Conditions: Cutaneous Common Warts
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 491
Healthy volunteers: no

Brief summary:
To evaluate the efficacy and safety of six (6) weeks of once daily application of Furosemide Topical Gel 0.125% (CLS006) compared to vehicle in subjects ≥ 2 years of age with nongenital cutaneous common warts (verruca vulgaris).

Detailed description:

Arms:
arm 1: Furosemide Topical Gel, 0.125% arm 2: Vehicle Topical Gel

Interventions: intervention 1: CLS006 intervention 2: CLS006 Vehicle
Intervention descriptions: intervention 1: Furosemide Topical Gel intervention 2: Vehicle Topical Gel

Protocol document:
Prot_000.pdf: 
Cutanea Life Sciences, Inc. / IND# 131395 
 
May 23, 2017 
Protocol CLS006-CO-PR-002 
 
Page 1 of 42 
 
 
 
PROTOCOL NUMBER CLS006-CO-PR-002 
Title: 
A Phase 3, Randomized, Double-Blind, Vehicle-Controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of CLS006 versus Vehicle in Subjects 2 years of age or older with Cutaneous 
Common Warts 
 
Test Product: 
Furosemide Topical Gel 0.125% w/w (CLS006) 
 
Sponsor: 
Cutanea Life Sciences, Inc. 
1500 Liberty Ridge, Suite 3000 
Wayne, PA  19087  
 
 
Sponsor Signature:
 
Print Name:
Title:
Kazumasa Hirata, Ph.D. 
Vice President, Corporate Development and Clinical Operations 
 
Date: 
May 23, 2017 
 
  
GCP Statement:   
This study will be conducted in accordance with United States Food and Drug Administration 
(FDA) and International Conference on Harmonization (ICH) guidelines on current Good Clinical 
Practice (GCP). 
Confidentiality Statement 
The confidential information in this document is provided to you, as an investigator or consultant, for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee.  
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Cutanea Life Sciences, Inc. 


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CONFIDENTIAL 
1. 
SYNOPSIS 
Title of Study: A Phase 3, Randomized, Double-Blind, Vehicle-Controlled, Multicenter Study 
to Evaluate the Efficacy and Safety of CLS006 versus Vehicle in Subjects 2 years of age or 
older with Cutaneous Common Warts 
 Phase of Development: Phase 3 
 
Objective:  To evaluate the efficacy and safety of six (6) weeks of once daily application of 
Furosemide Topical Gel 0.125% (CLS006) compared to vehicle in subjects ≥ 2 years of age 
with nongenital cutaneous common warts (verruca vulgaris). 
Methodology: Randomized, double-blind, vehicle-controlled, parallel group, multicenter 
study  
Number of Subjects Enrolled (planned): Approximately 480 (~240 per treatment group) of 
which approximately 160 of subjects enrolled will be pediatric subjects (~80 will be ≥2 to <12 
years of age and ~80 will be ≥12 to <18 years of age). Subjects will be randomized and 
stratified by age (≥2 to <12, ≥12 to <18 or ≥18) and investigative site to one of two treatment 
groups in a 1:1 ratio (CLS006 or vehicle gel). 
Number of Sites (planned): Approximately 40  
Diagnosis and Main Criteria for Inclusion: 
 Male or female subjects 2 years of age or older with 1 to 6 clearly identifiable common 
warts (verruca vulgaris) located on hands (dorsal, periungual, or palmar), feet (dorsal), 
limbs, and/or trunk. 
Total Duration of Subject Participation (Possible): up to 34 weeks  
 Screening: up to four (4) weeks 
 Treatment Period: six (6) weeks  
 Post-treatment Efficacy Evaluation Period: twelve (12) weeks  
 Follow-up Period: additional twelve (12) weeks following Post-treatment Efficacy 
Evaluation Period (only for subjects who achieved clearance of at least one treated 
wart at Week 18/End of Post-treatment Efficacy Evaluation period 
Investigational Product: Furosemide Topical Gel 0.125% w/w (CLS006) 
Comparator Product: Vehicle Topical Gel  
Mode of Administration:  Topical application to each wart 
Dose: Apply a small amount of gel to cover each Baseline Treatment wart once daily  


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CONFIDENTIAL 
Criteria for Evaluation:  
Efficacy:  Wart identification/counts, characteristics, location/mapping, and size.    
Clinical photography will be performed at selected centers (optional for subjects <12 years of 
age)  
Safety:  Adverse Events (AE), vital signs, physical examinations, and clinical safety 
laboratory evaluations as collected throughout the study. 
Statistical Methods: 
Efficacy (Primary):  Difference in the proportion of subjects with complete clearance of all 
treated warts between the active and vehicle at Week 18/End of Post-treatment Efficacy 
Evaluation will be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by age 
group ≥2 to <12, ≥12 to <18 or ≥18) and investigative site.  
Safety: AEs will be coded and tabulated using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by body system and preferred term.  Incidence of AEs 
will be presented overall, by body system and preferred term.  Severity and relationship to 
study drug of the incidence of AEs will also be presented.  AEs causing study drug withdrawal 
and/or early study discontinuation and incidence of SAEs will be summarized. 
Descriptive statistics and frequency tables will be prepared as appropriate for vital signs and 
safety laboratory measurements. 
 
 


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CONFIDENTIAL 
2. 
STUDY CONTACTS 
SPONSOR/CONTRACT COMPANIES 
COMPANY/VENDOR 
ADDRESS/PHONE 
AFFILIATION / RESPONSIBILITIES 
Cutanea Life Sciences, Inc. 
1500 Liberty Ridge 
Suite 3000 
Wayne, PA 19087 
Phone: 484-588-2036 
Sponsor 
PRA Health Sciences  
721 Arbor Way 
Blue Bell, PA 19422 
Phone: 215-591-8000 
CRO responsible for Medical Monitoring and Pharmacovigilance; 
Project and Vendor Management; Clinical Study Site Monitoring 
and Management; Data Management, IWRS, Biostatistics, Medical 
Writing, and Quality Assurance 
Biomedical Systems 
2464 W. Port Plaza 
St. Louis, MO 63146 
Phone: 314-576-6800 
Central ECG Equipment and Interpretation Vendor (as needed) 
Canfield Scientific, Inc. 
4 Wood Hollow Road 
Parsippany, NJ  07054 
Phone : 973-434-1200 
Central Photography Equipment Provider (at select centers) 
Eurofins Central Laboratory US
2425 New Holland Pike 
Lancaster, PA 17605 
Phone: 717-656-2300 
Central Clinical Safety Laboratory 
Xerimis, Inc. 
102 Executive Drive 
Moorestown, NJ  08057 
Phone: 856-727-9940 
Clinical Supply Management and Distribution 
Company representatives’ individual contact information will be maintained on a clinical study 
team contact list  
 
 
 
 


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CONFIDENTIAL 
3. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis Of Covariance 
AST 
Aspartate Aminotransferase 
BOCF 
Baseline Observation Carried Forward 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CLS 
Cutanea Life Sciences, Inc. 
CLS003 
Digoxin 0.125% w/w and Furosemide 0.125% w/w Topical Gel 
CLS006 
Furosemide Topical Gel 0.125% w/w 
CMH 
Cochran-Mantel-Haenszel  
CRO 
Contract Research Organization 
DBT 
Double-blind Treatment 
DNA 
Deoxyribonucleic Acid 
DNCB 
Dinitrochlorobenzene 
DPCP 
Diphenylcyclopropenone (or diphencyprone) 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
HDL 
High-Density Lipoproteins 
HPV 
Human Papillomavirus  
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ICVT 
Ionic Contra-Viral Therapy 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoproteins 
LOCF 
Last Observation Carried Forward 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 


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CONFIDENTIAL 
mg 
Milligram 
mL 
Milliliter 
MI 
Multiple Imputation 
NDA 
New Drug Application 
PI 
Principal investigator 
PP 
Per Protocol 
PTEE 
Post-treatment Efficacy Evaluation 
qPCR 
Quantitative Polymerase Chain Reaction 
RBC 
Red Blood Cell 
RDW 
Red Cell Distribution 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
Sub-I 
Sub-Investigator 
TEAE 
Treatment Emergent Adverse Event 
µg 
Microgram 
WBC 
White Blood Cell 
w/w 
Weight for Weight 
 
 


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CONFIDENTIAL 
4. 
TABLE OF CONTENTS 
                                                                                                                                               Page 
1. 
SYNOPSIS .......................................................................................................................................... 2 
2. 
STUDY CONTACTS ......................................................................................................................... 4 
3. 
LIST OF ABBREVIATIONS ............................................................................................................ 5 
4. 
TABLE OF CONTENTS ................................................................................................................... 7 
5. 
INTRODUCTION ............................................................................................................................ 10 
5.1. 
BACKGROUND ..................................................................................................................................... 10 
5.2. 
RATIONALE ......................................................................................................................................... 11 
6. 
STUDY OBJECTIVE ...................................................................................................................... 12 
7. 
INVESTIGATIONAL PLAN .......................................................................................................... 12 
7.1. 
OVERALL STUDY DESIGN .................................................................................................................... 12 
7.2. 
SELECTION OF STUDY POPULATION .................................................................................................... 13 
7.2.1. 
Inclusion Criteria ........................................................................................................................ 13 
7.2.2. 
Exclusion Criteria ....................................................................................................................... 14 
7.2.3. 
Discontinuation and Withdrawal from Treatment or Study ........................................................ 15 
7.3. 
CONDUCT OF STUDY ........................................................................................................................... 17 
7.3.1. 
Schedule of Visits and Study Assessments ................................................................................... 17 
7.3.2. 
Study Assessments by Visit .......................................................................................................... 18 
7.3.2.1. 
Screening ........................................................................................................................... 18 
7.3.2.2. 
Baseline (Day 1) ................................................................................................................ 19 
7.3.2.3. 
Interim Visits: Week 2 (Day 14) and Week 4 (Day 28) ..................................................... 20 
7.3.2.4. 
Week 6 (Day 42) / End of Treatment (or Early Termination during Double-Blind Treatment 
Period) 
 ........................................................................................................................................... 20 
7.3.2.5. 
Week 12 (Day 84) .............................................................................................................. 21 
7.3.2.6. 
Week 18 (Day 126) / End of Post-Treatment Efficacy Evaluation (or Early Termination during 
Post-treatment Efficacy Evaluation Period .......................................................................................... 21 
7.3.2.7. 
Follow-up# 1 (Week 24) Visit ............................................................................................ 21 
7.3.2.8. 
Follow-up# 2 (Week 30) Visit ............................................................................................ 22 
7.4. 
EFFICACY ASSESSMENTS ..................................................................................................................... 22 
7.4.1. 
Wart Assessments ........................................................................................................................ 22 
7.4.1.1. 
Wart Identification/Characteristics and Location/Mapping ............................................. 22 
7.4.1.2. 
Wart Size ........................................................................................................................... 23 
7.4.1.3. 
Wart Identification/Characteristic and Measurement Guidance ...................................... 23 
7.4.2. 
Clinical Photography .................................................................................................................. 24 
7.5. 
SAFETY AND TOLERABILITY ASSESSMENTS ........................................................................................ 24 
7.5.1. 
Demographics and Medical/Surgical History ............................................................................ 24 


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CONFIDENTIAL 
7.5.2. 
Limited Physical Exam and Vital Signs ...................................................................................... 24 
7.5.3. 
Clinical Safety Laboratory Testing ............................................................................................. 25 
7.5.4. 
Urine Pregnancy Test ................................................................................................................. 25 
7.5.5. 
Electrocardiogram ...................................................................................................................... 25 
7.5.6. 
Adverse Events ............................................................................................................................ 26 
7.5.6.1. 
Definition of Adverse Event ............................................................................................... 26 
7.5.6.2. 
Relationship of Adverse Event to Study Drug ................................................................... 27 
7.5.6.3. 
Severity of Adverse Event .................................................................................................. 27 
7.5.6.4. 
Serious Adverse Event ....................................................................................................... 27 
7.6. 
TEST MATERIALS ................................................................................................................................ 29 
7.6.1. 
Identity of Investigational Products ............................................................................................ 29 
7.6.2. 
Treatment Administration ........................................................................................................... 29 
7.6.2.1. 
Subject Dosing and Use Instructions ................................................................................ 30 
7.6.2.2. 
Treatment Compliance ...................................................................................................... 30 
7.6.3. 
Treatment Assignment................................................................................................................. 30 
7.6.4. 
Blinding ...................................................................................................................................... 30 
7.6.5. 
Packaging ................................................................................................................................... 31 
7.6.6. 
Labeling ...................................................................................................................................... 31 
7.6.7. 
Unblinding a Subject .................................................................................................................. 31 
7.6.8. 
Dispensing and Return of Study Drug ........................................................................................ 31 
7.6.9. 
Accountability ............................................................................................................................. 32 
7.6.10. 
Prior and Concomitant Medication/Treatment ...................................................................... 32 
7.6.10.1. 
Excluded Concomitant Medication/Treatment .................................................................. 32 
7.7. 
STATISTICAL METHODS PLANNED ...................................................................................................... 33 
7.7.1. 
General Considerations .............................................................................................................. 33 
7.7.2. 
Sample Size Determination ......................................................................................................... 33 
7.7.3. 
Randomization ............................................................................................................................ 34 
7.7.4. 
Analysis Populations................................................................................................................... 34 
7.7.5. 
Handling of Missing Data ........................................................................................................... 34 
7.7.6. 
Efficacy Endpoints ...................................................................................................................... 35 
7.7.6.1. 
Primary Endpoint .............................................................................................................. 35 
7.7.6.2. 
Secondary Endpoints ......................................................................................................... 35 
7.7.6.3. 
Tertiary Endpoints............................................................................................................. 35 
7.7.7. 
Efficacy Analysis ......................................................................................................................... 36 
7.7.8. 
Safety Endpoints ......................................................................................................................... 36 
7.7.9. 
Safety Analysis ............................................................................................................................ 36 
7.7.10. 
Multicenter Pooling ............................................................................................................... 37 


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CONFIDENTIAL 
8. 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS ...................................... 37 
8.1. 
ETHICAL CONDUCT OF THE STUDY...................................................................................................... 37 
8.2. 
PROTOCOL ADHERENCE ...................................................................................................................... 37 
8.2.1. 
Changes in Study Conduct/Statistical Analyses/Amendments .................................................... 37 
8.3. 
INSTITUTIONAL REVIEW BOARD /INDEPENDENT ETHICS COMMITTEE ................................................. 37 
8.4. 
SUBJECT INFORMATION AND CONSENT ............................................................................................... 37 
8.5. 
RECORD KEEPING................................................................................................................................ 38 
8.5.1. 
Data Collection ........................................................................................................................... 38 
8.5.2. 
Data Corrections ........................................................................................................................ 38 
8.5.3. 
Source Documentation ................................................................................................................ 38 
8.5.4. 
Monitoring/Auditing ................................................................................................................... 39 
8.5.5. 
Archives ...................................................................................................................................... 39 
8.6. 
CONTRACTUAL REQUIREMENTS .......................................................................................................... 39 
8.7. 
PUBLICATION POLICY .......................................................................................................................... 39 
9. 
REFERENCES ................................................................................................................................. 40 
10. 
INVESTIGATOR AGREEMENT .................................................................................................. 41 
APPENDIX A: Study Drug application instructions .................................................................................... 42 
 
 
 


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CONFIDENTIAL 
5. 
INTRODUCTION 
5.1. 
BACKGROUND 
Human papillomavirus (HPV) refers to a group of DNA tumor viruses that can induce neoplastic 
proliferation of human epithelial cells; this proliferation of cells is commonly known as warts. 
Cutaneous wart diagnosis is generally based on clinical examination, but can be determined by 
histological appearances. Some warts persist for many years and untreated warts represent a pool of 
HPV infection within the community. Many people find warts either unsightly or painful and there is 
considerable social stigma with visible warts. Current clinical treatments for cutaneous HPV 
infections mainly involve lesion destruction. The usual first line treatments are wart paints containing 
salicylic acid and/or cryotherapy, usually with liquid nitrogen. However, current available treatments 
are considered unsatisfactory and there is an unmet need to develop treatments with greater efficacy 
(Kwok, Gibbs, Bennett, Holland, & Abbott, 2012). 
In 2006, Hartley et al. (2006), conducted an in vitro study where the cardiac glycoside, digoxin, and 
loop diuretic, furosemide, known inhibitors of the coupled, cotransports NKATPase and NKCC1, 
inhibited replication of several DNA viruses in various cell types. This novel approach to treating 
DNA viruses by the inhibition of coupled contransporters in the host cell is referred to as Ionic 
Contra-Viral Therapy (ICVT) and is believed to target viral DNA synthesis through inhibition of the 
transport of sodium and potassium across cellular membranes. The disturbances in the intracellular 
environment created by this inhibition are believed to compromise the ability of viruses to proliferate, 
as intracellular K+ is necessary for viral DNA synthesis. This controlled depletion of cellular K+ has 
the potential to provide a novel approach to antiviral therapy (Hartley, Hartley, Pardoe, & Knight, 
2006).   
Initially, Cutanea Life Sciences, Inc. (CLS) evaluated a combination formulation of Digoxin 0.125% 
w/w and Furosemide 0.125%  w/w Topical Gel (CLS003) as well as single-agent formulations, 
Furosemide Topical Gel 0.125% w/w (CLS006) and Digoxin Topical Gel 0.125% w/w for the 
treatment of HPV-associated cutaneous lesions. Subsequently, it was determined that the 
development would focus on the Furosemide Topical Gel 0.125% w/w (CLS006) product.   
CLS is developing Furosemide Topical Gel 0.125% w/w (CLS006) as a treatment for various 
conditions associated with HPV. For the purposes of product development in support of a New Drug 
Application for the treatment indication of nongenital cutaneous warts, common and plantar warts 
(verruca vulgaris and verruca plantaris, respectively) will be studied separately.  Initial investigations 
will focus on nongenital cutaneous common warts (verruca vulgaris).   
Data on topical administration of furosemide is limited. However, orally administered furosemide is a 
frequently prescribed medication worldwide with a well-established safety profile.   


