sampling for PK 
analysis. Subjects who continue to meet the enrollment criteria will undergo 
randomization to 1 of 3 treatment groups: 5% VDA-1102, 10% VDA-1102, or placebo. 
5.2.1.4.1.3 
Three times during the Screening and Day 1 Pre-Dose Visits, subjects will be trained and 
tested in proper application of the study drug to the Treatment Field with the help of 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 evening. 
5.2.1.4.2 
Treatment Period (Day 1 Dosing through Day 28): 
5.2.1.4.2.1 
During the Day 1 Dosing Visit, randomized subjects (or their dosing partner) will apply 
the first dose of the study drug under the supervision of the site personnel in order to 
further assure proper application. 
5.2.1.4.2.2 
From Day 1 through Day 27, subjects will continue dosing the study drug to their 
respective Treatment Fields each evening while at home. Subjects will visit their 
respective investigative sites on Day 7 and Day 14 for safety and efficacy assessments, 
drug accountability, and re-training in proper application of the study drug. In addition, 
subjects in the PK Study Sub-Cohort will undergo a single blood sampling at 
approximately 12 h after the prior evening's dose. On the Day 28 Visit, subjects will 
return to the clinic for safety and efficacy assessments. Subjects in the PK Study Sub-
Cohort will have timed blood samples taken at approximately 12, 15, 18 and 21 hours 
after their Day 27 evening dose and a 24-hour Holter monitor will be attached. 
5.2.1.4.3 
Observation Period (Day 29 through 84): 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 13 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.2.1.4.3.1 
On Day 35 subjects will return to the site for efficacy and safety assessments. Subjects 
in the PK Study Sub-Cohort will undergo a single untimed blood sampling. Subjects in 
the PK Study Sub-Cohort will have a PK sample drawn at the time of their visit. Subjects 
will return to the sites on Day 56 for efficacy and safety assessments. At the End-of-
Study visit on Day 84, final efficacy and safety assessments will be performed followed 
by discharge from the study. Any subject with active TEAE(s) will be followed beyond 
this scheduled visit until resolution. 
  
Figure 1: Study Design Schematic 
 
 
 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 14 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Table 1. Periods, Study Day, and Visits 
 
PERIODS 
SCREENING 
TREATMENT 
OBSERVATION 
STUDY 
DAYS 
Day -21 to Day -1 
Day 1 
Day 
7±2 
Day 
14±2 
Day 
28±4 
Day 
35 
±2 
Day 
56  
±4 
Day 
84  
±4 
VISITS 
Screening Visit(s) 
Day 1   
Pre-Dose 
Visit 
Day 1 
Dosing 
Visit 
Day 7 
Visit 
Day 14 
Visit 
Day 28 
Visit 
Day 
35 
Visit 
Day 
56 
Visit 
Day 
84 
Visit 
PURPOSE 
• Screening Procedures 
• Baseline Assessments 
• Study drug application testing/ training 
• Randomization 
• PK sampling (PK Study Sub-Cohort) 
• Dosing Study Drug  
• Safety & Efficacy Assessments 
• PK sampling (PK Study Sub-Cohort) 
• Drug accountability 
• Safety & Efficacy 
Assessments 
• Day 35 PK sampling 
(PK Study Sub-
Cohort) 
 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 15 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
 
5.2.2 
Table of Study Assessments 
5.2.2.1 
Table 2 displays Schedule of Assessments for all subjects enrolled in the trial. 
5.2.2.2 
Table 3 displays Schedule of Assessments for subjects enrolled in the PK Study Sub-
Cohort.  
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 16 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Table 2: Schedule of Assessments for all subjects:  
 
Period 
SCREENING 
PERIOD 
TREATMENT PERIOD 
OBSERVATION 
PERIOD 
Study Day 
Day -21 to 
Day -1 
Day 1 
Day 
7±2 
Day 
14±2 
Day 
28±4 
Day   
35±2 
Day  
56±4 
Day  
84±4 
Procedure\Visit 
Screening 
Day 1   
Pre-Dose 
Day 1 
Dosing 
Day 7 
Day 14 
Day 28 
Day  
35 
Day 
56 
Day 
84 
ICF procedures, signature, dating confirmed 
√ 
 
 
 
 
 
 
 
 
Enrollment criteria and/or safety data review 
√ 
√ 
 
 
 
 
 
 
 
Demographics and Medical History 
√ 
 
 
 
 
 
 
 
 
Adverse events reporting 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Concomitant medications recorded 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Vital signs 
√ 
√ 
 
√ 
√ 
√ 
√ 
 
 
Physical examination 
√ 
√ 
 
√ 1 
√ 
√ 
√ 
 
 
Height / Weight / BMI calculated 
√ 
 
 
 
 
 
 
 
 
12-Lead ECG 
√ 
√ 
 
√ 1 
√ 
√ 
 
 
 
Clinical laboratory testing 
√ 
√ 
 
√ 1 
√ 
√ 
 
 
 
Fitzpatrick skin type 
 
√ 
 
 
 
 
 
 
 
Treatment Field Selection 
√ 
√ 
 
 
 
 
 
 
 
AK lesions in the Treatment Field count and 
grade 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Local Skin Reaction Score 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Study drug measurement & application review 
√ 
√ twice 
 
√ 
√ 
 
 
 
