Clinical trial NCT02462187
Conditions: Genital Warts Perianal Warts
Keywords: genital warts perianal warts
Sponsor: Novan, Inc.
Start date: 2015-06-12; Completion date: 2016-10-17
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Ascending Dose Study Assessing Tolerability, Safety, and Efficacy of Topical NVN1000 in Subjects with External Genital Warts and Perianal Warts

Detailed description:
This is a phase 2, multi-center, randomized, double-blind, vehicle-controlled, ascending dose study to assess safety, tolerability and efficacy of a topical nitric oxide releasing compound in subjects with external genital and perianal warts. Eligible subjects will be treated with a topical gel (active or vehicle) for up to 12 weeks.

Arms: arm 1: NVN1000 8% Gel twice daily arm 2: NVN1000 8% Gel once daily arm 3: NVN1000 16% Gel once daily arm 4: Vehicle Gel at frequency to match active arm 5: NVN1000 24% once daily
Interventions: intervention 1: NVN1000 8% Gel intervention 2: NVN1000 16% intervention 3: Vehicle intervention 4: NVN1000 24%
Intervention descriptions: intervention 1: once and twice daily intervention 2: once daily intervention 3: placebo comparator intervention 4: once daily

Protocol documents:
Prot_000.pdf: 
 
Confidential and Proprietary, Novan, Inc. 
  
 
STUDY TITLE 
A Phase 2 Multi-Center, Double-Blind, Randomized, 
Vehicle-Controlled, Ascending Dose Study Assessing 
Tolerability, Safety, and Efficacy of Topical 
NVN1000 in Subjects with External Genital Warts 
and Perianal Warts 
PROTOCOL NO. 
NI-WA201 
SPONSOR 
Novan, Inc. 
4222 Emperor Blvd., Suite 200 
Durham, NC 27703 
Tel: 919-485-8080 
AMENDMENT 3 
22 Mar 2016 
VERSION 
4.0 
 
The study will be conducted in compliance with the obligations as detailed in this 
protocol, and all applicable regulations and guidelines, (e.g., International Conference 
on Harmonisation, Good Clinical Practices guidelines). 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is provided to you in confidence as an Investigator, 
potential Investigator, or consultant for review by you, your staff, and an applicable Institutional 
Review Board.  The information is only to be used by you in connection with authorized clinical 
studies of the investigational product described in the protocol.  You may not disclose any of the 
information contained within to others without written authorization, except to the extent necessary 
to obtain informed consent from those persons to whom the investigational product may be 
administered. 
 




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SPONSOR INFORMATION PAGE 
Sponsor Contact Information: 
 
Novan, Inc. 
4222 Emperor Blvd., Suite 200 
Durham, NC 27703 
Tel:  919-485-8080 
Fax:  919-237-9212 
 
PPD Contact Information: 
 
Laura McKain, MD 
Medical Director 
Pharmacovigilance 
 
PPD 
929 North Front Street 
Wilmington, NC 28401-
3331 
Voice 
+1 800 201 8725 
eFax 
+1 888 488 9697 
e-mail 
laura.mckain@ppdi.com 
 
 
 
 
 
 
Sponsor Serious Adverse Event (SAE) and Safety Contact Information: 
SAEs are to be reported in the Medidata RAVE database.  If the database is not available 
then a paper SAE report form will be faxed to PPD at 1-888-529-3580.  
 
Safety Hotline number- 1-888-483-7729 
Safety Fax number-1-888-529-3580 
 
 
 
 
 
 


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PROTOCOL AMENDMENT 
RATIONALE FOR AMENDMENT 
This protocol amendment is being implemented to add a potential interim analysis for Cohorts 1 
and 2.  Results of the interim analysis will be used internally to facilitate planning of additional 
studies.  The amendment will also serve to provide clarification regarding females of 
childbearing potential. 
IDENTIFICATION OF CHANGES 
Any changes to the original protocol are identified below and incorporated into this protocol 
amendment.  All additions are identified using bold underlined text.  Any deletions are 
identified using strikethrough text.  The Table of Contents and internal references are updated to 
reflect current section numbers and minor formatting changes have been incorporated and not 
defined below. 
Change 1: PROTOCOL BODY: Section 4.1, Study Procedures and Methods, Subject Entry 
Procedures, Paragraph 4 
A female is considered to be of childbearing potential if she is sexually active with a non-
sterilized male partner UNLESS she is post-menopausal (no menses for 24 consecutive months), 
surgically sterilized, or without a uterus and/or both ovaries. 
Change 2: PROTOCOL BODY: Section 7.1, Statistical Analysis, General Considerations, 
Paragraph 2 
An interim analysis may be conducted upon completion of Cohorts 1 and 2.  A detailed 
description of the statistical methodology and data reporting for the interim and complete 
analysis for this study will be provided in the Statistical Analysis Plan (SAP). 
 