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CONFIDENTIAL 
5.2. 
RATIONALE  
An initial phase I/IIA study (CHDR1323) of the combination Digoxin 0.125% w/w and Furosemide 
0.125% w/w Topical Gel (CLS003) was conducted in Leiden, the Netherlands.  Subjects with 
cutaneous warts applied the study product once daily during a 7-day treatment period with a 7-day 
follow-up period to evaluate the pharmacodynamic response (wart size and morphology assessment 
by standardized clinical photography, and HPV viral load assessment of target lesions by quantitative 
PCR as an exploratory biomarker) and systemic exposure of after repeated topical applications of the 
combination product. Twelve healthy subjects with multiple cutaneous warts on the hands were 
enrolled in the study. This study showed that doses of 1000 mg CLS003 (equivalent to 1250 µg 
digoxin and 1250 µg furosemide) were well tolerated by the subjects and did not result in any 
clinically significant changes in any safety laboratory parameters, vital sign measures or 
electrocardiogram (ECG) recordings. All pharmacokinetic measurements, except for one furosemide 
measurement (Day 7, 2 hours post-dose of 91.1 pg/mL), were below the limit of quantification (50 
pg/mL).  No treatment related study discontinuations occurred.  The most frequent occurring adverse 
events (AEs) were headache, application site erythema and application site pruritus observed in 3/12 
(25%), 2/12 (16.7%) and 2/12 (16.7%) respectively, of the treated subjects; all were mild in severity. 
A follow-up phase II study (CHDR1423) was also conducted in Leiden, the Netherlands to explore 
the efficacy and safety of the combination Digoxin 0.125% w/w and Furosemide 0.125% w/w 
Topical Gel (CLS003) as well as single-agents Furosemide Topical Gel 0.125% w/w (CLS006) and 
Digoxin Topical Gel 0.125% w/w for treatment of cutaneous warts.  This was a randomized, 
double-blind, vehicle-controlled study in 80 subjects who were treated with study product daily for 42 
days with an 8-week follow-up period.  All active treatment groups (combination and single-agent) 
showed effects on wart size including statistically significant reductions in dimensions of all treated 
warts, and substantial effects on wart clearance. No serious adverse events (SAEs), discontinuations 
due to AEs, or deaths occurred during the study. All AEs were of mild (n=53) or moderate severity 
(n=2) and self-limiting without therapeutic intervention. The AE profile was similar for all subjects 
across treatment groups. Most treatment-emergent adverse events (TEAEs) were considered as 
unlikely related or unrelated (n=47) to treatment. Common TEAEs in the single-agent furosemide 
treated group included influenza-like illness and upper respiratory tract infections which occurred in 
2 / 20 (10%) subjects. No clinically significant changes were attributable to treatment in any of the 
three investigational products for hematology, clinical chemistry, urinalysis, vital signs, or ECG 
parameters. Overall, the safety profile of the investigational products containing single-agent 
furosemide or digoxin and furosemide-digoxin combination applied for 42 days supports the use of 
Furosemide Topical Gel 0.125% w/w (CLS006) for the treatment of nongenital cutaneous warts. 
Based upon the favorable risk/benefit outcomes to date, two larger Phase 3 studies of Furosemide 
Topical Gel 0.125% w/w (CLS006) will be conducted to validate the Phase 2 results of the single-
agent furosemide product for the treatment of nongenital cutaneous common warts (verruca vulgaris) 
and to support a new drug application (NDA) submission. 


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CONFIDENTIAL 
6. 
STUDY OBJECTIVE 
The objective of this study is to evaluate the efficacy and safety of six (6) weeks of once daily 
application of Furosemide Topical Gel 0.125% w/w (CLS006) compared to vehicle in subjects 
≥2 years of age with nongenital cutaneous common warts (verruca vulgaris). 
7. 
INVESTIGATIONAL PLAN 
7.1. 
OVERALL STUDY DESIGN 
This study will be conducted in accordance with the FDA and ICH guidelines on current GCP, 
following the ethical principles originating from the Declaration of Helsinki. Additionally, the study 
will be conducted in accordance with any applicable laws or regulations of the country in which the 
clinical research is conducted. 
The study will be conducted as a randomized, double-blind, vehicle-controlled, parallel group, 
multicenter study at approximately 40 sites involving approximately 480 subjects (~240 per treatment 
group) with nongenital cutaneous common warts. Approximately 160 of subjects enrolled will be 
pediatric subjects, (~80 will be ≥2 to <12 years of age and ~80 will be ≥12 to <18 years of age).  
After giving informed consent, subjects will be screened for study eligibility according to the 
specified inclusion/exclusion criteria.  Subjects must be male or female ≥2 years of age with 1 to 6 
clearly identifiable common warts (verruca vulgaris) located on hands (dorsal, periungual, or palmar), 
feet (dorsal), limbs, and/or trunk. Eligible subjects will be randomized and stratified by age ≥2 to 
<12, ≥12 to <18 or ≥18) and investigative site to one of two treatment groups in a 1:1 ratio (CLS006 
or vehicle gel).    
Subjects or their caregiver(s) will apply the first application of study drug under supervision at the 
study site to ensure understanding of the treatment application instructions.  Thereafter, subjects or 
their caregiver will apply study drug at home to all common warts treated at baseline once daily for 6 
weeks. The 6-week treatment period will be followed by a 12-week post-treatment efficacy 
evaluation period. After completion of the 12-week post-treatment efficacy evaluation period, 
subjects who achieved clearance of at least one treated wart at week 18 will continue into the 12-
week follow-up period for evaluation of recurrence and durability of response.    
Other than the study drug, no other treatment, product or therapy (prescription or over-the-counter) 
intended for the treatment of warts is permitted during the course of the study including the follow-up 
period in accordance with the excluded medications/treatments listed in Section 7.6.10.1. 


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CONFIDENTIAL 
7.2. 
SELECTION OF STUDY POPULATION 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria at the baseline visit 
prior to randomization to be considered eligible for enrollment into the study. 
7.2.1. 
Inclusion Criteria 
1. Subjects, and/or their legal guardians for subjects under the legal age of consent, who provide 
written informed consent to participate in the study. Subjects who are under the legal age of 
consent are to provide written informed assent to participate in the study as required, according to 
IRB guidelines for obtaining assent.  
2. Male or female subjects 2 years of age or older. 
3. Females of childbearing potential who are using a highly effective form of birth control or 
females of non-childbearing potential (as specified below).  
 Non-childbearing potential females are defined as females who are premenarchal, or 
postmenopausal (12 months with no menstrual period without an alternative medical cause), 
or who have undergone a hysterectomy, bilateral oophorectomy, tubal ligation, or bilateral 
occlusion of the fallopian tubes (e.g., Essure®) with post-placement confirmation of complete 
blockage.    
 Highly effective methods of birth control are defined as those, alone or in combination, that 
result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.   
o Forms of birth control include: Oral (e.g., birth control pills), Intravaginal (e.g., 
NuvaRing®), Implantable (e.g., Norplant®), Injectable (e.g., Depo-Provera®) or 
Transdermal (e.g., Ortho Evra®) contraception; Intrauterine device (IUD); double-
barrier (e.g., diaphragm or condom with spermicidal gel or foam); a vasectomized 
partner or abstinence from heterosexual intercourse when in line with preferred and 
usual lifestyle of subject (periodic abstinence e.g., calendar, ovulation, 
sympto-thermal, post-ovulation methods and withdrawal are not acceptable methods 
of contraception).  
 If an abstinent subject of childbearing potential becomes sexually active during 
the study, the subject must be willing to use effective birth control as 
described.   
o For subjects using an acceptable hormonal based form of birth control (e.g., oral birth 
control, Norplant), she must have been doing so for at least three (3) months prior to 
the Baseline Visit and be willing to continue stable birth control methods throughout 
the study. 
4. Females of childbearing potential with a negative in-office urine pregnancy test at Screening and 
Baseline (prior to being randomized to receive study drug). 


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CONFIDENTIAL 
5. Subjects must have 1 to 6 clearly identifiable common warts (verruca vulgaris). For clarity, 
subjects must not have > 6 cutaneous common warts at Baseline. All of the common warts must 
meet the following criteria at Baseline: 
 Warts must be located on hands (dorsal, periungual, or palmar), feet (dorsal), limbs, and/or 
trunk,  
 Each wart must measure 3 to 10 mm in their longest dimension (diameter) on the epidermal 
plane of the skin at the baseline visit,  
 Each wart must be present for at least 4 weeks at the baseline visit,  
 Plantar, facial, subungual, and other warts (e.g., flat, genital) are excluded from treatment (i.e., 
these wart types are excluded from treatment, however the subject is not excluded). 
6. Subjects free of any clinically significant dermatologic disorder in the treatment area 
(e.g., eczema, psoriasis, atopic dermatitis, etc.). 
7. Subjects free of any clinically significant systemic condition which, in the opinion of the 
investigator, will interfere with the study assessments or increase the risk of AEs.  
8. Subjects willing to refrain from using other topical products in the treatment area, or prohibited 
medications for the duration of the study (refer to Section 7.6.10.1). 
9. Subjects able and willing to comply with all study procedures, restrictions and visit requirements. 
7.2.2. 
Exclusion Criteria 
1. Female subjects who are pregnant, nursing/breastfeeding, or plan to become pregnant within the 
study period including the follow-up period. 
2. Subjects who are immunocompromised.  
3. Subjects who have used any wart treatments/therapies, prescription or over-the-counter, as 
follows:  
 Salicylic acid, cantharidin, sinecatechins (VeregenTM), simple occlusion (e.g., duct tape), 
and/or any other over-the-counter wart-removing products in the treatment area within 
4 weeks of the Baseline Visit. 
 Cryotherapy (e.g., treatment with liquid nitrogen), carbon dioxide, electrodessication, laser, 
surgery, or other forms of mechanical destruction (e.g., emery boards, clippers, debriders, etc.) 
in the treatment area within 8 weeks of the Baseline Visit. 
 Treatment with immunotherapy (DPCP, DNCB or other), imiquimod, 5-fluorouracil, 
bleomycin, podophyllin or any other wart immunotherapy or treatment (e.g., Candida antigen) 
designed to stimulate immune response within 12 weeks of the Baseline Visit. 


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4. Subjects who have taken, within 30 days prior to the Baseline visit, or require treatment with 
systemic immunosuppressive or immunomodulatory medication (including oral or parenteral 
corticosteroids) during the course of the study.   
 Routine use of inhaled or intranasal corticosteroids is allowed. 
5. Subjects who require ongoing treatment with oral or injectable furosemide. 
6. Subjects who have used an investigational drug/device within 30 days of the Baseline visit or who 
are currently participating in an investigational drug/device study.  Use of an investigational 
drug/device and/or participation in another investigational study is prohibited during this study.  
7. Subjects with known sensitivities to any of the investigational product ingredients including 
furosemide (or other sulfonamides). 
8. Subjects who have a clinically significant abnormality of the cardiovascular, hepatic or renal 
systems that, based on the Investigator’s opinion, would compromise subject safety.  
9. Subjects with clinically relevant/significant abnormal laboratory results, vital signs, ECG, and/or 
physical findings at Screening and/or Baseline that, based on the Investigator’s opinion, would 
interfere with the study objectives or compromise subject safety (e.g. subjects who have common 
warts in a region of pre-existing inflammatory condition). 
10. Subjects with a chronic medical condition or clinically significant abnormal physical or 
laboratory finding(s) that may require the use of a prohibited medication/treatment.  
11. Subjects who currently abuse alcohol or drugs or who have a history of chronic alcohol or drug 
abuse within the past year. 
7.2.3. 
Discontinuation and Withdrawal from Treatment or Study 
A subject is free to discontinue treatment or withdraw from the study at any time and for any reason, 
specified or unspecified, without prejudice to his/her medical care by the physician.  
Reasons for discontinuation from Treatment or the Study include, but are not limited to, the 
following: 
 Adverse Event  
 Lack of Efficacy 
 Pregnancy  
 Withdrawal By Subject 
 Subject Lost To Follow-Up   
o The Investigator will attempt to reach the subject twice by telephone and once by certified 
letter before considering the subject lost to follow-up.  Lost to follow-up discontinuation 
and actions taken should be appropriately documented and a copy of the follow-up letter 
maintained in the Investigator’s file.  
 Physician Decision 


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 Non-Compliance with Study 
 Study Terminated by Sponsor 
 Other 
All premature discontinuations from treatment or the study must be appropriately documented in the 
source documents.    
All efforts should be made to evaluate subjects not completing the study (e.g., Early Termination 
Visit procedures performed).   
Subjects who withdraw from treatment or the study will not be replaced. 


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7.3. 
CONDUCT OF STUDY 
7.3.1. 
Schedule of Visits and Study Assessments 
Study Period
Screening
Double-Blind Treatment (DBT) 
Post-treatment Efficacy 
Evaluation (PTEE) 
Follow-up1 
Visit
Time
Screening
Baseline
Week 2
Week 4
Week 6 / 
End of 
Treatment      
(or Early Term 
during DBT 
Period)
Week 12 
Week 18 /  
End of Post-tx 
Efficacy 
Evaluation (or 
Early Term during 
PTEE Period)
Follow-up 
#1 
Follow-up #2 
(Final) 
Day -28 
to -1 
Day 1
Day 14 Day 28
Day 42 
Day 84 
Day 126  
(3 mo post-
treatment) 
Week 24 
 
Week 30 
(6 mo post-
treatment)
Procedures                      (Visit Window)
(± 3 days)
(± 5 days)
(± 7 days)
Informed Consent
X
Demographics & Medical/Surgical History
X
X2
Prior & Concomitant Medication/Treatment 
X
Limited Physical Exam3
X
X
Vital Signs (BP, HR)
X
X
X
X
X
X
X
ECG
X
Urine Pregnancy Test4
X
X
X
Clinical Safety Lab Testing (Hematology, 
Chemistry) 
X 
 
 
 
X 
 
 
 
 
Wart Assessments 
X
X
X5
X5
X5
X5
X5
X5
X5
Clinical Photography (select sites only) 6
x
x
x
Inclusion/Exclusion Criteria
X
X
Enroll/Randomization
X
Dispense Study Drug & Diary
X
X
X
Treatment Compliance / Collect and Review 
Study Drug & Diary
 
 
X 
X 
X 
 
 
 
 
Apply Study Drug (Once Daily) 
X7
Concomitant Medication/Treatment Review
X
X
X
X
X
X
X8
X8
Adverse Events
X2
X
X
X
X
X
1 
Only required for subjects who achieved clearance of at least one treated wart as determined by the PI or an appropriately qualified Sub-I at week 18 / End of Post-tx Efficacy Evaluation.  
2 
Adverse event assessment will be performed following the first study drug application (any changes in subject’s health before first study drug application should be recorded as medical history). 
3 
A limited physical exam (refer to Section 7.5.2) including height & weight measurements at Screening and weight measurement only at the Week 6/EOT (or Early Termination during DBT Visit). 
4 
Urine pregnancy test for women of childbearing potential only. Urine pregnancy testing should also be conducted at any visit for any female who is suspected of being pregnant.   
5 
New common warts that appear after the Baseline visit will be identified, characterized and location recorded/mapped only, but not treated.  
6 
Clinical photography will be optional for subjects < 12 years of age.  
7 
The first application of study drug will be performed under supervision at the study center. 
8 
Concomitant medication/treatment review at Follow-up visits will focus on review of restricted concomitant medication/treatment only (refer to Section 7.6.10.1).