 
Pregnancy test (urine) at the site 
√ 
√ 
 
 
 
√ 
 
√ 
 
Subject randomization 
 
√ 
 
 
 
 
 
 
 
Application of the study drug each evening 
 
 
√ Day 1 through Day 27 
 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 17 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Period 
SCREENING 
PERIOD 
TREATMENT PERIOD 
OBSERVATION 
PERIOD 
Study Day 
Day -21 to 
Day -1 
Day 1 
Day 
7±2 
Day 
14±2 
Day 
28±4 
Day   
35±2 
Day  
56±4 
Day  
84±4 
Procedure\Visit 
Screening 
Day 1   
Pre-Dose 
Day 1 
Dosing 
Day 7 
Day 14 
Day 28 
Day  
35 
Day 
56 
Day 
84 
Supervised study drug application at the site 
 
 
√ 
 
 
 
 
 
 
Trial instruction review / Closure procedure 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Telephone contact by study staff 
 
Once-weekly communication between site visits 
 
 
 
Photographs of Treatment Field (at selected 
sites only) 
 
√ 
 
 
 
 
 
√ 
√ 
Study drug & tools given subject, as needed 
 
 
√ 
√ 
√ 
 
 
 
 
Study drug accountability/dosing compliance 2 
 
√ 
 
√ 
√ 
√ 
 
 
 
 
1 Only subjects enrolled in the Phase 1b Safety Cohort will undergo these assessments. 
2 Weigh study tube / record dates of any doses missed between Days 1 and 28 
 
 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 18 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Table 3: Schedule of Assessments for PK Study Sub-Cohort:  
  
 
Period 
SCREENING 
PERIOD 
TREATMENT PERIOD 
OBSERVATI
ON PERIOD 
Study Day 
Day -21 to 
Day -1 
Day 1 
Day 
7±2 
Day 
14±2 
Day 
28±4 
Day 
35±2 
Day 
56±4 
Procedure\Visit 
Screening 
Day 1   
Pre-Dose 
Day 1 
Dosing 
Day 7 
Day 14 
Day 28 
Day 35 
Day 56 
Additional Exclusion Criteria 
√ 
 
 
 
 
 
 
 
24-hour Holter monitor attached 
 
 
 
 
 
√ 
 
 
Blood sampling for PK 
 
√ 
 
√ 
√ 
4 √ 
√ 
 
 
 
5.2.3 
Nested Phase 1b Safety Sub-Cohort  
The first 15 (PK and non-PK) subjects enrolled in the trial will undergo on Day 7 the safety 
examinations planned for all other subjects plus a physical examination, clinical laboratory tests, 
and an ECG assessment. Once all 15 subjects in this Nested Phase 1b Safety Sub-Cohort have 
completed their Day 7 Visit, available blinded safety data (including AEs, LSR scores, clinical 
laboratory results, and ECG data) from Day 1 through Day 7 will be reviewed within 10 business 
days by a safety committee consisting of 3 Board-certified physicians not involved in the trial and 
the Study Medical Monitor. During this blinded interim safety review, enrolled subjects will 
continue dosing the study drug and study enrollment will remain open.  
5.2.4 
PK Study Sub-Cohort 
 