 


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INVESTIGATOR’S AGREEMENT 
I have carefully read the protocol entitled:  “A Phase 2 Multi-Center, Double-Blind, 
Randomized, Vehicle-Controlled, Ascending Dose Study Assessing Tolerability, Safety, and 
Efficacy of Topical NVN1000 in Subjects with External Genital Warts and Perianal Warts” and,  
I agree that the protocol contains the necessary information required to conduct the study.  I also 
agree to conduct this study as outlined in and according to the obligations of Clinical 
Investigators and all other pertinent requirements in the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) guideline. 
I agree to obtain approval of the protocol and informed consent prior to the start of the study by 
an Institutional Review Board (IRB). 
I agree to obtain formal written informed consent in accordance with applicable federal and local 
regulations and international guidelines from all subjects prior to their entry into the study. 
I have received and reviewed the Investigator’s Brochure including the potential risks and side 
effects of the product and instructions for use. 
I agree to report to Novan, Inc. or designee adverse events that occur during the course of the 
study in accordance with the ICH GCP guideline and the protocol. 
I agree to ensure that all associates, colleagues and employees assisting me with the conduct of 
the study are informed of their responsibilities in meeting the above commitments and the 
commitments set forth in this Investigator’s Agreement. 
I agree to maintain adequate and accurate records and to make those records available for 
inspection in accordance with the ICH GCP guideline, and federal and local requirements. 
The Investigator, agreeing to be fully bound, hereby executes this agreement on the date as set 
forth below. 
 
 
Investigator Signature 
 
 
 
 
 
 
Printed Name 
 
Date 
Address 
 
 
 
 
Phone Number 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Novan, Inc 
Name of Finished Product: 
NVN1000 
Title 
A Phase 2 Multi-Center, Double-Blind, Randomized, Vehicle-
Controlled, Ascending Dose Study Assessing Tolerability, Safety, and 
Efficacy of Topical NVN1000 in Subjects with External Genital Warts 
and Perianal Warts 
Study Objectives 
The objectives of this study are to assess tolerability, safety and efficacy 
of NVN1000 Gel in the treatment of external genital warts (EGW) and 
perianal warts (PAW). 
Study Population 
Approximately 120 male and female subjects, age 18 -50 years, with a 
minimum of 2 and a maximum of 20 warts at screening.  
Treatment 
Regimens 
Topical application of NVN1000 Gel mixed with an equal volume of 
hydrogel applied to warts for up to 12 weeks.    
Formulation 
Investigational Products:  
NVN1000 Gel: 8%, 16%, and 24%  
Vehicle Gel 
NVN1000 and Vehicle Gel will be co-administered with an equal 
volume of a phosphate buffered carboxymethyl cellulose based hydrogel 
to be dispensed and mixed prior to application. 
Study Design 
This is a phase 2, multi-center, double-blind, randomized, vehicle-
controlled, variable dose study to be conducted in approximately 120 
non-immunocompromised adult subjects with EGW/PAW.  After 
obtaining informed consent, subjects will be randomized 3:1 to active 
and  vehicle treatment.  After 12 subjects enrolled in each cohort have 
completed 2 weeks of treatment, the DSMB will review the available 
safety and tolerability data.  Using predetermined criteria documented in 
the DSMB charter, the DSMB will determine if the data supports 
escalating to the next highest dose.  Alternatively, other 
recommendations may be made based on safety/tolerability review, such 
as continued dosing at the same or lower dose frequency for subsequent 
cohort(s).  A cohort will include all subjects dosed with the same 
dose/dose frequency. The standard operating procedures of the DSMB 
will be documented in the DSMB charter, including the board’s 
accountability to Novan. 
 
NVN1000 Gel and Vehicle Gel will be co-administered with an equal 
volume of a cellulose based hydrogel provided to the subjects.  The 
subjects will dispense a pea-sized amount (approximately 250 mg) of the 
NVN1000 Gel or Vehicle Gel and a pea-sized amount (approximately 
250 mg) of the hydrogel and mix the two gels together prior to 
application of the mixed gel to their warts. 


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Subjects will apply the study drug (NVN1000 Gel or Vehicle Gel) for up 
to 12 weeks, to all warts identified at baseline and new warts that arise 
during treatment.  Warts that clear during the treatment period will not 
continue to be treated.   
 