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7.3.2. 
Study Assessments by Visit 
An unscheduled visit may occur at any time in the event that the investigator determines the subject 
should be seen for safety reasons. 
7.3.2.1. 
Screening   
Screening Visit procedures are to be conducted within 28 days prior to the subject’s Baseline (Day 1) 
Visit.   
The following procedures will be performed during Screening:  
1. Obtain subject’s and/or his/her legal guardian(s) for subjects under the legal age of consent, 
written informed consent prior to initiating any study procedures, including instructing the 
subject to discontinue excluded medications/treatments.  
a. Subjects who are under the legal age of consent are to provide written informed assent 
as required, according to IRB guidelines for obtaining assent; 
b. Provide subject and/or his/her legal guardian(s) with a copy of the signed and dated 
consent form (and assent form, if applicable); 
c. Document informed consent in the subject’s medical record. 
2. Obtain demographics including subject reported race and ethnicity. 
3. Screen the potential subject according to the study inclusion/exclusion criteria (refer to 
Sections 7.2.1 & 7.2.2). 
4. Perform an in-office urine pregnancy test on all females of childbearing potential. 
5. Review and record medical/surgical history including: 
a. Wart history;  
b. Identification of any history of significant cardiovascular, hepatic or renal disease. 
6. Review and record prior and concomitant medications/treatments (refer to Section 7.6.10) 
including: 
a. Wart medications/treatments used within one year; 
b. All non-wart medications/ treatments used within 1 month; 
c. Washout medications/treatments, if applicable. 
7. Obtain vital signs. 
8. Perform wart assessments (refer to Section 7.4.1).  
9. Perform a limited Physical Exam including height and weight measurements (refer to Section 
7.5.2). 
10. Perform a 12-lead electrocardiograph (ECG) (refer to Section 7.5.5).  
11. Collect blood samples for clinical safety laboratory testing (hematology, chemistry). 
12. As appropriate, schedule the Baseline (Day 1) visit, to occur after the results of the clinical 
safety laboratory tests are received and any required washout period has been completed. 


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7.3.2.2. 
Baseline (Day 1)  
The following procedures will be performed during the Baseline (Day 1) Visit:  
Baseline Procedures: 
1. Review study inclusion/exclusion criteria including review of the laboratory results for any 
clinically significant findings that would exclude the subject from the study. 
2. Review and document any changes to the subject’s health and concomitant 
medications/treatments since his/her Screening visit. 
3. Perform an in-office urine pregnancy test on all females of childbearing potential. 
4. Obtain vital signs. 
5. Perform wart assessments (refer to Section 7.4.1).  
6. Perform clinical photography, if applicable (select centers only). 
7. Review study inclusion/exclusion criteria to confirm eligibility for inclusion in the study 
(refer to Sections 7.2.1 & 7.2.2). 
Randomization/Dispense Study Drug: 
If the subject fulfills eligibility requirements, enroll/randomize the subject to treatment (refer to 
Section 7.6). 
First Treatment Application: 
1. Give a copy of the treatment application instructions (refer to Appendix A) and study diary to 
subject and/or his/her legal guardian(s) for subjects under the legal age of consent and allow 
time to review. 
2. Instruct subject and/or caregiver(s) on: 
o Study drug application and use (refer to Section 7.6 & Appendix A) 
o Study diary completion. 
3. Provide study drug tube to subject and/or caregiver(s) for treatment application. 
4. As a means of educating and confirming subject’s understanding of the treatment application 
and diary completion instructions, under supervision of the study coordinator or designee the 
subject and/or caregiver(s) should:  
o Apply the first dose of study drug to each wart according to the treatment application 
instructions (refer to Section 7.6.2 & Appendix A). 
o Record the first application of study drug in the study diary. 
After First Treatment Application: 
1. Observe the subject for any immediate adverse events. 
2. Remind subject and/or caregiver(s) about restricted medications/treatments (refer to Section 
7.6.10.1) 
3. Remind subject and/or caregiver(s) to contact the investigator if he/she experiences any severe 
or serious adverse events. 


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4. Remind subject and/or caregiver(s) to apply study drug once daily and follow treatment 
instructions, as directed. 
5. Remind subject and/or caregiver(s) to record study drug application in the study diary each 
day during the treatment period and to return the study diary to the site at the next study visit. 
6. Remind subject and/or caregiver(s) that the study drug tube is not to be discarded and that it 
must be returned to the site at the next study visit.  
o Instruct subject and/or caregiver(s) to immediately report a lost tube to the site. 
7.3.2.3. 
Interim Visits: Week 2 (Day 14) and Week 4 (Day 28)     
Interim Visits following the Baseline (Day 1) Visit are to occur at the end of weeks 2 (Day 14) and 4 
(Day 28) (± 3 days). The following procedures will be performed:  
1. Question the subject and/or caregiver(s) about any changes to his/her health. 
2. Review and question subject and/or caregiver(s) about any changes to his/her concomitant 
medications/treatments. 
3. Obtain vital signs. 
4. Perform wart assessments (refer to Section 7.4.1).  
Dispense and Return of Study Drug and Diary: 
1. Collect study drug and review the returned study diary for any missed doses (refer to Section 
7.6.8).  
2. Perform Treatment Compliance Check (refer to Section 7.6.2.2). 
o Review compliance based on subject’s reported number of treatment applications. If 
compliance is an issue, re-instruct subject on study drug application. 
3. Provide study drug and diary to subject and/or caregiver(s). 
7.3.2.4. 
Week 6 (Day 42) / End of Treatment (or Early Termination during Double-Blind 
Treatment Period) 
The Week 6 / End of Treatment (EOT) Visit is to occur at the end of Week 6 (± 3 days) or if the 
subject discontinues the study prior to the Week 6 visit.  The following procedures will be performed:  
1. Question the subject and/or caregiver(s).about any changes to his/her health. 
2. Review and question subject and/or caregiver(s).about any changes to his/her concomitant 
medications/treatments. 
3. Obtain vital signs. 
4. Perform a limited Physical Exam including weight measurement. 
5. Collect blood samples for clinical safety laboratory testing (hematology, chemistry). 
6. Perform an in-office urine pregnancy test on all females of childbearing potential. 
7. Perform wart assessments (refer to Section 7.4.1). 
8. Perform clinical photography, if applicable (select centers only). 
 


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Return of the Study Drug and Diary 
1. Collect and review the returned study diary for any missed doses. 
2. Collect the returned study drug. 
7.3.2.5. 
Week 12 (Day 84)   
The Week 12 visit is to occur at the end of Week 12 (± 5 days). The following procedures will be 
performed: 
1. Question the subject and/or caregiver(s) about any changes to his/her health. 
2. Review and question subject about any changes to his/her concomitant 
medications/treatments. 
3. Obtain vital signs. 
4. Perform wart assessments (refer to Section 7.4.1). 
7.3.2.6. 
Week 18 (Day 126) / End of Post-Treatment Efficacy Evaluation (or Early 
Termination during Post-treatment Efficacy Evaluation Period  
The Week 18 / End of Post-treatment Efficacy Evaluation Visit is to occur at the end of Week 18 
(±5 days), or for any subject that discontinues the study after the Week 6 Visit and prior to Week 18. 
The following procedures will be performed:  
1. Question the subject and/or caregiver(s) about any changes to his/her health. 
2. Review and question subject about any changes to his/her concomitant 
medications/treatments. 
3. Obtain vital signs. 
4. Perform wart assessments (refer to Section 7.4.1). 
5. Perform clinical photography, if applicable (select centers only). 
6. If subject achieved clearance of at least one treated wart as determined by the PI or an 
appropriately qualified Sub-I at Week 18 / End of Post-treatment Efficacy Evaluation visit, 
schedule the Follow-up visits (#1/Week 24 and #2/Week 30). 
 Remind the subject and/or caregiver(s) about restricted medications/treatments (refer to 
Section 7.6.10.1). 
7.3.2.7. 
Follow-up# 1 (Week 24) Visit   
The Follow-up# 1 Visit is to occur at the end of Week 24 (±7 days). The following procedures will be 
performed during this visit: 
1. Review and question subject and/or caregiver(s) about use of any restricted concomitant 
medications/treatments (refer to Section 7.6.10.1). 
2. Perform wart assessments (refer to Section 7.4.1). 
3. Confirm Follow-up #2 / Week 30 Visit. 


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 Remind the subject and/or caregiver(s) about restricted medications/treatments (refer to 
Section 7.6.10.1). 
7.3.2.8. 
Follow-up# 2 (Week 30) Visit   
The Follow-up Visit is to occur at the end of Week 30 (±7 days). The following procedures will be 
performed during this visit: 
1. Review and question subject and/or caregiver(s) about use of any restricted concomitant 
medications/treatments (refer to Section 7.6.10.1). 
2. Perform wart assessments (refer to Section 7.4.1). 
7.4. 
EFFICACY ASSESSMENTS 
Efficacy assessments will be performed at the time points indicated in the Schedule of Visits and 
Study Assessments (refer to Section 7.3.1). 
7.4.1. 
Wart Assessments 
Wart assessments, as specified, should be performed by the Principal Investigator (PI) or an 
appropriately qualified Sub-Investigator (Sub-I).  Evaluator initials will be recorded on applicable 
wart assessments.  
In order to reduce inter-evaluator variability, it is important that the same evaluator perform 
the wart assessments for the same subject at baseline and at all subsequent study visits, 
whenever feasible.   
7.4.1.1. 
Wart Identification/Characteristics and Location/Mapping  
The PI or an appropriately qualified Sub-I will assess each subject to document/review all clearly 
identifiable common warts (verruca vulgaris).   
 In order to reduce inter-evaluator variability, it is important that the same evaluator assess 
the same subject at baseline and at all subsequent study visits, whenever feasible. 
All clearly identifiable common warts will be identified, counted, characterized (solitary, 
cluster/splitting/satellite, or merging/confluent), location recorded (e.g., hands: dorsal, periungual, or 
palmar; feet: dorsal; limbs; trunk) and mapped, and numbered (e.g., 1 through 6) at the Screening 
Visit, reviewed and updated at the Baseline Visit (Day 1, pre-treatment) and reviewed at each 
subsequent visit.  The warts confirmed at the Baseline Visit will be considered the “Baseline 
Treatment” warts. The number assigned to each Baseline Treatment wart will remain the same and 
will be used throughout the study to refer to the same wart or wart area.  The objective of wart 
identification/characterization, location/mapping and numbering is to provide a systematic approach 
to identifying and assessing Baseline Treatment warts to promote accurate and consistent evaluations 
throughout the study. 


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Any new common warts that appear after baseline will be identified, characterized and location 
recorded/mapped, however they will not be treated. 
7.4.1.2. 
Wart Size 
The size of each Baseline Treatment Wart will be measured in millimeters (mm) using a standardized 
ruler.  The longest dimension (diameter) on the epidermal plane of the skin will be recorded.   
 In order to prevent inter-evaluator variability, it is important that the same evaluator 
measure the subject’s wart(s) at baseline and at all subsequent study visits, whenever 
feasible. 
Clinical Clearance: 
Clinical clearance of a wart, as determined by the PI or an appropriately qualified Sub-I, should 
be recorded with a measurement of 0 mm.   
7.4.1.3. 
Wart Identification/Characteristic and Measurement Guidance 
Solitary Wart:  
 Identification/Characteristic: a singular discrete and distinct wart  
 Measurement: record the size of the longest dimension on the epidermal plane of the skin of 
the wart 
Cluster/Satellite/Splitting Warts:  
 Identification/Characteristic: 
o Two or more warts that are closely clustered together and not discrete/distinct from the 
other 
o A Baseline Treatment wart that changes to form 2 or more warts 
 Considered 1 “wart” 
 Measurement: record the size of the longest dimension on the epidermal plane of the skin of the 
outermost wart considered part of the wart cluster/satellite  
Merging/Confluent Warts:  
 Identification/Characteristic:  
o 2 or more Baseline Treatment  warts that grow together to form 1 wart  
o A Baseline Treatment cluster/satellite/splitting wart that changes to form 1 distinct wart 
 Measurement: record the size of the longest dimension on the epidermal plane of the skin of the 
wart.  
Clinical Clearance: 
Clinical clearance of a wart, as determined by the PI or an appropriately qualified Sub-I, should 
be recorded with a size of 0 mm and the subject should be instructed to stop applying study drug to 
that specific wart (spot) only.   


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7.4.2. 
Clinical Photography 
Clinical Photography will be conducted at approximately 5 selected centers for photo-documentation 
purposes only. Photography will be optional for subjects < 12 years of age. 
At Baseline (pre-treatment), Week 6/EOT, and Week 18/End of Post-treatment Efficacy Evaluation, a 
standardized set of photographs will be taken of each wart identified at baseline. A Photography 
Manual will be provided by the vendor and will include further instructions and details for collecting 
the photographs.  
7.5. 
SAFETY AND TOLERABILITY ASSESSMENTS 
Safety assessments will be performed at the time points indicated in the Schedule of Visits and Study 
Assessments (refer to Section 7.3.1). 
7.5.1. 
Demographics and Medical/Surgical History 
Demographic information including the subject’s date of birth, sex, and subject reported ethnicity and 
race will be collected at Screening.  
A medical/surgical history including wart history and identification/review of any history of 
significant cardiovascular, hepatic, or renal diseases will be collected at Screening and 
reviewed/updated at baseline prior to study drug application.   
7.5.2. 
Limited Physical Exam and Vital Signs 
A limited physical exam will be performed at the Screening Visit, including height and weight 
measurements, and at the Week 6/EOT (or Early Termination during DBT Visit) with weight 
measurement only. 
The limited Physical Exam should include an assessment of the following: 
 General Appearance 
 Head 
 Eyes 
 Ears 
 Nose 
 Throat 
 Lungs 
 Heart 
 Skin  
 
Vital signs (blood pressure [BP], heart rate [HR]) will be measured at each visit during Screening, 
Double-blind Treatment and Post-treatment Efficacy Evaluation Periods.   
 


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7.5.3. 
Clinical Safety Laboratory Testing 
Blood samples will be collected at the Screening and Week 6/EOT visits (or, if the subject is 
terminated prior to the EOT visit). A central laboratory will perform the sample analysis for all study 
sites. It is anticipated that the minimum amount of blood required for analysis (approximately 3.5 mL 
to 5.5 mL) will be collected from each subject age ≥2, not to exceed more than 2% of estimated total 
blood volume in a 24 hour period. Instructions for sample collection, preparation, labeling, and 
shipping will be provided by the laboratory. 
The clinical safety laboratory tests will include the following parameters: 
 Hematology:  hemoglobin, hematocrit, red blood cell (RBC) including mean corpuscular 
volume (MCV) and red cell distribution with (RDW), white blood cell (WBC) count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelet count. 
 Chemistry/Lipids:   
o General: calcium, glucose, lactate dehydrogenase (LDH) 
o Electrolytes: carbon dioxide (bicarbonate), chloride, magnesium, sodium, potassium 
o Kidney/Liver: blood urea nitrogen (BUN), creatinine, uric acid, total protein, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline 
phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin  
o Lipids: total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins 
(LDL), triglycerides 
7.5.4. 
Urine Pregnancy Test 
An in-office urine pregnancy test will be performed at the Screening, Baseline and Week 6/EOT 
visits (or, if the subject is terminated prior to the EOT visit).  All female subjects of childbearing 
potential must have a negative urine pregnancy test at Baseline prior to randomization.  Urine 
pregnancy testing should also be conducted at any visit for any female who is suspected of being 
pregnant.   
Any female who becomes pregnant during the Double-blind Treatment Period should be withdrawn 
from the study and the Sponsor must be notified.  This should be done by sending a copy of the 
Pregnancy Reporting Form (via fax or email pdf copy) plus other supporting documentation, as 
required, to the Safety Contact (refer to Section 7.5.6.4) within 24 hours (1 business day) of 
becoming aware of the event.  The pregnancy should be followed until a final outcome is known and 
a final outcome report should be submitted as soon as possible. 
7.5.5. 
Electrocardiogram 
A resting (at least 5 minutes) 12-lead electrocardiogram (ECG) including ventricular rate (beats per 
minute), PR interval (msec), QRS interval (msec), QT interval (msec), and QT interval corrected for 
heart rate (QTc interval) (msec) calculated using the Fridericia method, will be performed at 
Screening.  