 
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PAGE: 19 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.2.4.1 
Of the approximate 84 subjects to be enrolled in this trial, a maximum of 18 subjects 
(who meet more stringent enrollment criteria than the other subjects enrolled) at select 
sites, will undergo blood sampling for PK analysis on Day 1 Pre-Dose as well as on 
Days 7, 14, 28, and 35 . In addition, these subjects will undergo 24-hour cardiac 
Holter monitoring on Day 28 so that ECGs may be extracted based upon the other 
safety findings and the plasma PK data.   
5.2.4.2 
Subjects included in this Sub-Cohort may also be included in the Nested Phase 1b 
Safety Sub-Cohort if they are one of the first 15 subjects to be enrolled into the study. 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 20 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.2.5 
Randomization, Blinding and Un-blinding 
5.2.5.1 
Assignment of study drug will be performed using a web-based Interactive 
Responsive Technology (IRT)-based randomization system (TrialMaster, 
OmniComm Systems, Fort Lauderdale, FL USA) . On Day 1 Pre-dose Visit, after 
confirming the subject’s eligibility, the Investigator (or his designee) may approve the 
subject’s blinded randomization.  
5.2.5.2 
The web-based IRT will randomize subjects in a fashion that will maintain a balance 
among the 3 treatment groups (5% and 10% VDA-1102, and placebo) across all 
subjects enrolled (not per site) and within the PK Study Sub-Cohort. (For further 
details see "VDA-CP-03 final randomization plan v1.1 15-06-2016.docx") 
5.2.5.3 
Subjects who withdraw or are terminated after the first study dose has been applied 
will not be replaced in the trial. Subjects who withdraw or are terminated before the 
first study dose has been applied due to error or violation of an enrollement criterion 
will be replaced and not included in the Intent-To-Treat (ITT) population.  
5.2.5.4 
All site staff at the investigative sites, Sponsor, CROs, and vendors as well as all 
enrolled subjects will be masked to the study drug assignments throughout the trial. 
One pre-designated statistician at MediStat (Tel Aviv, Israel) will have access to the 
blinded treatment assignments and be responsible for all activities that require un-
blinding, including the per protocol Interim Efficacy Analysis. 
5.2.5.5 
In the event of an emergency, the Investigator (or designee) should contact the Study 
Medical Monitor to discuss the case before un-blinding of an individual subject’s 
treatment code is broken by the site. If the medical condition of the subject warrants 
immediate un-blinding, the treatment assignment of the subject may be obtained from 
the IWRS without first consulting the Study Medical Monitor. However, the site must 
contact the Study Medical Monitor as soon as possible after the un-blinding.  
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 21 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.3 Selection of Study Population 
5.3.1 
Study Population 
5.3.1.1 
In this clinical protocol, study drug will be applied once-daily for 28 days to the 
Treatment Field on the scalp or face of subjects with AK. Approximately 84 male 
and female subjects aged 18 or older with 4-8 discrete Grade 1 and/or 2 AK lesions 
who sign informed consent and meet the study enrollment criteria will be randomly 
assigned in a double-blinded fashion to 1 of 3 parallel treatment cohorts (5% or 10% 
VDA-1102 ointment, or placebo) at a ratio of 1:1:1.  
5.3.2 
Sample Size Justification 
5.3.2.1 
The primary objective of the trial is to compare the reduction on Day 56 in the number 
of the AK lesions (or % reduction if baseline measure will be found different between 
the groups) in the Treatment Field of subjects receiving 5% or 10% VDA-1102 
ointment to the reduction in the number of AK lesions in subjects receiving placebo. 
The sample size calculation was based on demonstrating effect size of 0.83 using a 
two group t-test with a 0.045 two-sided significance level. The total significance level 
of 5% was divided between the interim analysis 0.5% (0.005) and the final analysis 
4.5% (0.045). The sample size calculation was based on the final significance. The 
spending function calculation for alpha will be performed using the O'Brien-Fleming 
approach. Assuming a drop-out rate of 10%, approximately 84 subjects will be 
recruited in order to complete the study with a sample of approximately 75 evaluable 
subjects.  
5.3.2.2 
A sample size of 25 in each group will have 80% power to detect an effect size of 
0.83 using a two group T-test with a 0.045 two-sided significance level. 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 22 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.4 Statistical Analysis Software 
5.4.1 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, 
and graphical representations will be performed using SAS® version 9.3 or higher for 
Windows. If the use of other software is warranted, the final statistical methodology 
report will detail what software was used for what purposes. 
5.4.2 
Data Management 
5.4.2.1 
The EDC system that will be used in the study is TrialMaster® (OmniComm 
Systems, Inc., Fort Lauderdale, FL, USA). It is a web-based software solution that 
allows clinical trial Sponsors and investigative sites to easily and securely collect, 
validate, transmit and analyze clinical study data. The system will be developed using 
OmniComm TrialMaster® EDC platform version: 4.2.1.23. OmniComm 
TrialMaster® EDC platform is compliant with the Food and Drug Administration 
(FDA) 21 CFR Part 11 regulations - electronic records; electronic signatures (last 
revised 01-Apr-2014)  
5.4.2.2 
Cardiac data should be transferred to eRT (eResearch Technology, Inc., Philadelphia, 
PA) the same day the data are obtained, if possible. Central Laboratory samples 
should be shipped to Clinical Reference Laboratory (Kansas, USA) on a daily basis, 
if possible, unless specific holiday or weekend schedules are in effect .  
5.4.2.3 
Data should be entered into the EDC (or paper CRF) within 5 business days of the 
study visit; queries should be appropriately addressed within 3 business days of 
receipt. During data cleaning and preparations for data lock, queries must be 
appropriately addressed by the site in a timely manner (2-3 business days). 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 23 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.4.3 