Safety and tolerability assessments will include: adverse events, 
laboratory assessments (including chemistry, hematology, coagulation 
times, and measurement of methemoglobin by pulse co-oximetry), and 
local application assessments.  
 
The primary efficacy endpoint will be the proportion of subjects with 
complete clearance of baseline warts at or before Week 12.  Secondary 
endpoints will include the time to clearance, the decrease in overall wart 
burden (complete or partial clearance), and the total number of warts at 
Week 12. 
Main Inclusion / 
Exclusion Criteria 
Inclusion Criteria: 
 Be male or female, 18-50 years old, and in good general health; 
 Have between 2 and 20 external genital warts/perianal warts, with a 
maximum total wart surface area less than the area of the subject’s 
palm (approximately 1% BSA); 
 Women of childbearing potential (WOCBP) must have a negative 
urine pregnancy test (UPT) prior to randomization; 
 WOCBP must agree to use an effective method of birth control 
during the course of the study and for 30 days after their final study 
visit;   
 Be willing and able to follow study instructions and likely to 
complete all study requirements;   
Exclusion Criteria:   
 History of neoplasia including cervical intraepithelial neoplasiaon 
2/3,  invasive cervical carcinoma, or other HPV associated 
malignancies within 5 years or current neoplasia (with the exception 
of non-melanoma skin cancer on non-genitals); 
 Any recent (< 6 months) history of other genital infections, or other 
genital diseases including Bowens disease, Lichen Sclerosis et 
Atrophicus, Bowenoid papulosis, erythroplasia of Querat, verrucous 
carcinoma, lichen planus, and psoriasis that requires use of 
interfering topical or systemic therapy or makes evaluations and wart 
counting inconclusive; 
 Have active HSV infection of the genitals as defined by initial 
outbreak within the 2 weeks prior to screening or during the 
screening period or frequent recurrences (more than 4 events within 
one year prior to screening) if not receiving HSV suppressive 
therapy; 
 Have received treatment for EGW/PAW during the 28 days prior to 


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baseline including podophyllotoxin, imiquimod, sinecatechins, or 
surgical procedures (cryotherapy, laser surgery, cold steel, 
electorfulgeration); 
 Have a confirmed methemoglobin level of > 3.0% at Screening or 
Baseline per handheld pulse co-oximeter device; 
 Have hemoglobin at Screening  < 10 g/dL. 
Sample Size 
Approximately 120 subjects will be randomized into the study in a 3:1 
ratio of active:vehicle in 4 different cohorts.   
Safety/Tolerability 
Assessments 
Adverse events reported from the time of informed consent through end 
of the final study visit will be collected.  Methemoglobin will be 
measured at Baseline, Week 2, and Week 12/early termination (ET). 
Vital signs (blood pressure and pulse) will be measured at Baseline, 
Weeks 2, 4, 8 and 12/ET.  Clinical laboratory tests (hematology, 
chemistry, and coagulation times) will be collected at Screening, 
Baseline and Week 12/ET.  Tolerability will be assessed by the 
Investigator at Baseline and Weeks 2, 4, 8, and 12/ET. 
Endpoints 
Tolerability Endpoint:  Tolerability of NVN1000 Gel and Vehicle Gel 
will be collected using a 4 point tolerability scale to assess erythema, 
erosions/ulcers, edema and stinging/burning. 
 
Safety Endpoints: 
Safety endpoints will include adverse events, changes in physical 
examination including vital signs and changes in laboratory examination 
including methemoglobin.  Any clinically significant changes noted 
during the physical exam as well as from the vital sign measurements or 
laboratory examinations will be recorded as adverse events and included 
in the comparison. 
 
Efficacy Endpoints: 
For all efficacy analyses, unless otherwise specified, efficacy will be 
based on warts which are present at baseline.  
 
Selected summaries will be presented for total warts.  Total wart 
summaries will be based on any wart(s) observed at the given visit, 
including warts  that were not present at baseline. 
 