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ECG equipment will be provided to sites by a central ECG vendor. A central reader may be used to 
interpret subject ECGs. User instructions for the ECG equipment will be provided by the central ECG 
vendor.     
7.5.6. 
Adverse Events 
7.5.6.1. 
Definition of Adverse Event 
An adverse event (AE) means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE can therefore be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug, and does not imply any judgment about causality.  
Any condition, event and/or signs and symptoms occurring after signing the informed consent form 
and before starting study drug treatment should be recorded as medical history in the eCRF.  Medical 
conditions/diseases are considered AEs only if they worsen after starting study drug treatment (first 
application of study drug).  Any clinically significant change from baseline, based upon the opinion 
of the investigator, in physical examination findings, vital signs, and/or laboratory values should be 
recorded as an AE. 
Study personnel should question and observe subjects for evidence of AEs paying particular 
attention to local application site reactions and any potential cardiovascular or hematologic AEs.  
At each visit during the double-blind treatment and post-treatment efficacy evaluation period, the 
study site personnel should assess for the presence of local application site reactions and question the 
subject about AEs using an open question taking care not to influence the subject’s (or caregiver’s) 
answer, e.g., "Have you (or your child for caregivers) had any changes in your (or your child’s) health 
since your last visit?”   
Any AE, whether or not it is related to the test products, will be recorded in the source documents and 
reported on the appropriate eCRF page along with the date of onset, the severity, the relationship to 
the test product and the outcome.  Under certain circumstances, additional information may be 
requested. 
When an AE persists at the end of the study, the Investigator will ensure a follow-up of the subject 
until the Investigator/ Sponsor agree that the event is satisfactorily resolved or that no further follow-
up is required. 
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens or 
intensity increases after receiving the study medication.  Events which occur more than thirty days 
after the last dose of study medication will not be considered treatment emergent. 


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7.5.6.2. 
Relationship of Adverse Event to Study Drug 
The relationship of an AE to study drug is to be assessed according to the following definitions: 
 Not Related – no temporal association or the cause of the event has been identified, or the 
drug cannot be implicated based upon available information. 
 Possibly Related – temporal association, but other etiologies are likely to be the cause.  
However, involvement of the drug cannot be excluded, based upon available information. 
 Definitely Related – established temporal or other association (e.g., re-challenge) and event is 
not reasonably explained by the subject’s known clinical state or any other factor, based on 
available information. 
7.5.6.3. 
Severity of Adverse Event 
The severity of an AE is to be scored according to the following scale: 
 Mild - Awareness of sign or symptom, but easily tolerated 
 Moderate - Moderate Discomfort enough to cause interference with usual activity 
 Severe - Severe Incapacitation with inability to work or perform usual activity 
7.5.6.4. 
Serious Adverse Event  
An adverse event or adverse reaction is considered “serious” if, in the view of either the investigator 
or Sponsor, it results in any of the following outcomes: 
 Death; 
 A life-threatening AE,  
o The term "life-threatening" in the definition of "serious" refers to an event or suspected 
adverse reaction in which in the view of either the investigator or Sponsor, its occurrence 
places the patient or subject at immediate risk of death.  It does not include an AE or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions; or 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in the serious AE (SAE) definition above.  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.   


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The Investigator or designee must report any SAE occurring in a subject receiving study drug to the 
Safety Contact immediately (within 24 hours (1 business day) of becoming aware of the event), even 
if the SAE does not appear to be drug-related.  This should be done by sending a copy (via email pdf 
copy or fax) of the Serious Adverse Event Report Form plus other supporting documentation, as 
required. 
All additional follow-up evaluations must also be reported as soon as possible.  All SAEs will be 
followed until the Sponsor agrees that the event is satisfactorily resolved or that no further follow-up 
is required. 
Safety Contact Details (for SAE Reporting): 
PRA Drug Safety Hotline:  +1 800-772-2215 
SAE Reporting Email:        CHOSafety@prahs.com 
SAE Reporting Fax No.:    +1 888-772-6919 
The Sponsor will be responsible for notifying the relevant authorities of any SAE according to 
applicable regulations.  The CRO/Sponsor will also ensure that any central Institutional Review 
Board (IRB) /Independent Ethics Committee (IEC) and any other participating Investigators are 
notified of the SAE.  The PI is responsible for ensuring that their local IRB/IEC, if applicable, is 
notified of the SAE, as per the IRB/IEC standard operating procedures. 


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7.6. 
TEST MATERIALS 
7.6.1. 
Identity of Investigational Products 
 
TEST PRODUCT 
Furosemide Topical Gel 0.125% w/w 
(CLS006) 
Vehicle 
(Comparator Product) 
Active Ingredient
Furosemide 
None
Concentration
0.125% w/w furosemide
NA
Inactive Components 
Dehydrated Alcohol, 200 Proof, Undenatured, USP 
Propylene Glycol, USP 
Hydroxypropyl Cellulose NF 
Sodium Citrate, Dihydrate, USP 
Citric Acid Anhydrous, USP 
Purified Water, USP 
Dosing Schedule
Once daily
Route of Administration
Topical 
Manufacturer 
Ei LLC 
2865 North Cannon Blvd 
Kannapolis, NC 28083 
Packaging
3 gram laminate tube
Storage Requirements
Controlled Room Temperature (15°C – 30°C) [59°F - 86°F] 
7.6.2. 
Treatment Administration 
Subjects will be instructed to apply a small amount of gel [approximately 20-30 mg CLS006 
(equivalent to 0.025-0.0375 mg of furosemide)] to cover each wart identified at baseline once daily 
for 6 weeks (42 consecutive days).  Subjects will be instructed to gently rub the gel into each wart for 
approximately 20 seconds or until the gel is fully absorbed.   
Subjects (or caregivers) will apply study drug to each “Baseline Treatment” wart one time per day 
for the entire treatment period or until instructed to stop by study personnel.   
 If clinical clearance of a wart is determined by the PI or an appropriately qualified Sub-I, 
subjects should be instructed to stop applying study drug to that specific “wart” (spot) only.   
 Merging/Confluent warts should be treated with a small amount of study drug to cover the 
merged/confluent wart. 
 Cluster/Satellite (Splitting) warts should be treated with a small amount of study drug to cover 
the area (to the outermost wart) considered part of the wart cluster/satellite. 


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7.6.2.1. 
Subject Dosing and Use Instructions 
Prior to the first application of study drug, subjects and/or caregiver(s) will be given a copy of the 
study drug application instructions and study diary for review.  The study coordinator or designee 
should instruct the subject and/or caregiver(s) on proper study drug application and diary completion.     
The first application of study drug and documentation of treatment in the study diary will be 
performed by the subject and/or caregiver(s) under the supervision of the study coordinator or 
designee as a means of confirming proper study drug application technique and completion of the 
study diary (refer to Appendix A for detailed instructions).   
Thereafter, subjects and/or caregiver(s) will apply at home the daily dose of study drug to the 
“Baseline Treatment” warts once daily for 6 weeks or until instructed to stop by study personnel.  The 
subject and/or caregiver(s) will be asked to choose a similar time each day, based on convenience, to 
apply the study drug (e.g., in the morning after showering or in the evening prior to bedtime). 
Subjects and/or caregiver(s) will be instructed to record the date of each study drug application in the 
study diary provided.   
The study drug should not be applied more than one time per day. 
7.6.2.2. 
Treatment Compliance 
Study drug treatment compliance will be assessed based on the subject’s and/or caregiver(s) reported 
number of treatment applications.  The subject and/or caregiver(s) should record the date of each 
study drug application in his/her study diary.   
Site personnel should review and/or discuss treatment compliance with subject and/or caregiver(s) 
since last visit based on the completed study diary and/or verbally reported information.  Any missed 
applications should be documented in the source documents (i.e., by subject in the study diary or by 
site personnel in subject chart). If compliance is an issue, site personnel should re-instruct subject 
and/or their caregiver(s) on study drug dosing, application and diary completion, as appropriate. 
7.6.3. 
Treatment Assignment  
Prior to the start of the study, a randomization list will be generated by the CRO responsible for 
biostatistics in the trial.  Once it has been established that subjects are eligible to participate in this 
study, eligible subjects will be randomized within each age group strata (≥2 to <12, ≥12 to <18 or 
≥18) for each study center and assigned a randomization number corresponding to one of two  
treatment groups in a 1:1 ratio.  
7.6.4. 
Blinding 
This study will be performed in a double-blind fashion. The investigator, study staff, subjects, 
sponsor, and monitor will remain blinded to the treatment until study closure. The investigational 
drug and its matching placebo are indistinguishable. 


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7.6.5. 
Packaging 
Study drug will be provided in 3-gram tubes and packaged into individual subject kits for use by a 
subject for the duration of the treatment period.  Each kit will be numbered with a unique number 
according to the randomization list generated.  Each tube within the kit will be labeled with the 
matching kit number to correlate with the contents of the kit according to the randomization list 
generated.   
Prior to the start of the study, a randomization list assigning kit numbers to one of two treatment 
groups in a 1:1 ratio will be generated by the study biostatistician.  The drug packaging company will 
use this randomization list to package study drug into treatment kits.   
7.6.6. 
Labeling 
Study drug tubes and kits will be labeled in a blinded manner in accordance with applicable 
regulatory requirements of the country where the clinical trial will be conducted.   
7.6.7. 
Unblinding a Subject 
Study drug supplies will be packaged in a manner supporting the blinding of the study.  
Unblinding a subject’s treatment assignment should ONLY be performed in an emergency, when 
knowing the identity of a subject’s assigned treatment is essential to their continuing medical care. If 
at all possible, every attempt should be made to contact the Medical Monitor/Safety Contact to 
discuss before unblinding.  In the event of unblinding, the Medical Monitor/Safety Contact and/or 
Project Manager must be notified immediately (within 24 hours (1 business day)), and the 
circumstances under which the blind for a given subject was broken must be appropriately 
documented in the source documents. 
7.6.8. 
Dispensing and Return of Study Drug 
Each eligible subject will be assigned a kit from those available at the site according to the 
randomization schedule using the Interactive Web Response System (IWRS). When the kit is 
assigned, study personnel must record the required information on the kit and tube labels and attach 
the label(s) to the appropriate source document.  The kit assignment must be recorded in the source 
document.   
From the subject’s assigned kit, one tube of study drug will be dispensed to the subject and/or 
caregiver(s) from his/her assigned study drug kit at Baseline, and again at his/her Week 2 and 4 visits.  
One extra tube will be in the kit in the event it is needed (e.g., tube is lost).  Tube dispensation and 
return must be recorded in the source document. 
The subject and/or caregiver(s) will be instructed to return the tube of study drug at each study visit.  
At the Week 2 and 4 Visit, the used tube will be exchanged and a new tube of study drug will be 
dispensed from the subject’s kit.    


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7.6.9. 
Accountability 
In accordance with federal regulations, the Investigator must agree to keep all clinical supplies in a 
secure location with restricted access.   
Upon receipt of the clinical supplies, the Investigator or designee will conduct a complete inventory 
of all study drug and assume responsibility for storage and dispensing.  Dispensation and return of 
study drug must be appropriately documented.  Under no circumstance should any of the clinical 
supplies sent to the Investigator be used in any unauthorized manner.   
All used and unused clinical supplies will be appropriately inventoried and returned to the designated 
facility as specified by the Sponsor. 
7.6.10. 
Prior and Concomitant Medication/Treatment 
Prior and concomitant medication/treatment history will be collected at Screening and 
reviewed/updated at the Baseline visit.  Medications/Treatments used within 1 month prior to the 
Baseline visit and any washout medications/treatments specified (refer to Section 7.6.10.1) should be 
appropriately documented in the source documents.  Wart treatments used within the last year should 
be recorded. 
Any medication/treatment used by the subject either at or following the Baseline visit through study 
completion will be considered concomitant medication/treatment (e.g., aspirin, Tylenol, birth control 
pills, vitamins).  Every attempt should be made to keep concomitant medication/treatment dosing 
constant during the study.  Any change to concomitant medication/treatment should be appropriately 
documented in the source documents.   
An AE should be recorded for any subject starting a concomitant medication/treatment (except 
medications/treatments used as prophylaxis) to treat any health condition/event not identified in the 
subject’s medical history. 
7.6.10.1.   Excluded Concomitant Medication/Treatment 
Other than the study drug, no other treatment, product, or therapy (prescription or over-the-counter) 
intended for the treatment of warts is permitted during the course of the study including the follow-up 
period, according to the instructions listed below.   
The following treatments/medications are prohibited in the treatment area during the study including: 
 Use of any wart treatments/therapies, prescription or over-the-counter products as follows:  
 Salicylic acid, cantharidin, simple occlusion (e.g., duct tape), and/or any other over-the-
counter wart-removing products in the treatment area. 
 Cryotherapy (e.g., treatment with liquid nitrogen), carbon dioxide, electrodessication, 
laser, surgery, or other forms of mechanical destruction (e.g., emery boards, clippers, 
debriders, etc.) in the treatment area. 


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The following treatments/medications are prohibited in the treatment area and/or outside the 
treatment area during the study, including the follow-up period: 
 Use of systemic immunosuppressive or immunomodulatory medication (including oral or 
parenteral corticosteroids) during the course of the study.  
 Routine use of inhaled or intranasal corticosteroids during the study is allowed;  
 Treatment with immunotherapy (DPCP, DNCB or other), imiquimod, 5-fluorouracil, 
bleomycin, podophyllin or any other wart immunotherapy or treatment designed to stimulate 
immune response. 
 Use of sinecatechins (VeregenTM) 
 Use of topical and/or systemic Isotretinoin (e.g. Accutane). 
 Ongoing treatment with cimetidine or other H2 receptor antagonists. 
 Ongoing use of oral or injectable furosemide during the course of the study.  
 Use of an investigational drug/device and/or participation in another investigational study. 
7.7. 
STATISTICAL METHODS PLANNED 
7.7.1. 
General Considerations 
A Statistical Analysis Plan (SAP) will be developed and finalized prior to unblinding of the study.  
The SAP will include detailed methods of analysis, algorithms for handling data, any deviations from 
the protocol methods, and mock data displays. 
7.7.2. 
Sample Size Determination 
The sample size estimates for the current study are based upon the rates of clearance of warts in the 
previous Phase 2 study (CHDR1423).  This was a randomized, double-blind, vehicle-controlled, 
Phase II study in 80 subjects who were treated with topical digoxin, furosemide, digoxin/furosemide, 
or vehicle for 42 days daily with an 8-week follow-up period.   For the furosemide treatment group, 
the proportion of subjects with all cleared warts was 0.1 (10%) versus 0 in the vehicle.  
The difference in the proportion of subjects with all treated warts cleared (complete clearance) at the 
Week 18/End of Post-treatment Efficacy Evaluation period (is the primary endpoint of the current 
study.  For conservative purposes, assuming 10% and 2% complete clearance rates in the furosemide 
and vehicle treated groups respectively 200 subjects randomized per treatment group will provide for 
92% power at a two-sided α of 0.05 to detect a difference between active and placebo.  
With the inclusion of an additional 80 subjects in the ≥ 2 to < 12 cohort, the total sample size of 480 
will provide 96% power with the assumption unchanged. 
 