Coding 
5.4.3.1 
Concomitant medications entered into the database will be coded using the WHO 
(World Health Organization) Drug Public Website Dictionary named WHOCC-
ATC/DDD index, which employs the Anatomical Therapeutic Chemical 
classification system.  
5.4.3.2 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 19.1 terminology or higher. 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 24 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.4.4 
Handling of Missing Data 
5.4.4.1 
Assuming the scope of missing data of the primary efficacy endpoint will be 
significant, data imputation will be applied. Missing data at random imputation 
(MAR) will be performed for those subjects with missing efficacy data. Multiple 
imputation will be applied using SAS PROC MI to perform the imputations. 
Sensitivity analysis will be used for detecting differences between the analyses with 
and without data imputation. 
5.4.5 
Protocol Violations and Deviations 
5.4.5.1 
Violation – Any enrolled subject who does not meet the study enrollment criteria (see 
Inclusion and Exclusion Criteria in Section 8 in the study protocol) will be considered 
a violation.  
5.4.5.2 
Deviation – Any activity that diverges from the procedures defined by this clinical 
protocol will be considered a deviation.  
5.4.5.2.1 
A major deviation is one that will definitely, probably or possibly significantly impact the 
subject safety or the quality of the trial data. Major deviation includes: 
5.4.5.2.1.1 
Subject was reduced to every other day dose by investigator at any point during the study 
5.4.5.2.1.2 
Subject who received study drug dosing on fewer than 20 days. The number of days of 
dosing will be based upon: (a) the “start dose date” and “stop dose date” days and (b) the 
compliance data reported in the EDC from the subject diaries and coordinator telephone 
calls.  Subjects who received 1 or 2 doses of study drug on Day 1 Dosing will both be 
considered having been dosed once, not twice, for this calculation only. 
5.4.5.2.2 
A minor deviation is one that does not, or is unlikely to, significantly impact subject safety 
or the quality of the trial data.  
5.4.5.3 
All violations and deviations must be recorded in the study site’s electronic system 
and signed by the Investigator (or designee).  
5.4.5.4 
It is the Sponsor’s responsibility to determine whether the event will be considered a 
violation, major deviation, or minor deviation. 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 25 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 26 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.5 Subject Population for Analyses 
5.5.1 
Intent-to-Treat Population  
5.5.1.1 
The ITT population will be defined as all subjects who are randomized and who 
receive at least one dose of study drug. This is an appropriate population for the 
primary analysis and for exploratory analyses because this is a blinded trial and the 
1st dose will be applied in the clinic by the research clinic staff per protocol.  
5.5.1.2 
All safety analyses will be performed on the ITT population. Subjects will be 
analyzed according to the treatment actually received, not the treatment they were 
supposed to have received. 
5.5.2 
Modified ITT (mITT) Population  
5.5.2.1 
The mITT population includes all ITT patients who completed the study and have 
protocol deviations or protocol violations that are not expected to significantly impact 
efficacy (e.g. the total treatment area > or < 25 cm2).  
5.5.2.2 
The mITT population will also be used for the primary efficacy endpoint analysis.  
5.5.2.3 
The mITT population will also be used for exploratory analyses. Analyses on Day 56 
will include mITT subjects who completed Day 56 regardless of whether or not they 
also completed Day 84, and analysis on Day 84 will include mITT subjects who 
completed Day 84. 
5.5.3 
Per-Protocol Population  
5.5.3.1 
The PP population includes all ITT patients who have no violations or major protocol 
deviations.  
5.5.3.2 
The PP population will also be used for the primary efficacy endpoint analysis.  
5.5.3.3 
The PP population will also be used for exploratory analyses. Analyses on Day 56 
will include PP subjects who completed Day 56 regardless of whether or not they also 
completed Day 84, and analysis on Day 84 will include PP subjects who completed 
Day 84. 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 27 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.5.4 
Pharmacokinetic Population  
5.5.4.1 
The subjects (maximum of 18) enrolled in the PK Study Sub-Cohort at 
approximately 3 sites will constitute the PK population. 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 28 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6 Statistical Analysis 
5.6.1 
General 
5.6.1.1 
All measured variables and derived parameters will be listed individually and, if 
appropriate, tabulated by descriptive statistics. For categorical variables summary 
tables will be provided giving sample size, absolute and relative frequency and 95% 
CI (Confidence Interval) for proportions (if appropriate) by treatment group. For 
continuous variables summary tables will be provided giving sample size, arithmetic 
mean, standard deviation, coefficient of variation CV% (if appropriate), median, 
minimum and maximum and 95% CI (Confidence Interval) for means of variables 
(if appropriate) by treatment group. The data will be analyzed using the SAS ® 
version 9.3 or higher (SAS Institute, Cary North Carolina). Analyses presented in the 
clinical report but not mentioned in the SAP are unplanned or ad-hoc analyses. 
5.6.1.2 
Statistical methods presented in the SAP may be slightly different from those that are 
presented in the protocol. Differences are clearly stated in this SAP which supersedes 
the protocol only with regard to the way data will be handled and analysed. 
5.6.2 
Derived Data 
5.6.2.1 
Definition of baseline 
5.6.2.1.1 
Baseline is defined as the last non-missing value prior to the patient start of treatment (i.e., 
Day1 Pre-dose, if available, otherwise Screening). All tabulations involving change from 
baseline data will only include patients with data at baseline and at follow-up. 
5.6.2.2 
End of Study  
5.6.2.2.1 
The end-of-study visit is defined as Day 56 for protocol Version 1 and protocol amendment 
1 and as Day 84 for protocol Amendment 2.  
5.6.2.3 
Early Termination  