Primary 
 Proportion of subjects with complete clearance of baseline  
EGW/PAW at or before Week 12  
 
Secondary 
 Proportion of subjects with complete clearance of total EGW/PAW at 
or before Week 12  
 Proportion of subjects with a complete or partial clearance of 
baseline  EGW/PAW  at or before Week 12. A partial clearance is 
defined as a reduction in the number of baseline warts   


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 Proportion of subjects with complete clearance of baseline  
EGW/PAW at Weeks 2, 4, 8 and 12 
 Proportion of subjects with complete clearance of total EGW/PAW at 
Weeks 2, 4, 8 and 12 
 Proportion of subjects with a complete or partial clearance of 
baseline  EGW/PAW at Weeks 2, 4, 8 and 12 
 Percent reduction in baseline EGW/PAW wart counts at Weeks 2, 4, 
8 and 12 
 Count  of baseline warts and count of total warts at Weeks 2, 4, 8 and 
12  
 Time to complete clearance of baseline warts 
 Recurrence of baseline warts cleared prior to Week 12 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
BSA 
Body Surface Area 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
ET 
Early Termination 
EGW 
External Genital Warts 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUD 
Intrauterine Device 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LOCF 
Last Observation Carry Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOVAN 
Novan, Inc. 
OTC 
Over-the-Counter 
PAW 
Perianal Warts 
PP 
Per-Protocol 
PPD PVG 
PPD Pharmacovigilance 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TBSA 
Total Body Surface Area 
TEAE 
Treatment Emergent Adverse Events 
UPT 
Urine Pregnancy Test 
US 
United States 
WOCBP 
Women of Child-Bearing Potential 
 


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TABLE OF CONTENTS 
SPONSOR INFORMATION PAGE ............................................................................................2 
PROTOCOL AMENDMENT.......................................................................................................3 
INVESTIGATOR’S AGREEMENT ............................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................9 
TABLE OF CONTENTS ............................................................................................................10 
1. INTRODUCTION..................................................................................................................13 
1.1 Background .....................................................................................................................13 
1.2 Investigational Product ...................................................................................................13 
1.3 Nonclinical Studies with NVN1000 ...............................................................................14 
1.4 Clinical Studies with NVN1000 Gel...............................................................................15 
1.5 Summary of Benefits and Risks ......................................................................................18 
2. RATIONALE AND OBJECTIVES .....................................................................................19 
2.1 Study Rationale ...............................................................................................................19 
2.2 Study Objectives .............................................................................................................19 
3. STUDY DESIGN ....................................................................................................................20 
3.1 Study Endpoints ..............................................................................................................20 
3.1.1 Efficacy Endpoints ..............................................................................................20 
3.1.2 Tolerability Endpoints ........................................................................................21 
3.1.3 Safety Endpoints .................................................................................................21 
3.2 Structure ..........................................................................................................................21 
3.3 Duration ..........................................................................................................................22 
3.4 Dosage/Dose Regimen ....................................................................................................22 
3.5 Visit Schedule .................................................................................................................22 
3.6 Study Population .............................................................................................................22 
3.7 Eligibility Criteria ...........................................................................................................23 
3.7.1 Informed Consent and Authorization to Release Health Information ................23 
3.7.2 Inclusion Criteria ................................................................................................23 
3.7.3 Exclusion Criteria ...............................................................................................24 
4. STUDY PROCEDURES AND METHODS ........................................................................25 
4.1 Subject Entry Procedures ................................................................................................25 
Schedule of Events ...................................................................................................................27 
4.1.1 Screening (Day -35 to Day – 1) ..........................................................................28 
4.1.2 Baseline (Day 0) .................................................................................................28 
4.1.3 Week 2 (Day 14 ± 3) ...........................................................................................29 


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4.1.4 Week 4 (Day 28 ± 5) ...........................................................................................30 
4.1.5 Week 8 (Day 56 ± 5) ...........................................................................................30 
4.1.6 Week 12/ET (Day 84 ± 5) ...................................................................................31 
4.1.7 Discontinuation/Withdrawal Procedures ............................................................31 
4.2 Efficacy Assessments......................................................................................................33 
4.2.1 WART Counts ....................................................................................................33 
4.3 Tolerability Assessments ................................................................................................33 
4.4 Safety Assessments .........................................................................................................34 
4.4.1 Adverse Events ...................................................................................................34 
4.4.2 Physical Exam.....................................................................................................35 
4.4.3 Vital Signs...........................................................................................................35 
4.4.4 Laboratory Assessments .....................................................................................35 
4.4.5 Methemoglobin ...................................................................................................35 
4.4.6 Pregnancy Testing...............................................................................................36 
4.5 Screen Failures ................................................................................................................36 
4.6 Protocol Deviations .........................................................................................................36 
5. PROHIBITED THERAPIES AND MEDICATIONS ........................................................37 
6. EVALUATION OF ADVERSE EVENTS ...........................................................................37 
6.1 Definitions.......................................................................................................................37 
6.1.1 Adverse Event Severity Grades ..........................................................................38 
6.1.2 Investigational Product Causality .......................................................................38 
6.2 Reporting Adverse Events ..............................................................................................39 
6.3 Immediately Reportable Events ......................................................................................39 
6.4 Pregnancy ........................................................................................................................40 
6.5 Follow-Up of Adverse Events ........................................................................................41 
6.5.1 Follow-Up of Non-Serious Adverse Events .......................................................41 
6.5.2 Follow-Up of Post Study Serious Adverse Events .............................................41 
6.6 Overdosage .....................................................................................................................42 
6.7 Discontinuation of Individual Subjects from the Study ..................................................42 
7. STATISTICAL ANALYSIS .................................................................................................42 
7.1 General Considerations ...................................................................................................42 
7.2 Populations ......................................................................................................................42 
7.2.1 Intent to Treat (ITT) Population .........................................................................42 
7.2.2 Safety Population ................................................................................................43 
7.2.3 Per-Protocol Population ......................................................................................43 
7.3 Demographic and Baseline Characteristics ....................................................................43 
7.4 Descriptive Statistics .......................................................................................................43 