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7.7.3. 
Randomization  
Subjects that meet all inclusion and exclusion criteria will be randomized to one of two treatment 
groups in a 1:1 ratio for each study center according to a predetermined computer-generated 
randomization code.  
Subjects will be randomized to treatment using an IWRS.  The randomization scheme will include 
age stratum at 3 levels (≥2 to <12, ≥12 to <18 or ≥18) and investigative site.  
7.7.4. 
Analysis Populations 
The ‘Intent-to-Treat’ (ITT) analysis population will include all randomized subjects.  The ITT 
population will be the primary population for all efficacy analyses. 
The “All-treated” analysis population will consist of all subjects receiving at least one application of 
study drug.  All safety analyses will be performed on the all-treated population. 
The Per-Protocol (PP) population will include all subjects in the ITT population who complete 
6 weeks of treatment and 12 weeks of post-treatment efficacy evaluation without any major 
deviations from the protocol.  The subjects to be included in the PP analysis population will be 
determined by the Sponsor prior to the unblinding of the study. The PP population will be secondary 
for the primary endpoint only. 
7.7.5. 
Handling of Missing Data 
The primary method of dealing with missing data is multiple imputations (MI).  Last Observation 
Carried Forward (LOCF) and Baseline Observation Carried Forward (BOCF) will be used as 
sensitivity analyses. 
For the multiple imputations, twenty sets of imputed data will be generated.  These will be imputed 
using SAS Proc MI as shown below. 
 
Proc MI NIMPUTE=20 SEED=861879112 ROUND=. . . . 1 1 1 1 1 1 
 
 
 
MINIMUM=. . . . 1 0 0 0 0 0 MAXIMUM=. . . .  6 6 6 6 6 6; 
class treat site sex agegrp; 
var treat site sex agegrp w0 w2 w4 w6 w12 w18; 
fcs logstic(treat) logistic(site) logistic(sex) logistic(agegrp) reg(w0) reg(w2) 
reg(w4) reg(w6) reg(w12) reg(w18); 
run; 
Where: 
treat 
= study treatment (CLS006, Vehicle) 
site 
= investigative site 
sex 
=sex (male, female) 


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agegrp   = age group (≥2 to <12, ≥12 to <18 or ≥18) 
w0 = number of warts at baseline (total number to be treated during the study)  
w2 = number of remaining treated warts at Week 2 
w4 = number of remaining treated warts at Week 4 
w6 = number of remaining treated warts at Week 6 
w12 
= number of remaining treated warts at Week 12 
w18 
= number of remaining treated warts at Week 18 
Note:  Variable names may differ from those used in the actual programs, but the methodology will 
be the same. 
If an imputed value is not within the appropriate range after the default of 100 tries, the SAS Proc MI 
option MINMAXITER may be increased in order to impute appropriate values. 
In general, data will not be imputed for safety analysis.  
7.7.6. 
Efficacy Endpoints 
7.7.6.1. 
Primary Endpoint 
The primary analysis of efficacy will be made on the difference in the proportion of subjects with 
complete clearance of all treated warts (i.e., Baseline/Treated warts) between the active and vehicle at 
Week 18 /End of Post-treatment Efficacy Evaluation.  This comparison will be made using a CMH 
test stratified by age group (≥2 to <12, ≥12 to <18 or ≥18) and investigative site.  
7.7.6.2. 
Secondary Endpoints 
Secondary efficacy analyses will be conducted sequentially as follows:   
 The ratio of cleared warts to all treated warts at Week 18/End of Post-treatment Efficacy 
Evaluation. 
 Difference in the proportion of subjects with complete clearance of all treated warts at Week 
12, then Week 6/EOT. 
 The ratio of cleared warts to all treated warts at Week 12, then Week 6/EOT. 
 Comparisons of reduction from baseline in wart size of treated warts at Week 18/End of Post-
treatment Efficacy Evaluation. 
To control type-1 error, the statistical testing will stop if non-significant superiority of active to 
vehicle (p>0.025 one-sided) is observed for any of the primary or secondary endpoints. 
7.7.6.3. 
Tertiary Endpoints 
 All endpoints will be compared at all other time-points. 


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 Evaluation of durability of response (clearance and/or wart size reduction) and incidence of 
recurrence of treated warts from Week 18/End of Post-treatment Efficacy Evaluation period to 
the end of the follow-up period (week 30).  
These data are considered tertiary and exploratory to gain insight regarding the pharmacodynamic 
nature of the treatment response.  No formal hypothesis testing is planned.  Therefore, any statistical 
testing done will be considered to be descriptive and not inferential. 
7.7.7. 
Efficacy Analysis 
Comparisons of proportions of subjects with all treated warts cleared will be made using Cochran-
Mantel-Haenszel (CMH) test for treatment stratified by age group (≥2 to <12, ≥12 to <18 or ≥18) and 
investigative site at α= 0.05. Because of the low complete clearance rate, sites will be pooled in a 
manner ensuring that each pooled site will have sufficient number of subjects cleared for a stratified 
CMH analysis. The algorithm for pooling sites will be described in the SAP and finalized prior to 
unblinding. Comparisons of clearance rates of treated warts (number of cleared warts/number of 
treated warts) will be made using two-sided Wilcoxon rank sum testing at α= 0.05. 
For the continuous variables of wart size (diameter), analysis of covariance (ANCOVA) will be used 
to test CLS006 versus vehicle at Week 6/EOT, Week 18/End of Post-treatment Efficacy Evaluation 
and each week of the Post-treatment Efficacy Evaluation period and Follow-up period using a mixed 
effects model with site, age group (≥2 to <12, ≥12 to <18 or ≥18) and Baseline Treatment Wart size 
(i.e., diameter) as covariates (baseline wart size will be used  as a covariate for comparison of wart 
size).  
Data listings and averages will be presented for safety measures. 
7.7.8. 
Safety Endpoints 
Safety variables including AEs, vital signs, and laboratory parameters will be collected according to 
the Schedule of Visits and Study Assessments (refer to Section 7.3.1). 
7.7.9. 
Safety Analysis 
Safety variables will be tabulated and presented for all patients in the Safety population. AEs will be 
categorized by system organ class and Preferred Term from the current version of MedDRA.  AEs 
will be summarized overall, by seriousness, severity, and relationship to treatment. Incidence of AEs 
will be presented overall, by system organ class and preferred term.  Severity and relationship to 
study drug of the incidence of AEs will also be presented.  AEs causing study drug withdrawal and/or 
early study discontinuation and incidence of SAEs will be summarized.   
Changes from baseline in vital signs and laboratory parameters, and shifts from baseline in laboratory 
parameters will be summarized by treatment. Descriptive statistics and frequency tables will be 
prepared as appropriate for laboratory measurements.  


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7.7.10. 
Multicenter Pooling  
Approximately 40 centers are planned in this study; whenever possible, approximately at least 12 
subjects will be enrolled per center. In the event a center has a low number of subjects enrolled or an 
insufficient number of subjects with complete clearance for the stratified CMH analysis, pooling of 
centers will be performed based on geographical center location.  The algorithm for pooling of 
centers will be described in the Statistical Analysis Plan. Descriptive summary statistics will be 
generated including center and pooled-center (when appropriate) by primary and secondary efficacy 
endpoints. 
8. 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS 
8.1. 
ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with the FDA and ICH guidelines on current GCP 
following the ethical principles originating from Declaration of Helsinki.  Additionally, the study will 
be conducted in accordance with any applicable laws or regulations of the country in which the 
clinical research is conducted. 
8.2. 
PROTOCOL ADHERENCE 
The Investigator must read the protocol thoroughly and must follow the instructions exactly.  Any 
change should be agreed upon by prior discussion between the Sponsor and the Investigator, with 
appropriate written protocol amendments made prior to implementation of the agreed-upon changes.   
8.2.1. 
Changes in Study Conduct/Statistical Analyses/Amendments 
No change in the conduct of the study should be instituted without written approval from the 
Sponsor.  Any amendment containing major modifications (particularly if it may involve an increased 
risk to the subjects) will require written approval from the Sponsor and IRB/IEC before it may be 
implemented.   
8.3. 
INSTITUTIONAL REVIEW BOARD /INDEPENDENT ETHICS COMMITTEE  
This study, all appropriate amendments, all advertising, and written materials given to the subjects 
will be reviewed and approved by an IRB/IEC, prior to use. 
8.4. 
SUBJECT INFORMATION AND CONSENT 
The study personnel will inform all subjects in this study in accordance with GCPs, about the study.  
The study personnel will review the informed consent form (ICF) with each subject and give the subject 
an opportunity to read the consent and have all questions answered before proceeding.  A current written 
consent form, approved by an IRB, is to be supplied by the Investigator and willingly signed by each 
subject, or their legal guardian, prior to initiating any study procedures, including instructing the 
subject to discontinue the use of medications requiring wash-out.  A written assent form, approved by 


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an IRB, is to be supplied by the Investigator and willingly signed by each subject who is legally not 
able to sign an informed consent form, as required, in accordance with IRB guidelines for providing 
assent.  The Investigator is responsible for maintaining each subject’s consent form and assent form, 
if applicable, in the study file and providing each subject with a copy of the signed form(s). 
8.5. 
RECORD KEEPING  
8.5.1. 
Data Collection 
The Investigator must maintain detailed records on all study subjects.  Data for this study will be 
appropriately documented in the source documents and entered into eCRFs through the eDC system 
provided by the Sponsor’s designated data management group.  Applicable data from the subject’s 
source documents should be recorded in the eCRFs completely, promptly, taking time to correct any 
mistakes as prompted by the eCRF system.   
Throughout the study, representative(s) of the Sponsor (e.g., CRO’s Monitor) will review the 
appropriate eCRF pages.  eCRFs should be completed and ready for review by the Sponsor/CRO’s 
Monitor, within one (1) week of each study visit for a given subject. 
8.5.2. 
Data Corrections 
Corrections of data entered into the eCRF must be made in the system for electronic case report 
forms and supported by source documents, as appropriate. 
 The Sponsor’s Monitor will review the eCRFs, evaluate them for completeness and 
accuracy, and ensure that all appropriate information is entered. 
 No changes will be made to the data on the eCRF pages after the data are determined to be 
final by the Sponsor’s Monitor and data management group.  Corrections to the eCRF 
through queries and comments will be tracked by the eCRF internal audit trail as outlined in 
the eDC system. 
8.5.3. 
Source Documentation 
Investigators must keep accurate separate records (other than the eCRF) of all subjects’ visits, which 
include all pertinent study-related information including the original signed/dated informed consent 
and assent forms, and drug accountability records.  As a minimum, a statement should be made in the 
subject’s record indicating that the subject (or caregiver) has signed an informed consent form and 
has been enrolled in Protocol CLS006-CO-PR-002.   
Any AEs must be thoroughly documented.  Results of any diagnostic tests conducted during the 
study should also be included in the source documentation.  Relevant telephone conversations with 
the subject and/or the Sponsor/CRO concerning the study must also be recorded. 


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8.5.4. 
Monitoring/Auditing 
Representatives of the Sponsor, following GCP guidelines, will monitor the conduct of the study.  In 
addition, inspections or on-site audits may be carried out by the FDA, local regulatory authority or by 
the Sponsor’s independent Quality Assurance Department.  The Investigator will allow the Sponsor’s 
representatives and any regulatory agency to examine all study records, eCRFs, corresponding 
subject medical records, clinical drug dispensing records, drug storage area, and any other documents 
considered source documentation. 
8.5.5. 
Archives 
Records must be retained in accordance with the current ICH Guidelines on GCP.  All essential study 
documents including records of subjects, source documents, eCRFs and study drug inventory must be 
kept on file.  
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational products.  However, essential documents may be retained for a 
longer period if required by the applicable regulatory requirements or by agreement with the Sponsor. 
The Sponsor is responsible for informing the Investigator when these documents no longer need to be 
retained. The Investigator will not dispose of any records relevant to this study without written 
permission from the Sponsor, and will provide the Sponsor the opportunity to collect such records.   
The Investigator shall take responsibility for maintaining adequate and accurate source documents of 
all observations and data generated during the study.  Such documentation is subject to inspection by 
the Sponsor, its representatives, and regulatory authorities. If the Principal Investigator retires, 
relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody 
must be transferred to a person who will accept the responsibility and the Sponsor must be notified in 
writing of the name and address of the new custodian. 
8.6. 
CONTRACTUAL REQUIREMENTS 
A contractual agreement will be signed between the Sponsor/CRO and the Investigator.  This 
document will contain complementary information, i.e. financial agreement, confidentiality, study 
payment schedule, and publication of study results. 
8.7. 
PUBLICATION POLICY 
All data generated from this study are the property of the Cutanea Life Sciences, Inc.  Publication of 
data will be done in accordance with the contractual agreement between the Sponsor/CRO and 
Investigator/clinical site. 
 
 
 


Cutanea Life Sciences, Inc. / IND# 131395 
 
May 23, 2017 
Protocol CLS006-CO-PR-002 
 
Page 40 of 42 
 
 
CONFIDENTIAL 
9. 
REFERENCES 
Hartley, C., Hartley, M., Pardoe, I., & Knight, A. (2006). Ionic Contra-Viral Therapy (ICVT); a new 
approach to the treatment of DNA virus infections. Archives of Virology, 151(12):2495-501. 
Kwok, C. S., Gibbs, C., Bennett, C., Holland, R., & Abbott, R. (2012). Topical treatments for 
cutaneous warts. Cochrane Database of Systematic Reviews. 
 
 
 
 


Cutanea Life Sciences, Inc. / IND# 131395 
 
May 23, 2017 
Protocol CLS006-CO-PR-002 
 
Page 41 of 42 
 
 
CONFIDENTIAL 
10. 
INVESTIGATOR AGREEMENT 
I have read the protocol entitled “A Phase 3, Randomized, Double-Blind, Vehicle-Controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of CLS006 versus Vehicle in Subjects 12 years 
of age or older with Cutaneous Common Warts”.   
 
I agree that the Protocol CLS006-CO-PR-002 contains all of the information necessary to conduct the 
study.  I agree to conduct the study as described herein. 
 
 
 
 
 
 
Principal Investigator Name 
(Printed)
Principal Investigator Signature 
 
Date 
 
 
 


Cutanea Life Sciences, Inc. / IND# 131395 
 
May 23, 2017 
Protocol CLS006-CO-PR-002 
 
Page 42 of 42 
 
 
CONFIDENTIAL 
APPENDIX A: STUDY DRUG APPLICATION INSTRUCTIONS 
For this research, it’s important to standardize the way study drug is applied to each wart. Please read these 
instructions carefully. 
APPLY STUDY DRUG ONCE DAILY, AS DIRECTED. 
 
Study drug must be used to treat the wart(s) ONLY as directed by study personnel.   
 
For children under the age of 12, an adult caregiver (a parent/guardian) should apply the study drug.  
 
Each wart needs to be treated daily (one time per day) or until advised to stop by study personnel.  
 Choose a regular time each day, based on convenience, to apply the study drug (e.g., in the morning 
after showering or in the evening prior to bedtime). If you/your child are not able to apply the study 
drug at the regular time, you/your child should still apply but be careful, you/your child should not 
apply the gel on the wart more than 1x per day. 
 
Applying study drug: 
1. Wash, rinse and thoroughly dry your (or your child’s) hands before applying study drug.  
2. Remove the cap from the study drug tube and squeeze a small amount of the study drug gel (see 
photo) to cover each wart as directed by study personnel. 
3. Gently rub the gel into the wart for approximately 20 seconds or until the gel is fully absorbed.  
 Avoid contact with your (or your child’s) eyes, mouth, and inside the nose. If study drug comes 
in contact with eyes, flush the area with water. 
 Avoid contact with others while the gel dries. 
 
              After applying study drug: 
1. Return the cap to the study drug tube and store the study drug tube at room temperature. 
2. Record each study drug application in the study diary provided. 
3. Keep the skin dry as long as possible, at least for an hour!  
 
Unless hands are being treated, wash hands after application. 
 