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 29 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.2.3.1 
If a subject who received at least 1 dose of the study drug wishes to withdraw from the trial, 
study staff should ask the subject to complete as many as possible of the planned evaluations 
scheduled through Day 84, as appropriate. If the subject declines, the subject should be asked 
to undergo the Day 28 safety and efficacy procedures.  
5.6.2.4 
Incomplete dates 
5.6.2.4.1 
All incomplete dates will be entered in the database as they were recorded in the CRF.  
Thereafter, for calculation purposes, the incomplete dates will be completed using pre-
defined rules.  If a day or month is recorded as UNK it will be replaced by the first day of the 
month or January respectively, provided this does not contradict any other dates recorded.   
 
5.6.3 
Disposition of subjects (Table 14.1-1 – 14.1-2) 
5.6.3.1 
The number of subjects that randomized into the study, the number of subjects in the 
ITT, mITT and PK populations, and the number of study completers will be 
presented. 
5.6.3.2 
The reasons for early termination/ withdrawal and any randomization errors will be 
summarized. 
 
5.6.4 
Demographic and Baseline data (Tables 14.1-3 -14.1-6) 
5.6.4.1 
Baseline and demographic data will be summarized in appropriate tables by treatment 
group and overall using the ITT population. These data includes demographic 
characteristics (age, gender, ethnicity and race), weight, height, BMI, medical history 
and disease-related information. 
. 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 30 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.5 
 Efficacy Primary Analysis  
5.6.5.1 
The efficacy analysis will be performed with the ITT, mITT and PP populations (see 
Tables 14.2-1 - 14.2-9). The primary efficacy endpoint is the decrease from baseline 
in number of AK lesions. The within-group decrease in number of AK lesions from 
baseline to each visit will be analyzed using paired t-test or signed rank test for two 
means (paired observations, as is appropriate).  
5.6.5.2 
Comparative analysis of the decrease at Day 56 (mentioned above) will be applied 
between each of the active groups versus the placebo group using the two-sample t-
test, the non-parametric Wilcoxon-Mann-Whitney rank sum test for independent 
samples, or the Median test (as appropriate) and using the Analysis of Covariance 
(ANCOVA), after optionally ranking transformation of the variable, with adjustment 
for sites and for other covariates suspected as affecting the outcome and which will 
be found different between the treatment groups.  
5.6.5.3 
Figures depicting the number of lesions by visit and by treatment group and depicting 
the reduction in number of lesions from Baseline to Day 56 will be generated 
5.6.5.4 
Binary variable will be defined based on the decrease in number of AK lesions at Day 
56 according to a relevant cutoff (first quartile, median, third quartile or other cutoff 
computed by ROC curve sensitivity analysis). Comparative analysis of this variable 
will be applied between each of the active groups versus the placebo group using Chi-
square test or Fisher's Exact test and using logistic regression with adjustment for site 
and for other covariates suspected as affecting the outcome and which will be found 
different between the treatment groups. 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 31 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.5.5 
If the two active VDA-1102 groups trend similarily then these two groups may be 
pooled and compared to the placebo group in order to achieve higher statistical power.  
5.6.5.6 
The overall effect and trend of differences in the decrease over time between the 
groups will be analyzed using a mixed-effect model for repeated measures. The 
model will include decrease from baseline at any time, the fixed effect time, and the 
interaction of treatment and time. Contrast will be calculated for each time point 
(Days 7, 14, 28 and 56) versus baseline and the overall effect. The model will be 
adjusted for site and for other covariates suspected as affecting the outcome and 
which will be found different between the treatment groups.  
5.6.5.7 
For the ANCOVA analysis, logistic regression and mixed-effect model for repeated 
measures detailed above, if necessary, grouping of sites will be done based on 
similarities and differences observed between sites by post-hoc contrasts of ANOVA.  
5.6.6 
Exploratory Analysis  
5.6.6.1 
Two  new variables will be defined and all comparative analyses that were done for 
the primary analysis above will be repeated for these two new variables: 
5.6.6.1.1 
 The number of grade ≥ 2 lesions  
5.6.6.1.2 
An adjusted number of lesions weighted by grade. The weighted grade  will be computed as 
follows: (Number of grade I lesions) + (2 × Number of grade II lesions) + (3 × Number of 
grade III lesions). 
5.6.6.2 
Comparative analysis of the decrease in number of grade ≥ 2 lesions will be applied 
on a sub-group of subjects with at least one grade ≥ 2 lesion at baseline. 
5.6.6.3 
Figures displaying the reduction in number of grade ≥ 2 lesions and the reduction of 
adjusted number of lesions weighted by grade from Baseline to Day 56  will be 
generated. 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 32 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.6.4 
Chi-square test or Fisher’s exact test (as is appropriate) will be used for analyzing the 
difference in percent of subjects with complete clearance of study AK lesions at Day 
56 between each of the active groups versus the placebo group. Logistic regression 
will be applied for analyzing the difference in proportions of  complete clearance with 
adjustment for site and for other covariates suspected as affecting the outcome and 
which will be found different between the treatment groups.  
5.6.6.5 
All analyses mentioned above on complete clearance will be performed on ≥75% 
clearance, ≥50% clearance and  ≥ overall median% clearance as well. 
5.6.6.6 
Analyses mentioned above on complete clearance will be performed on clearance of 
grade ≥ 2 lesions as well. 
5.6.6.7 
The within-group decrease in number of AK lesions from baseline to each visit will 
be analyzed using paired t-test or signed rank test for two means (paired observations, 
as is appropriate) on the Day 84 completers subgroup. 
5.6.6.8 
Comparative analysis of the decrease in number of AK lesions from baseline to day 
84 will be applied between each of the active groups versus the placebo group using 
the two-sample t-test, the non-parametric Wilcoxon-Mann-Whitney rank sum test for 
independent samples, or the Median test (as appropriate).  
5.6.6.9 
The effect of compliance (e.g. days dosed and tube weight) on the primary endpoint 
will be tested by sensitivity analysis. If the effect of compliance will be found 
significant, two additional analyses will be performed: 
5.6.6.9.1 
 Analysis of Covariance (ANCOVA) will be applied in order to test the differences in change 
in number of AK lesions between the treatment groups adjusted for subject compliance. This 
analysis is included in primary analysis (see 5.6.3.2) 
5.6.6.9.2 
A relevant compliance cutoff will be computed and a stratified analysis will be performed 
according to this cutoff. 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 33 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.7 
Safety analysis 
5.6.7.1 
All safety data will be summarized for the ITT population.  
5.6.7.2 
Adverse events will be coded according to coding dictionaries (MedDRA version 
19.1 or higher) and presented in tables by System Organ Class (SOC) and Preferred 
Term (PT) and by treatment group.  
5.6.7.3 
Secondary analysis  
5.6.7.3.1 
The within-group changes from baseline to each visit in the Composite Local Skin Reaction 
score and in all of its components will be analyzed using Paired t-test or Signed- rank test for 
two means (paired observations, as is appropriate). 
5.6.7.3.2 
The within-group changes from baseline to each visit in the Composite Local Skin Reaction 
score and in all of its components will be analyzed using Paired t-test or Signed- rank test for 
two means (paired observations, as is appropriate) on the Day 84 completers subgroup. 
5.6.7.3.3 
A figure of the Composite Local Skin Reaction score, of the erythema component, and of 
the edema component by visit and by treatment group will be generated. 
5.6.7.4 
The incidence of AEs and TEAEs, as well as the intensity and relationship to study 
drug will be summarized by treatment group. 
5.6.7.5 
Safety will also be assessed by evaluating findings of physical examinations, vital 
signs, clinical laboratory test results, 12-lead ECG tracings, concomitant medications, 
and withdrawals/terminations/drug holiday/dosing adjustment by treatment group.  
5.6.7.6 
ECG data will be derived from 12-lead ECG tracings (and from cardiac Holter 
monitoring recordings, if appropriate).  
5.6.7.7 
Summary statistics for observed measures and changes from pre-dose in the 
following ECG variables will be tabulated at each post-baseline visit: 
5.6.7.7.1 
Heart rate (bpm) 
5.6.7.7.2 
PR interval (ms)  
5.6.7.7.3 
QRS complex (ms)   
5.6.7.7.4 
QT interval (ms)  