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7.5 Efficacy Analysis ............................................................................................................43 
7.5.1 Primary Efficacy Analysis ..................................................................................44 
7.5.2 Secondary Efficacy Analyses .............................................................................44 
7.6 Tolerability Analysis .......................................................................................................45 
7.7 Safety Analysis ...............................................................................................................45 
7.7.1 Adverse Events ...................................................................................................45 
7.7.2 Physical Examination .........................................................................................46 
7.7.3 Vital Signs...........................................................................................................46 
7.7.4 Laboratory Assessments .....................................................................................46 
7.7.5 Methemoglobin ...................................................................................................46 
7.7.6 Urine Pregnancy Tests ........................................................................................46 
7.8 Sample Size and Power Considerations ..........................................................................46 
8. INVESTIGATIONAL PRODUCT MANAGEMENT .......................................................47 
8.1 Receipt of Investigational Product ..................................................................................47 
8.2 Storage of Investigational Product ..................................................................................47 
8.3 Treatment Assignment and Blinding ..............................................................................47 
8.4 Unblinding of Treatment Assignment ............................................................................47 
8.5 Investigational Product Accountability ...........................................................................48 
8.6 Clinical supplies Return and Destruction .......................................................................48 
9. RECORDS MANAGEMENT ...............................................................................................48 
9.1 Data Collection ...............................................................................................................48 
9.2 File Management at the Study Site .................................................................................50 
9.3 Records Retention at the Study Site................................................................................50 
10. MONITORING, COMPLIANCE, AND QUALITY ..........................................................51 
10.1 Quality Assurance Audits and Quality Control ..............................................................52 
11. ETHICS AND RESPONSIBILITY ......................................................................................52 
12. CONFIDENTIALITY ...........................................................................................................52 
13. AMENDMENT POLICY ......................................................................................................52 
14. USE OF INFORMATION AND PUBLICATION..............................................................53 
15. REFERENCES .......................................................................................................................54 
16. APPENDICES ........................................................................................................................55 
16.1 APPENDIX 1:  List of Restricted Medications and Supplements:.................................55 
 


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1. INTRODUCTION 
1.1 BACKGROUND 
External genital warts (EGW) and perianal warts (PAW) are a common sexually transmitted 
disease due to infection with human papillomavirus (HPV).  Current EGW/PAW treatments 
include local destructive procedures and topical treatments.  These treatments are associated with 
local application site adverse reactions and wart recurrence rates of 10-30%.   
Nitric oxide is a free radical gas naturally produced by the human body which has anti-virucidal 
and anti-inflammatory activity.  Novan, Inc. has developed a topical gel containing NVN1000, a 
drug which releases nitric oxide to the skin after application.  In an animal model of skin 
papillomas, topical NVN1000 gel prevented wart growth in a dose responsive fashion.  
NVN1000 is also in development for the treatment of acne vulgaris.  To date, approximately 400 
subjects have been treated with topical NVN1000, and 200 subjects have been treated with the 
Vehicle Gel.  In the completed studies for acne vulgaris, NVN1000 has been generally safe and 
well tolerated.  
Novan is conducting this Phase 2, variable dose, randomized, double-blind study to assess 
tolerability, safety and efficacy of topical NVN1000 in subjects with EGW/PAW.   
1.2 INVESTIGATIONAL PRODUCT  
NVN1000 delivers nitric oxide from micron sized polysiloxane macromolecules in the presence 
of water.  The active agent, NVN1000, is formulated in an alcohol-based topical gel and will be 
dispensed in multi-use 15-gram tubes.  In the proposed study, the NVN1000 Gel will be the same 
as in the acne vulgaris trials; the hydrogel co-administered with NVN1000 Gel will have a different 
chemical composition. 