DO NOT apply bandages or dressings to the treated wart(s). 
4. If the study drug is applied by an adult caregiver (a parent/guardian), they will need to wash their 
hands after application.  
 Reminder: Bring the study drug tube and study diary to the clinic at EVERY visit; do NOT discard the 
study drug tube (even if it’s empty)!  Please call the clinic immediately if you have lost the tube. 
Approximate 
amount of gel 
to be applied 
to each wart
Side view

SAP_001.pdf: 
 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
Statistical Analysis Plan 
 
Sponsor: 
Cutanea Life Sciences, Inc. 
Protocol No: 
CLS006-CO-PR002 
PRA Project Id: 
CUSL006C-CLS06C 
Seizure frequency 
 
Version No.: 
1.0 
Title: 
A Phase 3, Randomized, Double-Blind, Vehicle-Controlled, Multicenter Study to 
Evaluate the Efficacy and Safety of CLS006 versus Vehicle in Subjects 2 years 
of age or older with Cutaneous Common Warts 
CRF Version 
No./Date: 
Version 4.0 /25-Oct-2017 
SAP No. 
1.0 
 
 Approvals 
Sponsor 
Sponsor Name: 
Cutanea Life Sciences, Inc. 
Representative/ Title: 
Gary Feiss / VP Clinical Operations 
Signature /Date: 
 
PRA 
Project Manager/Title:
Nikki Bindra / Project Manager 
Signature /Date: 
 
Biostatistician / Title 
(Owner): 
Sheila Quinn / Senior Principal Biostatistician 
Signature /Date: 
 
*If using eTMF3, this section should be removed from the document as document approvals are recorded electronically 
through the eApproval workflow. 
(NOTE: Electronic Signatures should only be used if all parties have the ability to eSign.) 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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Table of Contents 
 Approvals ........................................................................................................................................................................................................ 1 
Table of Contents ................................................................................................................................................................................................ 2 
 Purpose ............................................................................................................................................................................................................. 4 
 Scope .................................................................................................................................................................................................................. 4 
 Introduction ................................................................................................................................................................................................... 4 
4.1 
Changes from Protocol ............................................................................................................................................................ 4 
 Study Objectives........................................................................................................................................................................................... 4 
 Study Design .................................................................................................................................................................................................. 5 
6.1 Sample Size Considerations ............................................................................................................................................................... 7 
6.2 Randomization .......................................................................................................................................................................................... 7 
 Study Variables and Covariates ........................................................................................................................................................... 7 
7.1 
Primary Efficacy Variable ....................................................................................................................................................... 7 
7.2 
Secondary Efficacy Variables ................................................................................................................................................ 8 
7.3 
Tertiary Efficacy Variables ..................................................................................................................................................... 8 
7.4 
Other Variables ............................................................................................................................................................................ 8 
7.5 
Safety Variables ........................................................................................................................................................................... 8 
7.6 
Predetermined Covariates and Prognostic Factors .................................................................................................. 8 
 Definitions ....................................................................................................................................................................................................... 8 
 Analysis Sets ............................................................................................................................................................................................... 10 
9.1 
Intention-to-Treat ................................................................................................................................................................... 10 
9.2 
All Treated ................................................................................................................................................................................... 10 
9.3 
Per Protocol ................................................................................................................................................................................ 10 
 Interim Analyses .................................................................................................................................................................................... 11 
 Data Review .............................................................................................................................................................................................. 11 
11.1 
Data Handling and Transfer ............................................................................................................................................... 11 
11.2 
Data Screening .......................................................................................................................................................................... 11 
 Statistical Methods................................................................................................................................................................................ 11 
12.1 
Subject Disposition ................................................................................................................................................................. 12 
12.2 
Important Protocol Deviations ......................................................................................................................................... 12 
12.3 
Treatments .................................................................................................................................................................................. 13 
12.3.1 
Extent of Study Drug Exposure .......................................................................................................................................13 
12.3.2 
Prior/Concomitant Medications .....................................................................................................................................13 
12.4 
Demographic and Baseline Characteristics ................................................................................................................ 13 
12.5 
Efficacy Analyses ...................................................................................................................................................................... 13 
12.5.1 
Primary Variable .....................................................................................................................................................................14 
12.5.2 
Methods for Handling Dropouts and Missing Data ...............................................................................................15 
12.5.3 
Multiplicity ................................................................................................................................................................................17 
12.5.4 
Pooling of Sites ........................................................................................................................................................................17 
12.5.5 
Secondary Variables .............................................................................................................................................................17 
12.5.6 
Tertiary Variables ..................................................................................................................................................................20 
12.5.7 Other Variables .............................................................................................................................................................................21 
12.6 
Safety Analyses ......................................................................................................................................................................... 21 
12.6.1 
Adverse Events ........................................................................................................................................................................21 
12.6.2 
Deaths and Serious Adverse Events .............................................................................................................................23 
12.6.3 
Laboratory Data ......................................................................................................................................................................24 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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12.6.4 
Vital Signs ...................................................................................................................................................................................24 
12.6.5 
Physical Examinations, ECGs, and Other Observations Related to Safety .................................................24 
 Validation .................................................................................................................................................................................................. 25 
 References ................................................................................................................................................................................................. 25 
Appendix 1 Glossary of Abbreviations .................................................................................................................................................. 26 
 
 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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 Purpose 
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Cutanea Life Sciences, Inc. Protocol CLS006-CO-PR-002. 
 
 Scope 
This plan is a living document that will be created during the trial start-up. The Statistical Analysis Plan 
will be finalized prior to database lock. SAP will require sign off from the Project Manager and the 
sponsor. 
The Statistical Analysis Plan outlines the following: 
 Study objectives 
 Study design 
 Variables analyzed and analysis sets 
 Applicable study definitions 
 Statistical methods regarding important protocol deviations, study drug exposure, efficacy 
analysis, concomitant medications, adverse events handling, laboratory data and physical 
examinations 
 
 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Cutaneous Life Sciences, Inc. Protocol CLS006-CO-PR-002. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This 
version of the plan has been developed using the protocol dated 23May2017 and CRF dated 
02Aug2017. Any further changes to the protocol or CRF may necessitate updates to the SAP. 
4.1 Changes from Protocol 
No changes as of this version of the SAP. 
 
 Study Objectives  
The objective of this study is to evaluate the efficacy and safety of six (6) weeks of once daily 
application of Furosemide Topical Gel 0.125% (CLS006) compared to vehicle in subjects ≥2 years of 
age with nongenital cutaneous common warts (verruca vulgaris). 
 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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 Study Design 
The study will be conducted as a randomized, double-blind, vehicle-controlled, parallel group, 
multicenter study at approximately 40 sites involving approximately 480 subjects (~240 per treatment 
group) with nongenital cutaneous common warts. Approximately 160 subjects enrolled will be 
pediatric subjects (~80 will be ≥ 2 to <12 years of age and ~80 will be ≥12 to <18 years of age). 
Subjects may be in the study up to 34 weeks. 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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Table 1 Schedule of Visits and Study Assessments 
 
 
Study Period
Screening
Double-Blind Treatment (DBT) 
Post-treatment 
Efficacy Evaluation (PTEE) 
Follow-up1 
  
  
  
  
  
Week 6 / 
  
Week 18 / 
 
  
Visit
Screening
Baseline
Week 
2 
Week 
4 
End of 
Treatment (or 
Early Term 
during DBT 
Period) 
Week 12
End of Post-tx 
Efficacy 
Evaluation (or 
Early Term 
during PTEE 
Period)
Follow-up
#1 
Follow-up #2 
(Final) 
  
  
  
  
  
  
  
  
  
Time
Day -28 
to -1 
Day 1 
Day 
14 
Day 
28 
Day 42 
Day 84 
Day 126 (3 
mon post-
treatment) 
Week 24 
Week 30 
(6 mo. post-
treatment)
  
 
 
Procedures (Visit Window) 
  
(± 3 days) 
(± 5 days) 
(± 7 days) 
Informed Consent 
X 
  
  
  
  
  
  
  
 
Demographics & Medical/Surgical 
History 
X 
X2 
  
  
  
  
  
  
 
Prior & Concomitant 
Medication/Treatment 
X 
  
  
  
  
  
  
  
 
Limited Physical Exam3 
X 
  
  
  
X 
  
  
  
 
Vital Signs (BP, HR) 
X 
X 
X 
X 
X 
X 
X 
  
 
ECG 
X 
  
  
  
  
  
  
  
 
Urine Pregnancy Test4 
X 
X 
  
  
X 
  
  
  
 
Clinical Safety Lab Testing 
(Hematology, Chemistry) 
X 
  
  
  
X 
  
  
  
 
Wart Assessments 
X 
X 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
Clinical Photography (select sites 
only) 6 
  
X 
  
  
x 
  
x 
  
 
Inclusion/Exclusion Criteria 
X 
X 
  
  
  
  
  
  
 
Enroll/Randomization 
  
X 
  
  
  
  
  
  
 
Dispense Study Drug & Diary 
  
X 
X 
X 
  
  
  
  
 
Treatment Compliance / Collect 
and Review Study Drug & Diary 
  
  
X 
X 
X 
  
  
  
 
Apply Study Drug (Once Daily) 
  
X7 
  
  
  
  
  
  
 
Concomitant 
Medication/Treatment Review 
  
X 
X 
X 
X 
X 
X 
X8 
X8 
Adverse Events 
  
X2 
X 
X 
X 
X 
X 
  
 
 
1 
Only required for subjects who achieved clearance of at least one treated wart as determined by the PI or an appropriately qualified Sub- 
I at week 18 / End of Post-tx Efficacy Evaluation. 
2 
Adverse event assessment will be performed following the first study drug application (any changes in subject’s health before first study 
drug application should be recorded as medical history). 
 
3 
A limited physical exam (refer to Section 7.5.2 of the protocol) including height & weight measurements at Screening and weight 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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measurement only at the Week 6/EOT (or Early Termination during DBT Visit). 
4 
Urine pregnancy test for women of childbearing potential only. Urine pregnancy testing should also be conducted at any visit for any 
female who is suspected of being pregnant. 
5 
New common warts that appear after the Baseline visit will be identified, characterized and location recorded/mapped only, but not 
treated. 
6 
Clinical Photography will be optional for subjects < 12 years of age. 
7 
The first application of study drug will be performed under supervision at the study center. 
8 
Concomitant medication/treatment review at Follow-up visit will focus on review of restricted concomitant medication/treatment only 
(refer to Section 7.6.10.1 of the protocol). 
 
6.1 Sample Size Considerations 
The sample size estimates for the current study are based upon the rates of clearance of warts 
in the previous Phase 2 study (CHDR1423). This was a randomized, double blind, vehicle 
controlled, Phase II study in 80 subjects who were treated with topical digoxin, furosemide, 
digoxin/furosemide, or vehicle for 42 days daily with an 8-week follow-up period. For the 
furosemide treatment group, the proportion of subjects with all cleared warts was 0.1 (10%) 
versus 0 in the vehicle. 
The difference in the proportion of subjects with all treated warts cleared (complete 
clearance) at the Week 18/End of Post-Treatment Efficacy Evaluation period (EOS) is the 
primary endpoint of the current study. For conservative purposes, assuming 10% and 2% 
complete clearance rates in the furosemide and vehicle treated groups, respectively, 200 
subjects randomized per treatment group will provide for 92% power at a two-sided α of 0.05 
to detect a difference between active and vehicle treated groups. 
With the inclusion of an additional 80 subjects in the ≥ 2 to < 12 cohort, the total sample size of 
480 will provide 96% power with the assumption unchanged. 
6.2 Randomization 
Subjects that meet all inclusion and exclusion criteria will be randomized to one of two 
treatment groups in a 1:1 ratio for each study center according to a predetermined computer-
generated randomization code. 
Subjects will be randomized to treatment using an Interactive Web Response System (IWRS). 
The randomization scheme will include age stratum at 3 levels (≥2 to <12, ≥12 to <18 or ≥18) 
and investigative site. 
 
 Study Variables and Covariates 
7.1 Primary Efficacy Variable 
Proportion of subjects with complete clearance of all treated warts (i.e., Baseline Treated 
warts) between the active and vehicle at Week 18 /End of Post-treatment Efficacy Evaluation. 
 
 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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7.2 Secondary Efficacy Variables 
 The ratio of cleared warts to all treated warts for each subject at Week 18/End of Post- 
treatment Efficacy Evaluation.
 Proportion of subjects with complete clearance of all treated warts at Week 12, then 
Week 6/EOT.
 The ratio of cleared warts for each subject to all treated warts at Week 12, then Week 
6/EOT.
 Reduction from baseline in wart size of treated warts at Week 18/End of Post- 
treatment Efficacy Evaluation
7.3 Tertiary Efficacy Variables 
 All endpoints at all other time-points.
 Evaluation of durability of response and incidence of recurrence of treated warts from 
Week 18 end of post-treatment efficacy evaluation period to Week 30 the end of the 
follow-up period.
7.4 Other Variables 
 
New common warts that appear after Baseline by visit
 
7.5 Safety Variables 
Safety variables including AEs, vital signs, and laboratory parameters will be collected 
according to the Schedule of Visits and Study Assessments (refer to Table 1). 
7.6 Predetermined Covariates and Prognostic Factors 
Subject age (> 2 - < 12, > 12 - < 18, and > 18) and investigator site will be used as covariates for 
Cochran-Mantel-Haenszel (CMH) analyses. 
Baseline Treatment Wart size (i.e., diameter) will also be included as a covariate in the analysis of 
covariance (ANCOVA).  
 
 Definitions 
Baseline and Change from Baseline 
Baseline is defined as the last available pre-dose value. 
 
 
Change from Baseline = (post-Baseline value – Baseline value). For the purpose of tabulations, 
the unscheduled post-Baseline values generally will be excluded. 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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Completion of study 
The completion of study is defined as an answer of “Yes” to the question “Did the subject complete 
the study at Week 18?” on the form of Study Completion in the CRF. 
Prior and Concomitant Medications 
Prior medications will be any medication with a start date before the first day of treatment. 
Concomitant medications are defined as any medications ongoing at the start of treatment or with 
a start date on or after the first dose date. Consequently, medications ongoing at the start of 
treatment will be reported as both prior and concomitant medications. 
Treatment-Emergent Adverse Events 
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens or 
intensity increases after receiving the study medication. Events which occur more than thirty days 
after the last dose of study medication will not be considered treatment emergent. Adverse Events 
will be considered treatment-emergent if they have missing or have partial start dates for which it 
cannot be determined whether the AE started before or after the first dose of study medication. 
Adverse Events with Outcome of Death 
Any AE with an outcome of fatal will be considered as AE with an outcome of death. 
Imputation of AE (for determination of TEAE only) and concomitant medication start and 
stop dates: 
Start Date: If only ‘day’ is missing, and the month and year are not the same as the month of 
first dose, then impute day with ‘01’. Otherwise, if the month and year are the same as the first 
dose date, use the first dose date. If ‘day’ and ‘month’ are missing, and ‘year’ is not missing, 
then impute month and day with month and day of the first dose date (assuming same ‘year’). 
If ‘day’ and ‘month’ are missing and ‘year’ is not missing and is not the same year as first dose 
date, then impute with ‘01’ for both ‘day’ and ‘month’. If the start date is completely missing, 
it will be set to the first dose date. 
Stop Date: If only ‘day’ is missing, impute day with last day of the month. If ‘day’ and ‘month’ 
are missing, and ‘year’ is not missing, then impute month with ‘12’ and day with ‘31’ (or date 
of study discontinuation/completion if earlier than 12-31 and year is the same as the year of 
discontinuation). If the stop date is completely missing, it will be set to the date of study 
discontinuation/completion. A stop date will not be applied to ongoing AEs. 
 
Treatment-related Adverse Events 
Any AE with a relationship to study treatment of “Possibly Related” or “Definitely Related” or 
missing will be considered a treatment-related AE as determined by the Investigator. 
Study Day 1 
The first day of medication administered. 
Study Day 
Study day is defined as the number of days from Study Day 1. 
 Before Study Day 1, Study Day = (Date of Interest – Date of Study Day 1) 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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 On or After Study Day 1, Study Day = (Date of Interest – Date of Study Day 1) + 1 
Therefore, the day prior to Study Day 1 is -1. 
Analysis Visit Window 
Analysis window won’t be required for this study. The unscheduled post-Baseline values will be 
excluded from the summary table, but only listed. 
 