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 34 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.7.7.5 
QTcF interval (ms) 
5.6.7.7.6 
QTcB interval (ms) 
5.6.7.8 
The mean from Day 1 Pre-dose will serve as the ECG baseline to which all post dose 
ECG data will be compared.  If the Day 1 value is missing, the Screening Visit value 
will be used as baseline.  
5.6.7.9 
For QT, QTcB and QTcF, absolute and relative frequency of patients with absolute 
result ≥ 500 ms at each visit will be displayed. 
5.6.7.10 
The changes from baseline in vital signs, ECG derived variables, clinical laboratory 
tests results will be analyzed by treatment group, using the Paired T-test if data is 
considered normally distributed or using the non-parametric Signed rank test (paired 
observations) if considered non-normal. 
5.6.7.11 
For QT, QTcB and QTcF (ECG data), absolute and relative frequency of increase 
above baseline divided into three categories  < 30 ms, 30-60 ms and > 60 ms at each 
visit will be displayed. 
5.6.7.12 
Concomitant medication verbatim terms (as recorded on the CRFs) will be coded to 
Anatomical Therapeutic Chemical (ATC) Level 2 and 4 using the World Health 
Organization (WHO) dictionary.  
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 35 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
 
5.6.8 
PK Analysis 
5.6.8.1 
Non-compartmental PK will be calculated where applicable, if there are sufficiently 
high concentrations of VDA-1102 and/or its main metabolite for consistent 
calculations, using appropriate software. The PK sub-cohort including up to 18 
subjects will be used. 
5.6.8.2 
The following PK parameters will be calculated: 
5.6.8.2.1 
C0 – Pre-dose plasma concentration; 
5.6.8.2.2 
Cmax - Maximum plasma concentration; 
5.6.8.2.3 
Tmax - Time to reach the maximum plasma concentration; 
5.6.8.2.4 
AUClast - Area under the plasma concentration-time curve from time of administration up to 
the last time point with a measurable concentration post dosing, calculated by linear up-
logarithmic down trapezoidal summation. 
5.6.8.2.5 
AUC∞ - Area under the plasma concentration-time curve extrapolated to infinity, calculated 
as: AUC∞ = AUClast + Clast/λz, where Clast is the last measurable concentration.  
5.6.8.2.6 
λz - Elimination rate constant, determined by linear regression of the terminal points of the 
ln-linear plasma concentration-time curve; 
5.6.8.2.7 
T1/2 - Terminal elimination half-life, defined as 0.693/λz; 
 
 
5.6.8.3 
Total AUC is calculated by summation of partial AUCs using the trapezoidal rule. 
5.6.8.4 
An individual segment (AUCi) is calculated using the following formulation: 
 
AUC1 = ( (C0 + C1) X Time1-0 ) / 2 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 36 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.8.5 
Where:  
5.6.8.5.1 
C0 is the concentration measured on time 0 
5.6.8.5.2 
C1 is the concentration measured on time point 1 (the next time point) 
5.6.8.5.3 
Time1-0 is the time difference between time 1 and time 0. 
5.6.8.6 
The total AUC equals a summation of all partial AUC segments. 
 