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Table 1: 
Characteristics of Investigational Product 
 
Investigational Products 
Name of Active 
Ingredient 
NVN1000 
None 
Drug Name/ 
Concentration 
 
NVN1000 8% Gel, NVN1000 16% 
Gel, or NVN1000 24% Gel 
Vehicle Gel  
Manufacturer 
Novan, Inc. 
Novan, Inc. 
Packaging 
15g aluminum tubes 
15g aluminum tubes 
Storage Requirements 
Refrigerated, 2-8 °C prior to 
dispensing to subject; store at room 
temperature after dispensing.  
Refrigerated, 2-8 °C prior to 
dispensing to subject; store at room 
temperature after dispensing. 
Appearance Post-
Mixing 
Opaque white gel  
Opaque white gel 
Dosing Schedule 
Twice daily, Once daily, or Once 
Daily 3 Times per Week on Non-
Consecutive Days 
Twice daily, Once Daily, or Once 
Daily 3 Times per Week on Non-
Consecutive Days 
Route of 
Administration 
Topical Application 
Topical Application 
 
Subjects in this study will dispense a pea-sized (approximately 250 mg) of NVN1000 Gel per 
application to be mixed with an equal volume of hydrogel.  The mixed product will be applied to 
each EGW/PAW identified by the investigator and to approximately 1 cm of surrounding skin.  
The maximal dose of NVN1000 per application is depicted in the table below. 
Table 2: 
NVN1000 Dosing Calculations 
NVN1000 Gel Dose 
Amount NVN1000 (mg)  
per application 
Amount NVN1000 per 
treatment area (mg/cm2)  
per application 
8% 
20 
0.114 
16% 
40 
0.227 
24% 
60 
0.341 
 
1.3 NONCLINICAL STUDIES WITH NVN1000  
The development program for NVN1000 includes non-clinical studies to assess safety following 
topical application.  Studies performed to date with NVN1000 demonstrated the safety of the inert 
carrier silica particles and the lack of systemic silica particle bioavailability when applied topically.  


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Following daily topical administration of NVN1000 Gel to miniature pigs (at NVN1000 Gel doses 
of 4, 8, and 16% which corresponds to SB204 doses of 2, 4, and 8%, respectively) for 13 weeks 
(10% TBSA), systemic exposure (blood levels) of nitrate and silicon were not statistically different 
from background levels and there were no significant toxicologic findings in treated animals. In a 
13-week dermal toxicity study in rats, local application events led to unscheduled study 
termination of all dose groups in a time-dependent manner.  Pharmacokinetic studies to date in 
rats and minipigs with the NVN1000 Gel have led to no systemic exposure to NVN1000 or related 
compounds following repeated topical administration.  
NVN1000 Gel will be co-administered with a carboxymethyl cellulose hydrogel in this Phase 2 
study in EGW/PAW.  A 28-day bridging study in minipigs with NVN1000 Gel 8% and 16% 
coadministered with the carboxymethyl cellulose hydrogel has completed the in-life portion with 
no significant local application site events.  Histologic analysis and toxicokinetic analysis will be 
completed prior to first dosing of subjects with EGW/PAW. 
NVN1000 Gel demonstrated mutagenicity in an Ames assay, but was not mutagenic in two in vivo 
genotoxicity tests in two tissue types: bone marrow via intraperitoneal (IP) administration and skin 
via topical administration. 
For additional information refer to the Investigator’s Brochure. 
1.4 CLINICAL STUDIES WITH NVN1000 GEL 
The topical administration of NVN1000 Gel to healthy volunteers or subjects with acne vulgaris 
has generally been well-tolerated with no safety concerns identified.  In eight completed clinical 
studies, approximately 250 subjects have been treated with NVN1000 Gel or SB204 Gel and 
approximately 150 subjects have been treated with Vehicle Gel.  No treatment related SAEs have 
been reported and the AE profile has been similar in subjects treated with active (NVN1000 or 
SB204 Gel) and Vehicle Gel.  Asymptomatic, transient erythema has been observed in some 
subjects treated with higher concentrations of NVN1000.  There have been no clinically significant 
changes in laboratory results including methemoglobin, or in physical examinations.   
A cross-over pharmacokinetic (PK) study (NI-AC101) was conducted in 18 subjects with 
moderate to severe acne. Subjects received nine applications of SB204 8% Gel (containing 
NVN1000 Gel 16%) or Vehicle Gel to the face, chest, upper back, and shoulders (~17% TBSA) 
over five days, had a nine day washout, then crossed over to the other treatment for nine 
applications over five days.  There was no systemic exposure to hydrolyzed MAP3, a marker for 
exposure to the parent compound, NVN1000, and no difference in serum nitrate levels on Day 1 
or Day 5 in subjects treated with NVN1000 Gel 8% twice daily.  Subjects treated in the PK study 
(NI-AC101) received 288 mg of NVN1000/application.  Subjects in the NI-WA201 study will 
receive a maximum amount of NVN1000 per application of 20 mg twice daily (Cohort 1); 20 mg 
once daily (Cohort 2); 40 mg (16%) once daily (Cohort 3 ); or 60 mg (24%) once daily (Cohort 4). 