 Analysis Sets 
9.1 Intention-to-Treat 
The ‘Intent-to-Treat’ (ITT) analysis set will include all randomized subjects. The ITT population 
will be the primary population for all efficacy analyses. 
9.2 All Treated 
The “All-treated” analysis set will consist of all subjects receiving at least one application of 
study drug.  All safety analyses will be performed on the all-treated analysis set. 
9.3 Per Protocol 
The Per-Protocol (PP) analysis set will include all subjects in the ITT population who complete 
6 weeks of treatment and 12 weeks of post-treatment efficacy evaluation without any major 
deviations from the protocol. The subjects to be included in the PP analysis population will be 
determined by the Sponsor prior to the unblinding of the study. The PP population will be used 
as secondary for the primary endpoint only. 
Subjects potentially excluded from the PP population will be based on the following criteria and 
reviewed by the clinical team: 
 
1 - Subjects who have not completed 6 weeks of treatment and 12 weeks of post-treatment 
efficacy evaluations 
2- Subjects less than 2 years of age 
3 - Subjects with more than 6 common warts at baseline 
 
4 - Subjects without a pre-treatment wart assessment 
5 - Subject who have taken an excluded prior and concomitant medications / therapies as listed in 
the protocol 
6 - Subjects whose warts are not present for at least 4 weeks before treatment (baseline) as 
reported in Medical History 
7 - Subjects with clinically significant dermatological disorders in the treatment area 
8 - Subjects who require ongoing treatment with furosemide 
9 - Subjects whose study drug compliance is as follows: missing more than 12 doses in total 
throughout the study 
10 - Subjects with week 18 visits out of window more than 14 days outside the target visit date  


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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11 - Subjects who received the wrong assigned treatment medication 
12 – Subjects who violated key inclusion/exclusion criteria 
Subject listings will be provided to the Sponsor based on the above criteria for review and final 
determination of the PP population. Subjects to be excluded from the PP will be determined 
before the study is unblinded and listed in a separate document. 
 
 Interim Analyses 
No interim analyses are planned for this study. 
 
 Data Review 
11.1 Data Handling and Transfer 
Data will be entered and exported as SAS® version 9.4 or higher datasets. Converted datasets will 
be created using SAS and following standard Clinical Data Interchange Standards Consortium 
Standard Data Tabulation Model (CDISC SDTM, version 1.3, Implementation Guide version 
v3.1.3) conventions. Analysis datasets will be created using SAS and following CDISC Analysis 
Data Model (ADaM, version 2.1, Implementation Guide 1.0) standards. 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 21.0 at the time of the analysis to assign a system organ class (SOC) and 
preferred term (PT) to each event. Prior and concomitant medications and steroids will be coded 
using the World Health Organization Drug Dictionary 2018MAR01 DDE + HD at the time of the 
analysis. 
Additional details can be found in the PRA Data Management Plan for this study. 
11.2 Data Screening 
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of 
analysis datasets, tables, figures, and listings (TFL) provides additional data screening. Presumed 
data issues will be output into SAS logs identified by the word “Problem” and extracted from the 
logs by a SAS macro and sent to Data Management. 
Review of a pre-freeze TFL run on clean subjects and a post- freeze TFL run on the frozen 
database allow for further data screening prior to lock. The post- freeze TFL will be discussed 
with the sponsor in a data review meeting to identify any final data issues and seek corrections 
prior to database lock. The PRA statistician and the sponsor must approve database lock.  
 
 Statistical Methods 
All statistical analyses will be performed using SAS version 9.4 or higher. 
The final analysis will be performed at the end of the study (end of trial) after all subjects have 
completed the Week 18 assessments and the Week 30 follow-up assessments or terminated early. 
Please note that only the subset of subjects who achieved clearance of at least one treated wart at 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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Week 18/End of Post-treatment Efficacy Evaluation period will continue to the Follow-up period. 
Unless otherwise specified, descriptive data summaries will be tabulated for all endpoints. 
Categorical data will be summarized using number of subjects (n), frequency and percentages of 
subjects falling into each category, with the denominator for percentages being the number of 
subjects in the study population, unless otherwise noted. Percentages will be rounded to one 
decimal place except for 100%, which will have no decimal place. Counts of zero will not display 
a percentage. 
All continuous variables will be summarized using mean, standard deviation, median, minimum, 
maximum, and number of subjects with observations. The mean and median will be presented to 
one decimal place greater than the original data, standard deviation will be to two decimal places 
greater than the original data, and the minimum and maximum will have the same number of 
decimal places as the original data. 
12.1 Subject Disposition 
The number and percentage of subjects in ITT analysis set will be summarized. A listing by subject 
will be provided to indicate which subjects are included in each analysis set. 
The number and percentage of subjects enrolled, ITT analysis set, All-Treated analysis set, Per-
Protocol analysis set, who complete the study and who are in Follow-up period will be presented 
by treatment, together with the number and percentage of subjects who withdrew from the study 
prematurely and a breakdown of the corresponding reasons for withdrawal. 
A listing of all subjects’ analysis set inclusions, disposition, and subjects who discontinued will be 
presented. 
12.2 Important Protocol Deviations 
 
Important protocol deviations (IPD) are a subset of protocol deviations that might significantly 
affect the completeness, accuracy, and/or reliability of the study data or that might significantly 
affect a subject's rights, safety, or well-being.  
 
Protocol deviations will be determined based on programmed checks of the study database. These 
Protocol deviations are based on the following categories deemed to be important: 
1. Subjects that violate key inclusion/exclusion criteria 
2. Subjects who received the wrong treatment 
3. Subjects who received prohibited medications/treatment during the trial 
4. Subjects who met withdrawal criteria but were not withdrawn 
5. Subjects who did not have necessary data collected to interpret the primary endpoint 
a. Missed Week 18 visit 
b. Week 18 more than 14 days outside target visit date 
 
6. Subjects with a deviation that significantly affects safety or well-being 
a. Physical exam, labs or ECG not performed at screening prior to randomization 
b. Week 6 physical exam or labs not performed 
c. Pregnancy test not preformed prior to randomization 
d. Pregnancy test not performed at Week 6 
 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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For reporting purposed Protocol Deviations will be assigned to the following categories: 
Inclusion Criteria, Exclusion Criteria, Study Drug, Assessment Safety, Visit Window, and 
Prohibited concomitant medications. 
 
The protocol deviation list will be finalized prior to the database lock, and important protocol 
deviation data will be listed and tabulated using incidence by deviation type. 
12.3 Treatments 
12.3.1 Extent of Study Drug Exposure 
Exposure to study drug (e.g. at least 1 dose etc.), duration of exposure, and number of missed doses 
(Day 1-Week 2, Week 2-Week 4, Week 4-Week 6) will be summarized by group for the All- 
Treated analysis set. Summary statistics will be provided for total duration (days) of study drug 
exposure and treatment compliance for the All-Treated analysis set. 
Duration of exposure will be defined as the total number of days a subject was exposed to study 
drug, calculated as (last dose date - first dose date+1). 
Study drug dosing information will be presented by subject in data listings 
12.3.2 Prior/Concomitant Medications 
Prior/concomitant medications will be coded by World Health Organization Drug Dictionary 
2018Mar01 DDE + HD and will be summarized by Anatomic Therapeutic Classification (ATC) 
class and preferred name. The analysis will be performed using the ITT population. 
The numbers and percentages of subjects using each medication will be displayed for within 
double-blind treatment period and throughout the study. Subjects taking more than one medication 
in the same ATC class or preferred name will be counted once for the number of subjects taking 
that preferred name. 
12.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics (sex, ethnicity, race, age, age group (≥2 to <12, ≥12 
to <18 or ≥18), weight [kg], height [cm], body mass index [BMI; kg/m2] will be summarized by 
treatment using descriptive statistics for subjects in ITT Analysis Set. Qualitative variables (age 
group, sex, ethnicity, race, wart characterization category, and wart location) will be summarized 
using frequencies while quantitative variables (age, weight, height, BMI, wart size, and number of 
warts) will be summarized using mean, SD, median, minimum, and maximum. Demographic and 
baseline data will also be listed for subjects for the ITT Analysis Set. 
General Medical/Surgical History will be coded by MedDRA version 19.1 or later, as applicable 
at time of analysis and will be presented by subject listing. 
Cutaneous Common Wart History will be listed by subject. 
 
 
12.5 Efficacy Analyses 
The primary and secondary efficacy analyses are planned analyses and the tertiary analyses are 
exploratory only in order to gain insight regarding the pharmacodynamic nature of the treatment 
response. 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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Wart assessments are conducted at Screening, Baseline, Week 2, Week 4, Week 6/EOT, Week 12, 
Week 18/End of Post-treatment Efficacy Evaluation, and Week 30 Follow up (for the subset of 
subjects). Wart characterization categories (solitary and cluster/splitting/satellite), the total number 
of warts, and the location (hands: dorsal, periungual, and palmar; foot: dorsal, limbs: arm and leg; 
and trunk) will be tabulated for the baseline visit for the ITT analysis set, using descriptive statistics. 
The changes from baseline in total wart sizes (mm) will be summarized by group and by visit. 
Clinical clearance of a wart, as determined by the PI or an appropriately qualified Sub-I, should be 
recorded with a size of 0 mm in the CRF. 
Wart assessment data will be listed for all subjects. 
New common warts that appear after the Baseline visit will be identified, characterized and 
location recorded/mapped only, but not treated in this study. Any new common warts will be 
summarized in ITT analysis set for descriptive purpose and listed by subject. 
 
Clinical Photography information collected in the CRF will be listed. 
 
12.5.1 Primary Variable 
The Primary efficacy analyses will be performed on the ITT analysis set to test the difference in 
the proportion of subjects with complete clearance of all treated warts (i.e., Baseline Treated 
warts) between the active and vehicle at Week 18 /End of Post-treatment Efficacy Evaluation. 
 
 Primary efficacy endpoint 
 Proportion of subjects with complete clearance of all treated warts at 
Week 18 End of Post-treatment Efficacy Evaluation. 
 
Proportion of subjects with complete clearance of all treated warts is defined as the 
percentage of the number of subjects who have all baseline treated warts as “clinical 
clearance” at Week 18 out of the total subjects in the ITT Analysis Set. 
Statistical comparisons of proportions of subjects with all treated warts cleared will be made 
using Cochran-Mantel-Haenszel (CMH) test for treatment stratified by age group (≥2 to <12, 
≥12 to <18 or ≥18) and investigative site at α= 0.05. The number and percentage of subjects 
achieving complete clearance of all treated warts (i.e., Baseline Treated warts) will be 
presented by group. The 95% confidence interval will be based on the asymptotic Wald CI 
and will be constructed for the difference of the proportions of 2 treatments. P-value from 
CMH test will be presented. 
The Breslow-Day chi-square test for homogeneity of the odds ratios across strata will be used to 
check the assumption. If the assumption test fails, the nature of the difference may be further 
explored, e.g. subgroup analysis by site and by age group may be explored. 
 
The above primary efficacy analysis will be repeated on the PP analysis set as supportive. 
 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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12.5.2 Methods for Handling Dropouts and Missing Data 
The frequency and percentage of missing values for each variable will be reported. 
The primary method of dealing with missing data will be fully conditional specification (FCS) 
multiple imputations (MI; also called multiple imputation by chained equation [MICE]). 
FCS MI relaxes the assumption of joint multivariate normality of all variables. FCS MI 
specifies the multivariate imputation model on a variable-by-variable basis on a set of 
conditional densities, one for each incomplete variable. Buuren, et al (2011) and Lee and 
Carlin (2012) provide results from simulation studies that suggest that FCS MI generally yields 
estimates that are unbiased with proper standard errors and provide appropriate coverage when 
data are missing at random (MAR). 
For the multiple imputations, twenty sets of imputed data will be generated. These will be 
imputed using SAS Proc MI as shown below. 
Proc MI NIMPUTE=20 SEED=861879112 ROUND=. . . . 1 1 1 1 1 1 
MINIMUM=. . . . 1 0 0 0 0 0 MAXIMUM=. . . .  6 6 6 6 6 6; 
class treat site sex agegrp; 
var treat site sex agegrp w0 w2 w4 w6 w12 w18; 
fcs logistic(treat) logistic(site) logistic(sex) logistic(agegrp) reg(w0) reg(w2) 
reg(w4) reg(w6) reg(w12) reg(w18); 
run; 
Where: 
treat 
= 
study 
treatment (CLS006, 
Vehicle) site 
= investigative site 
sex 
=sex (male, female) 
agegrp 
= age group (≥2 to <12, ≥12 to <18   or 
≥18) 
w0 
= number of warts at baseline (total number to be treated during the study) 
w2 
= number of remaining treated warts at Week 2 
w4 
= number of remaining treated warts at Week 4  
w6 
= number of remaining treated warts at Week 6  
w12 
= number of remaining treated warts at Week 12  
w18 
= number of remaining treated warts at Week 18 
 
Note: Variable names may differ from those used in the actual programs, but the methodology will be 
the same. 
If an imputed value is not within the appropriate range for each variable in the model after the 
default of 100 tries, the SAS Proc MI option MINMAXITER may be increased in order to 
impute appropriate values. 
The PROC FREQ procedure will be used to perform the Cochran–Mantel–Haenszel test and 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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will take the output dataset created from the MI procedure described above. 
 
*** Obtain Mantel-Haenszel estimates ***; 
PROC FREQ data=imputed; 
table site*agegrp*treat*response / cmh; 
ODS OUTPUT cmh=cmh; 
by _imputation_; 
RUN; 
 
The chi-square distribution is highly skewed for smaller degrees of freedom, and thus 
obtaining a combined result of the CMH test from multiply-imputed data requires a 
transformation that would normalize the CMH statistic that have a mean = 0 and unity variance. 
Given that the chi-square distribution for the CMH test has 1 degree of freedom, a square root 
transformation will be used for this purpose. 
 
*** Square root transformation of the CMH statistic resulting in a normalized variate ***; 
DATA cmh_std; 
SET cmh(WHERE=(AltHypothesis="General Association")); 
cmh_value_std= value**.5; 
cmh_sterr_std = 1.0; 
RUN; 
 
The multiple results from the CMH will be combined using PROC MIANALYZE 
 
*** Combine transformed estimates; 
PROC MIANALYZE DATA=cmh_std; 
ODS OUTPUT PARAMETERESTIMATES=mian_cmh_std; 
MODELEFFECTS cmh_value_std; 
STDERR cmh_sterr_std; 
RUN; 
 
A one-sided p-value for the combined CMH will be obtained from the normal test produced 
by PROC MIANALYZE on the transformed statistic. This will be done using the SAS Code 
below. 
 
*** Compute one-sided p-value; 
DATA mian_cmh_std_p; 
SET mian_cmh_std; 
IF tValue > 0 THEN Probt_upper = Probt/2; 
 
 
ELSE Probt_upper = 1-Probt/2; 
RUN; 
 
Last Observation Carried Forward (LOCF) and Baseline Observation Carried Forward 
(BOCF) will be used as sensitivity analyses. 
LOCF sensitivity analysis will be performed on the primary endpoint, where values from a 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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subject’s prior non-missing observation (including baseline and post-baseline) will be imputed 
for any missing post baseline visit for which there is a prior non-missing value. 
BCOF sensitivity analysis will also be performed on the primary endpoint, where the 
baseline observation is treated as the final response from the subject if it is missing. 
In general, data will not be imputed for safety analysis. 
 
 
12.5.3 Multiplicity 
The primary and secondary endpoints will be tested at a two-sided 0.05 level of significance 
sequentially in the order presented in sections 7.1 and 7.2. However, to control type-1 error, the 
statistical testing will stop if non-significant superiority of active to vehicle (p>0.025 one-sided) is 
observed. 
12.5.4 Pooling of Sites 
Approximately 40 centers are planned in this study; whenever possible, approximately at least 
12 subjects will be enrolled per center. In the event a center has a low number of subjects 
enrolled or an insufficient number of subjects with complete clearance for the stratified CMH 
analysis, sites will be pooled in a manner ensuring that each pooled site will have sufficient 
number of subjects cleared for a stratified CMH analysis. 
Planning of site pooling of sites by Meta-group will be finalized prior to database lock by a 
statistician independent from the study team. The pooling strategy will be 1 complete clearance 
and 1 not complete clearance as well as 1 in each treatment group for the given age group and 
site.  Note that each age group need not be present in each site. 
12.5.5 Secondary Variables 
Secondary efficacy analyses will be conducted sequentially as follows for the following 
endpoints: 
 
 Difference in ratio of cleared warts to all treated warts for each subject at Week 18/End 
of Post-treatment Efficacy Evaluation 
 Difference in the proportion of subjects with complete clearance of all treated warts at 
Week 12, then Week 6/EOT. 
 Difference in ratio of cleared warts to all treated warts for each subject at Week 12, then 
Week 6/EOT. 
 