5.6.8.7 
The calculated PK parameters as well as the raw data used for the calculations will be 
transferred to MediStat for generating a statistical report. 
5.6.8.8 
Medistat will further QA the data before generating the report. The QA will include 
checking for outlier measures and missing data.  
5.6.8.9 
MediStat will prepare a statistical report based on the raw data and the calculated PK 
parameters.  
5.6.8.10 
The data will be treatment blinded. Following data lock the treatment codes will be 
exposed and merged into the data and to be included in the statistical report 
5.6.8.11 
The report will include: 
5.6.8.11.1 Summary tables of VDA-1102 and jasmonic acid plasma concentration by treatment and 
time point 
5.6.8.11.2 Summary tables of PK parameters by treatment. 
5.6.8.11.3 Individual listings of VDA-1102  and jasmonic acid plasma concentration 
5.6.8.11.4 Individual listings of PK parameters 
5.6.8.11.5 Graphical displays presenting mean concentration by time point 
5.6.8.11.6 Individual figures presenting concentration by time point 
    


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 37 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
5.6.8.12 
Summary tables will be presented including sample size (N), mean, standard 
deviation, standard error, median, minimum and maximum values and 95% 
confidence intervals by treatment.  
5.6.8.13 
The data will be analysed using the SAS ® version 9.3 (SAS Institute, Cary North 
Carolina). 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 38 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
6. RELATED DOCUMENTS  
6.1 Internal Documents  
Not Applicable 
6.2 External documents 
 
6.2.1 
VDA-CP-03 P2a 09June2016_DI,pdf 
6.2.2 VDA-CP-03 Listing appendix of 029-BST-SOP-002  
6.2.3 VDA-CP-03 Tables appendix of 029-BST-SOP-002   


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 39 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
7. RELATED FORMS  
Not Applicable 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 40 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
 
8. REFERENCES 
Not Applicable 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 41 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
9. APPENDICES  
APPENDIX I: TABLE SHELLS 
Table 14.1-1: Subject Disposition 
Table 14.1-2: Demographic Data 
Table 14.1-3: Frequency of Medical History (except Actinic Keratosis) by Category 
Table 14.1-4: Any Medications within 30 Days Prior to Screening 
Table 14.1-5: Any Medications between Screening and Day 1 Dosing Visit 
Table 14.1-6: Disease-related information  
Table 14.1-7: Dermatological Evaluation at Pre-dose 
Table 14.1-8: Compliance Data  
Table 14.2-1: AK Lesions Count in ITT Population 
Figure 14.2-1: Total Number of Lesions by Visit and by Study Group in ITT Population 
Figure 14.2-2: Number of AK Grade ≥ 2 lesions by Visit and by Study Group in ITT Population 
Figure 14.2-3: Adjusted Number of Lesions by Visit and by Study Group in ITT Population 
Table 14.2-2: AK Lesions Count in mITT Population 
Table 14.2-3: AK Lesions Count in PP Population 
Table 14.2-4: AK Lesions Number: Absolute Changes from Baseline in ITT Population 
Table 14.2-5: AK Lesions Number: Changes from Baseline in mITT Population 
Table 14.2-6: AK Lesions Number: Changes from Baseline in PP Population 
Table 14.2-8: AK Lesions Number: Changes from Baseline for Day 84 Completers 
Table 14.2-9: AK Lesions Number: Relative Changes from Baseline in ITT Population (%) 
Table 14.2-10: AK Lesions Number: Relative Changes from Baseline in mITT Population (%) 
Table 14.2-11: AK Lesions Number: Relative Changes from Baseline in PP Population (%) 
Table 14.2-12: AK Lesions Number: Relative Change from Baseline for Day 84 Completers 
Table 14.2-13: Frequency of Decrease in AK lesions at Day 56 ≥ Cutoff Computed by Sensitivity Analysis/ Relevant Quartile in ITT 
Population 
Table 14.2-14: Frequency of Decrease in AK lesions at Day 56 ≥ Cutoff Computed by Sensitivity Analysis/ Relevant Quartile in mITT 
Population 
Table 14.2-15: Frequency of Decrease in AK lesions at Day 56 ≥ Cutoff Computed by Sensitivity Analysis/ Relevant Quartile in PP 
Population 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 42 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Table 14.2-16: AK Lesions Number: Change in Number of AK Grade ≥ 2 Lesions on Patients with at least one Grade ≥ 2 Lesion at 
Baseline (ITT Population)  
Table 14.2-17: AK Lesions Clearance (ITT Population)  
Table 14.2-18: AK Grade ≥ 2 Lesions Clearance (ITT Population)  
Table 14.2-19: ANCOVA Model at Day 56 (ITT Population)  
Table 14.2-20: Mixed Model for Repeated Measures (ITT Population)  
Table 14.2-21: Logistic Model for Change in Total Number of Lesions ≥ cutoff XX at Day 56 (ITT Population)  
Table 14.2-22: Logistic Model for Change in Number of AK Grade ≥ 2 lesions ≥ cutoff XX (ITT Population)  
Table 14.2-23: Logistic Model for Change in Adjusted Number of Lesions Weighted by Grade (ITT Population)  
Table 14.2-25: Logistic Model for Complete Clearance at Day 56 (ITT Population)  
Table 14.2-26: Logistic Model for 75% Clearance at Day 56 (ITT Population)  
Table 14.2-27: Logistic Model for 50% Clearance at Day 56 (ITT Population)  
Table 14.2-28: Logistic Model for XX% Clearance at Day 56 (XX is the median of  clearance percent  in all patients ) (ITT Population)  
Table 14.2.29 Summary of PK Parameters from VDA-1102 
Table 14.2.31 Summary of PK Parameters from Jasmonic Acid 
Table 14.3.1-1: Incidence of Adverse Events 
Table 14.3.1-2: Summary of Adverse Events  
Table 14.3.1-3: Summary of Adverse Events by Relationship to Study Medication 
Table 14.3.1-4: Summary of Adverse Events by Severity  
Table 14.3.1-5: Summary of Treatment Emergent Adverse Events  
Table 14.3.1-6: Summary of Treatment Emergent Adverse Events by Relationship to Study Medication 
Table 14.3.1-7: Summary of Treatment Emergent Adverse Events by Severity 
Table 14.3.1-8: Summary of Treatment Emergent Serious Adverse Events 
Table 14.3.5-1: Summary Statistics of Hematology Results 
Table 14.3.5-2: Summary Statistics of Hematology Change from Baseline 
Table 14.3.5-3: Summary Statistics of Chemistry Results 
Table 14.3.5-4: Summary Statistics of Chemistry Changes from Baseline 
Table 14.3.5-5: Summary Statistics of Coagulation Results 
Table 14.3.5-6: Summary Statistics of Coagulation Change from Baseline 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 43 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Table 14.3.5-5: Frequency of Urinalysis Results 
Table 14.3.5-6: Summary Statistics of Urinalysis Results 
Table 14.3.5-7: Summary Statistics of Urinalysis Changes from Baseline 
Table 14.3.5-8: Summary Statistics of Vital Signs 
Table 14.3.5-9: Summary Statistics of Vital Signs Change from Baseline 
Table 14.3.5-10: Frequency of Vital Signs Abnormalities 
Table 14.3.5-10: Physical Examination 
Table 14.3.5-11: Shift Tables from Baseline for Physical Examination 
Table 14.3.5-12: ECG  
Table 14.3.5-13: Shift Table for ECG  
Table 14.3.5-14: Individual Components of Local Skin Reaction Score 
Table 14.3.5-15: Local Skin Reaction Score  
Figure 14.3.1 Local Skin Reaction Score by Visit and by Study Group 
Figure 14.3.2 Erythema Component by Visit and by Study Group 
Figure 14.3.3 Edema Componentby Visit and by Study Group 
Table 14.3.5-16: Change in Individual Components of Local Skin Reaction Score from Baseline 
Table 14.3.5-17: Change in Local Skin Reaction Score from Baseline 
Table 14.3.5-18: Any Concomitant Medications 
 