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In a psoriasis microplaque assay, local application-site reactions following application of alcoholic 
NVN1000 Gel or Vehicle Gel under occlusion were observed in some treated subjects that led to 
treatment discontinuations.   
Table 3 provides a listing of the completed clinical studies conducted to date in subjects with acne.  
Additional details regarding these studies are in the Investigator’s Brochure. 
 
 


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Table 3: 
Completed Clinical Studies in the Acne Development Program 
Study 
Number 
Study Title 
Population 
Number 
Enrolled 
Treatment Groups 
Frequency / 
Duration of 
Treatment 
Phase 1 
 
 
 
 
NI-AC002 
[KGL 
7563] 
A Phase I, Multiple-Dose, Single-Center, 
Observer-Blind, Randomized, Parallel-Group 
Study Evaluating the 
Safety and Cutaneous Tolerability of NVN1000 
Topical Gel in HealthyVolunteers 
Healthy volunteers ≥ 18 
years of age with elevated 
P. acnes counts  
60 
NVN1000 2 % Gel  
NVN1000 4 % Gel  
NVN1000 8 % Gel  
Vehicle Gel 
 
Once daily for 4 
weeks (28 days) over 
entire face 
NI-AC004 
[KGL 
7603] 
A Phase 1, 3-Day Study of Safety and Tolerability 
of NVN1000 Topical Gel inHealthy Volunteers 
Healthy volunteers ≥ 18 
years of age with elevated 
P. acnes counts  
15 
NVN1000 8% Gel 
NVN1000 8% Gel 
and moisturizer 
Vehicle Gel 
Once daily for 3 days 
on forehead 
NI-AC006 
[KGL 
7666] 
A Phase 1, Multiple-Dose, Evaluator-Blind, 
Randomized, Parallel-Group Study Evaluating the 
Safety and Cutaneous Tolerability of SB204 
(NVN1000 Gel with Hydrogel) in Healthy 
Volunteers 
Healthy volunteers ≥ 18 
years of age with elevated 
P. acnes counts  
30 
SB204 4% 
(NVN1000 Gel with 
Hydrogel) 
Vehicle Gel with 
Hydrogel 
Twice daily for 14 
days to face 
NI-AC101 
A Phase 1, Single-center, Double-Blind, 
Randomized, Cross-over Pharmacokinetic, Safety, 
and Tolerability Study of SB204 8% (NVN1000 
Gel) and Vehicle Gel 
Subjects ≥ 18 years of age 
with moderate or severe 
acne vulgaris 
18 
SB204 8% Gel 
Vehicle Gel 
Twice daily for 4 
days and once on the 
5th day to 17% BSA 
for two dosing 
periods 
Phase 2 
 
 
 
 
NI-AC001 
A Single-Center, Randomized, Double-Blind, 
Vehicle-Controlled, Parallel Group Comparison, 
POC Study Comparing the Tolerability, Safety and 
Efficacy of NVN1000 Topical Gel and Gel 
Vehicle in the Treatment of Moderate to Severe 
Acne Vulgaris 
Subjects 12-40 years of age 
with moderate to severe 
acne vulgaris 
70 
NVN1000 2% Gel  
Vehicle Gel 
 
Once daily at bedtime 
for 8 weeks (56 days) 
over entire face 
NI-AC201 
A Multi-Center, Randomized, Evaluator-Blinded, 
Vehicle Controlled, Parallel Group, 3-arm Study 
Comparing the Efficacy, Tolerability, and  Safety 
of 2 Concentrations of SB204 (NVN1000 Gel and 
Vehicle Gel with Hydrogel) Twice Daily in the 
Treatment of Acne Vulgaris 
Subjects 12-40 years of age 
with mild to severe acne 
vulgaris 
153 
SB204 4% Gel ; 
SB204 1% Gel ; 
Vehicle Gel with 
Hydrogel 
Twice daily for 12 
weeks to face 