 Comparisons of reduction from baseline in wart size of treated warts at Week 18/End of 
Post-treatment Efficacy Evaluation 
(1) For secondary efficacy variables, including 
 
 Ratio of cleared warts to all treated warts for each subject at 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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o Week 18/End of Post-Treatment Efficacy Evaluation 
o Week 12 
o Week 6/End of Treatment 
 
Ratio of cleared warts to all treated warts for each subject are defined as the ratio of the 
number of cleared warts out of the number of treated warts. 
These endpoints will be analyzed using two-sided Wilcoxon rank sum testing at α= 0.05. P 
value from Wilcoxon rank sum test of no difference between the 2 groups will be produced. 
Summary statistics will be presented for the endpoints. 
(2) For secondary efficacy variables, including 
 
 Proportion of subjects with complete clearance of all treated warts at 
o Week 12 
o Week 6/End of Treatment 
 
Proportion of subjects with complete clearance of all treated warts is defined as the 
percentage of the number of subjects who have all baseline treated warts as “clinical 
clearance” at Week 12/week 6 out of the total subjects 
These endpoints will be analyzed using the Cochran-Mantel-Haenzsel (CMH) test as 
described in the primary efficacy analysis, including the use of age group (≥2 to <12, ≥12 to 
<18 or ≥18), and site serving as the stratifying variables. The number and percentage of 
subjects achieving complete clearance of all treated warts (i.e., Baseline Treated warts) will 
be presented by group. The 95% confidence interval based on the asymptotic Wald CI will be 
constructed for the difference of the proportions of 2 treatments. P-value from CMH test will 
be presented. The Breslow-Day chi-square test for homogeneity of the odds ratios across strata 
will also be used to check the assumption described in the primary efficacy analysis. 
 
(3) For secondary efficacy variables, including 
 
 Reduction from baseline in total wart size of treated warts at 
o 
Week 18/End of Post-treatment Efficacy Evaluation 
 
Reduction from baseline in total wart size (mm) at Week 18= total wart size of treated 
warts at Week 18 – total wart size of treated warts at baseline. 
 
 
This endpoint will be analyzed using the analysis of covariance (ANCOVA) model with the 
group (active drug and vehicle) as fixed effect factors and the baseline total wart size, age group 
(≥2 to <12, ≥12 to <18 or ≥18), and site serving as the covariates. Descriptive statistics will 
include the number of observations, unadjusted mean, standard deviation, median, minimum and 
maximum, and least squares means. Treatment differences from vehicle will be presented and 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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estimated by least squares means from the analysis model along with 95% confidence intervals 
and associated 2-sided p-values. 
 
Interactions between the main effects and each of the covariates will be tested in a separate 
model that includes the interaction terms. If the interaction terms are significant at 0.05 level, 
they will be further explored using descriptive statistics for each significant interaction. 
 
The assumptions of normality and homogeneity of variance from the ANCOVA model will be 
tested at 0.05 level of significance. If any failure of these assumptions is observed, a non- 
parametric test will be used to corroborate the results of the ANCOVA. The Shapiro-Wilk test 
for normality and Levene’s test for the homogeneity of variance will be implemented as follows: 
 
*** obtain residuals from ANCOVA; 
proc glm; 
class site agegrp treat; 
model change = baseline site agegrp treat / ss3; 
output r=resid out=residual; 
run;quit; 
 
*** perform Shapiro-Wilk test; 
ods select TestsForNormality; 
proc univariate data=residual normal; 
var resid; 
run; 
 
*** perform Levenes test; 
ods select hovftest; 
proc glm data=residual; 
class treat; 
model resid = treat / ss3; 
means treat / hovtest=levene; 
run;quit; 
 
If necessary, the Non-parametric ANCOVA will be performed based on Stokes et al. as follows 
 
1) Separately for each site and age group, Baseline and change from Baseline will be ranked 
across treatments using fractional ranks with tied values being assigned the mean of the 
corresponding ranks; 
 
2) Separate ANCOVAs will be conducted for each site and age group for the ranked change 
from Baseline data with the ranked Baseline result as a covariate; 
 
3) The residuals from the ANCOVA models will be tested using a single CMH test for 
treatment effect stratified by site and age group. 
 
 
If necessary, the Non-parametric ANCOVA will be implemented as follows: 
 
*** rank baseline and change from baseline within site and age group; 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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proc rank nplus1 ties=mean out=ranks; 
by site agegrp; 
var change baseline; 
ranks rchg rbase; 
run; 
 
*** get residuals within each site and age group; 
proc glm data=ranks; 
by site agegrp; 
model rchg = rbase; 
output r=resid out=residual; 
run;quit; 
 
*** perform stratified CMH test; 
proc freq data=residual; 
table site*agegrp*treat*resid / cmh noprint; 
run; 
 
Missing data will also be imputed for the secondary analyses on the same endpoint as the 
primary endpoint, but at different visits by multiple imputations. 
 
12.5.6 Tertiary Variables 
The following tertiary endpoints will be explored: 
 All endpoints will be compared at all other time-points. 
 Evaluation of durability of response and incidence of recurrence of treated warts from 
Week 18 end of post-treatment efficacy evaluation period to Week 30 the end of the 
follow-up period. 
 
A. All endpoints at all other time-points, including 
1) Proportion of subjects with complete clearance of all treated warts at 
o Week 2 
o Week 4 
 
Comparison of the active group and vehicle will be done by the same method employed for the 
primary analysis on the same endpoint (i.e. CMH test). 
 
2) Ratio of cleared warts to all treated warts for each subject at 
o Week 2 
o Week 4 
 
Comparison of the active group and vehicle will be done by the same method employed for 
secondary analysis on the same endpoints (i.e. Wilcoxon rank sum test). 
 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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3) Reduction from baseline in wart size of total treated warts at 
 
 
o Week 2 
o Week 4 
o Week 6 
o Week 12 
 
Comparison of the active group and vehicle will be done by the same method employed for 
secondary analysis on the same endpoints (i.e. ANCOVA). 
 
 
B. Durability/Recurrence 
o At Week 18, 3 groups of responders (non-responder, complete responder, and 
partial responder) will be summarized. 
 
The summary of durability and recurrence will be presented for the subjects who are complete or 
partial responders at Week 18 and continue to Week 30 Follow up. For the complete responders 
at Week 18, the number and percentage of subjects with durable response, with non-durable 
response from Week 18 to Week 30 will be summarized. For partial responders at Week 18, new 
complete responder, partial response, and non-responder at week 30 will be summarized by 
group. Complete responders are defined as all treated warts cleared. Partial responders are 
defined as at least 1 but not all treated warts cleared. Non-responders are defined as no treated 
warts cleared. Recurrence is defined as any treated wart not cleared at Week 30 for a complete 
responder at Week 18. Total complete responders at Week 30 are defined as maintenance of 
complete response at Week 30 plus new complete responders at Week 30. 
 
No formal hypothesis testing is planned for these tertiary analyses. Therefore, any statistical 
testing done will be considered to be descriptive and not inferential. 
 
12.5.7 Other Variables 
The number of new common warts will be presented by visit. 
12.6 Safety Analyses 
In general, missing data will not be imputed for safety analyses. 
 
12.6.1 Adverse Events 
Any condition, event and/or signs and symptoms occurring after signing the informed consent 
form and before starting study drug treatment should be recorded as medical history in the eCRF. 
Medical conditions/diseases are considered AEs only if they worsen after starting study drug 
treatment (first application of study drug). 
 
Therefore, An AE includes any condition (including a pre-existing condition) that: 1) was not 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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present prior to study treatment, but appeared or reappeared following initiation of study 
treatment, or 2) was present prior to study treatment, but worsened during study treatment. 
 
 
A treatment-emergent adverse event (TEAE) is defined as an AE with onset date at or after the 
first dose administration of treatment, but no more than 30 days after the last dose of study 
medication. Only TEAEs will be included in the summary tables. 
 
Adverse events will be coded using MedDRA version 21.0, as applicable at time of analysis. All 
reported AEs will be coded to the appropriate SOC and PT according to MedDRA Version 21.0. 
 
The relationship of an AE to study drug is to be assessed according to the following definitions: 
 Not Related – no temporal association or the cause of the event has been identified, or the 
drug cannot be implicated based upon available information. 
 Possibly Related – temporal association, but other etiologies are likely to be the cause. 
However, involvement of the drug cannot be excluded, based upon available information. 
 Definitely Related – established temporal or other association (e.g., re-challenge) and event 
is not reasonably explained by the subject’s known clinical state or any other factor, based 
on available information. 
The severity of an AE is to be scored according to the following scale: 
 
 Mild - Awareness of sign or symptom, but easily tolerated 
 Moderate - Moderate Discomfort enough to cause interference with usual activity 
 Severe - Severe Incapacitation with inability to work or perform usual activity
A high level overall summary of TEAEs will be presented to summarize AEs in any category. 
Subject incidence of the following AEs will be tabulated by SOC (descending order of frequency) 
and PT (descending order of frequency). The number and percentage of each TEAE will be 
calculated. 
 TEAEs 
 severe TEAEs 
 treatment-related TEAEs 
 maximum severity of TEAEs 
 TEAE with an outcome of death 
 TEAE leading to discontinuation of study treatment 
 TEAE leading to discontinuation of the study 
Subject incidence of the following AEs will be tabulated by PT in descending order of frequency: 
 TEAEs 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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 TEAEs experienced by ≥ 2 subjects (for any treatment) 
 treatment-related TEAEs by ≥ 2 subjects (for any treatment) 
 
 
Subjects will be counted only once within each SOC or PT. For tables categorized by severity, 
subjects with multiple events within a particular SOC or PT will be counted under the category of 
their most severe event for that SOC or PT. Treatment-related TEAEs included AEs from AE CRF 
page where relationship to study treatment is checked with either ‘Possibly Related’ or ‘Probably 
Related’. Missing values for severity will be assigned as ‘Severe’ and missing value for 
relationship to treatment will be considered as ‘Related’ in the summary. 
AEs leading to discontinuation of treatment are those with an action taken with study treatment 
on the AE CRF page of “Drug Withdrawn”. 
AEs leading to discontinuation from the study are those on the AE CRF page of “YES” to the 
question “Did the adverse event cause the subject to be discontinued from the study?”. 
By-subject listings will be provided for the following: All AEs, All TEAE, TEAEs leading to 
discontinuation of treatment and TEAEs leading to discontinuation of the study. 
The duration of AEs will be derived as the AE end date (including imputation date for 
incomplete AE end date) – AE onset date (imputed date for incomplete AE onset date) +1. 
AEs of Special Interest (AEOSI) 
Study personnel should question and observe subjects for evidence of AEs paying particular 
attention to local application site reactions and any potential cardiovascular or hematologic AEs. 
Subject incidence of the following AEs will be tabulated by SOC (descending order of frequency) 
and PT (descending order of frequency). The number and percentage of each TEAE will be 
calculated. 
 TEAE of special interest 
 Serious TEAE of special interest 
 TEAE of special interest leading to discontinuation of study treatment 
 TEAE of special interest related to study drug 
 Preferred terms used to identify adverse events of special interest (AEOSIs) will be 
provided by the medical team after a review of AEs appearing in the following system 
organ classes: general disorders and administration site conditions, cardiac disorders, 
blood and lymphatic system disorders, renal and urinary disorders, investigations, skin 
and subcutaneous tissue disorders, and metabolism and nutrition disorders. All AEOSIs 
will also be provided in a by-subject listing. Preferred terms used to identify adverse 
events of special interest (AESIs) will be determined by the medical team before 
database freeze. All AEOSIs will be provided by-subject listing.  
12.6.2 Deaths and Serious Adverse Events 
Serious TEAEs will be summarized by SOC and PT for the All-Treated analysis set. 
A further summary of treatment-related SAEs will be provided for the All-Treated analysis set. 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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A table presenting the number and subjects who died during the study will be presented for the 
All-Treated analysis set. 
By-subject listings will be provided for the following: All Deaths, SAEs. 
 
 
12.6.3 Laboratory Data 
Laboratory test results are reported in International System of Units (SI). 
Descriptive summaries of changes from baseline for each laboratory test listed below will be 
provided for numerical laboratory assessments by visit. 
Laboratory shift tables from baseline to each post baseline visit for lab values evaluation of 
‘High’ ‘Low’ or ‘Normal’, when available, will be planned when the baseline results are 
available. The categorical lab results will be summarized by frequency and percentage and by 
visit. 
The clinical safety laboratory tests will include the following parameters: 
 Hematology: hemoglobin, hematocrit, red blood cell (RBC) including mean 
corpuscular volume (MCV) and red cell distribution with (RDW), white blood cell 
(WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils), and platelet count. 
 Chemistry/Lipids: 
o General: calcium, glucose, lactate dehydrogenase (LDH) 
o Electrolytes: carbon dioxide (bicarbonate), chloride, magnesium, sodium, 
potassium 
o Kidney/Liver: blood urea nitrogen (BUN), creatinine, uric acid, total protein, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, 
alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total 
bilirubin 
o Lipids: total cholesterol, high-density lipoproteins (HDL), low-density 
lipoproteins (LDL), triglycerides 
 
 
12.6.4 Vital Signs 
Vital signs (blood pressure [BP], heart rate [HR]) will be measured at each visit during 
Screening, Double-blind Treatment and Post-treatment Efficacy Evaluation Periods. 
Observed values and changes from baseline in vital signs will be summarized by vital sign 
parameter and visit. Descriptive statistics will be shown for baseline, each post-baseline time 
point, and the change from baseline to each post-baseline time point. 
12.6.5 Physical Examinations, ECGs, and Other Observations Related to Safety 
A limited physical exam and only baseline ECG are conducted in this study. 
Physical exam, ECG, and urine pregnancy test data will be listed. 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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 Validation 
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our 
quality control procedures will be documented separately in the study specific quality control plan. 
 
 
 References 
Breslow NE, Day NE: The analysis of case–control studies. Statistical Methods in Cancer Research, 
Volume 1. Lyons: IARC Scientific Publications; 1980. 
Buuren, S.V., Brand, J.P., Groothuis-Oudshoom, C.G., & Rubin, D.B. (2006). Fully conditional specification 
in multivariate imputation, Journal of Statistical Computation and Simulation. 76(12), 1049-1064. 
 
Goria, M.N. (1992). On the fourth root transformation of chi-square. Australian Journal of Statistics, 34 (1), 
55-64. 
 
Lee, K.J. & Carlin, J.B. (2012). Recovery of information from multiple imputation: a simulation study, 
Emerging Themes in Epidemiology. 9(3), 1-10. 
 
Wilson, E.B. & Hilferty, M.M. (1931). The distribution of chi-squared. Proceedings of the National Academy 
of Sciences, Washington, 17, 684–688. 
 
Stokes, Maura E., Davis, Charles S., and Koch, Gary G. (2000), Categorical Data Analysis Using the SAS® 
System, Second Edition (pp. 174-179), Cary, NC: SAS Institute Inc. 
 
 


 
 
 
Sponsor: Cutanea Life Science, Inc                                                                                                                        Statistical Analysis Plan 
Protocol no: CLS006-CO-PR002                                                                                                                         Version Date:07-Dec 2018 
  
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
Appendix 1 Glossary of Abbreviations 
 
 
Glossary of Abbreviations: 
AE 
Adverse Event 
AEOSI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
ANCOVA
Analysis Of Covariance
AST
Aspartate aminotransferase
BOCF
Baseline Observation Carried Forward
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC
Complete blood count
CLS
Cutanea Life Sciences, Inc.
CLS006 
Furosemide Topical Gel 0.125% w/w 
CMH 
Cochran-Mantel-Haenszel 
ECG 
Electrocardiogram 
eCRF
Electronic Case Report Form
EOS
End of Study
EOT
End of Treatment
ET
Early Termination
GGT 
Gamma glutamyl transferase 
HDL
High-density lipoproteins
HR 
Heart rate 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LDH 
Lactic dehydrogenase 
LDL
Low-density lipoproteins
MedDRA 
Medical Dictionary for Regulatory Activities 
MI
Multiple Imputation
PI
Principal investigator
PP
Per Protocol
RBC
Red blood cell
SAE
Serious Adverse Event
SD 
Standard Deviation 
TEAE 
Treatment emergent adverse events 
WBC 
White blood cell 
w/w
Weight for weight