 


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 44 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
APPENDIX II: LISTINGS SHELLS 
Listing 16.2.1-1 Subject Disposition 
Listing 16.2.1-2 Visit Dates per Subject 
Listing 16.2.1-3 Unscheduled Visits per Subject 
Listing 16.2.1-4 Phone Contact with Subject 
Listing 16.2.2-1 Inclusion and Exclusion Criteria Violated 
Listing 16.2.2-2: Protocol Deviations 
Listing 16.2.3-1 Analysis Populations 
Listing 16.2.4-1: Demographic data 
Listing 16.2.4-2: Medical History Data 
Listing 16.2.4-3: Disease-related Information 
Listing 16.2.4-4: Dermatologic Assessment at Baseline 
Listing 16.2.5-1 Exposure Data (Day 1)  
Listing 16.2.5-2 Compliance Data (Days 7, 14, 28)  
Listing 16.2.5-3 Accountability data 
Listing 16.2.6-1: AK lesion count 
Listing 16.2.6-2: PK parameters from Jasmonic Acid 
Listing 16.2.6-3: PK parameters from VDA-1102 
Listing 16.2.6-4: Jasmonic Acid concentrations (ng/mL) by time 
Listing 16.2.7-1 Treatment Emergent Adverse Events 
Listing 16.2.7-2 Other Adverse Events 
Listing 16.2.8-1: Laboratory Tests 
Listing 16.2.8-2: Hematology Results 
Listing 16.2.8-3: Abnormal Hematology Results 
Listing 16.2.8-4: Chemistry Results 
Listing 16.2.8-5: Abnormal Chemistry Results 
Listing 16.2.8-6: Urinary Results 
Listing 16.2.8-7: Abnormal Urinary Results 
Listing 16.2.8-8: Pregnancy tests (females only)  


 
DOCUMENT NUMBER: 029-BST-PLN-001 
PAGE: 45 of 45 
TITLE: Statistical Analysis Plan for study: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Cohort Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Once-Daily Application of Topical VDA-
1102 Ointment for 28 Days in Subjects with Actinic Keratosis 
 
EFFECTIVE DATE : 22/MAY/2017 
REVISION NUMBER : 2.0 
 
Medistat Ltd. Confidential 
 
Listing 16.2.8-9: Vital Signs 
Listing 16.2.8-10: Abnormal Physical Examination 
Listing 16.2.8-11: ECG 
Listing 16.2.8-12: 24 Hour Holter Monitoring (PK population)  
Listing 16.2.8-13: Local Skin Reaction Score 
Listing 16.2.8-14: PK Samples 
Listing 16.2.8-15: Prior Medications Ongoing Within 30 Days before Screening 
Listing 16.2.8-16: Medications Started Between Screening and First Dose 
Listing 16.2.8-17: Concomitant Medications after First Dose 
Listing 16.2.8-18: Additional Comments