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1.5  SUMMARY OF BENEFITS AND RISKS 
External warts (EGW) and perianal warts (PAW) are sexually transmitted diseases caused by 
infection with papillomaviruses.  In the Shope Cottontail rabbit animal model, topical application 
of NVN1000 Gel inhibited growth of wild type and mutant papillomavirus (Coggan, 2014). 
Nitric oxide released from NVN1000 is anticipated to be pharmacologically active in the skin with 
no systemic exposure to NVN1000 or nitric oxide.  In a 5-day cross-over pharmacokinetic study 
in adults with moderate to severe acne in which NVN1000 Gel at a final concentration of 8% 
(SB204) was applied to 17% BSA, there was no systemic exposure to NVN1000 and no difference 
in serum nitrate levels following repeated topical administration.   
Dermal toxicology studies have demonstrated minimal evidence of toxicity in a 13-week miniature 
pig study, low dermal irritation in rabbits, and no dermal sensitization in guinea pigs.  Local 
application site events in a 13-week dermal toxicology study in rats led to premature 
discontinuation of all dose groups in a time-dependent manner.  These local adverse effects seen 
in the rat study are species specific and monitorable.  Tolerability will be assessed during the 
planned study, and discontinuation criteria for intolerance by subjects is described in Section 6.7.  
The independent DSMB will monitor safety and tolerability.  
Topical application has been associated with local application-site reactions including erythema, 
peeling, scaling, or burning/stinging.  These local application-site reactions may occur due to the 
active agent (NVN1000) or the vehicle.  Local application-site events including erosions and 
contact dermatitis were reported in subjects with psoriasis treated with NVN1000 Gel and Vehicle 
Gel under occlusion and in two subjects in the first cohort dosed in this study with NVN1000 Gel 
8% or Vehicle Gel.  Within 2 weeks of dosing, these subjects developed severe erythema, burning 
or erosions leading to treatment discontinuation.  At the time of this protocol amendment, it is 
unknown which treatment these subjects received.   
Based on the known mechanism of action of nitric oxide, theoretical risks from systemic exposure 
following topical administration of NVN1000 Gel include hypotension and headache. There have 
been no reports of hypotension or clinically significant changes in vital signs in subjects treated 
with NVN1000.  Reports of headache in the NVN1000 Gel development program are the same in 
NVN1000 Gel and Vehicle Gel treated subjects.   
Methemoglobinemia has been reported in patients treated with inhaled nitric oxide.  In the 
NVN1000 development program, there have been no clinically significant changes in 
methemoglobin following topical NVN1000 application in over 250 subjects treated in 8 clinical 
trials.  Methemoglobin will be monitored during the study via a hand-held co-oximeter and 
treatment stopped in any subject with a confirmed  methemoglobin > 5.0%.  A confirmed 


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methemoglobin is defined as at least two readings within 0.5% of each other taken within a 30 
minute period. 
Inadvertent administration to the eyes may result in ocular irritation and should be avoided.  Should 
the product be accidently instilled in the eye(s), prompt flushing with copious amount of normal 
saline or water is recommended.  
A transient (approximately 5-10 minutes), asymptomatic, application site erythema has been 
observed in some subjects shortly after application of NVN1000 Gel or SB204 Gel which is a 
physiologic response (vasodilation) to local nitric oxide release.   
Based on available data, Novan anticipates that the risks to subjects enrolling in this escalating 
dose Phase 2 study in subjects with EGW/PAW are minimal, and that appropriate monitoring is in 
place to assess safety.  At this stage of development, it is unknown if a clinical benefit will be 
observed in subjects with EGW/PAW following treatment with NVN1000 for 12 weeks; there is 
no anticipated benefit for subjects randomized to Vehicle Gel.   
2. RATIONALE AND OBJECTIVES 
2.1 STUDY RATIONALE 
Novan is conducting this study to evaluate the tolerability, safety and efficacy of variable doses of 
NVN1000 8% Gel, NVN1000 16% Gel, NVN1000 24% Gel and Vehicle Gel administered to 
EGW/PAW. 
Subjects will dose for up to 12 weeks (84 days + 5) with NVN1000 Gel or Vehicle Gel co-
administered with an equal volume of a carboxymethyl cellulose hydrogel.  Approximately 250 
mg (a pea-sized amount) of NVN1000 Gel or Vehicle Gel and an equal volume of hydrogel will 
be dispensed per application.  The subjects will mix the two gels together and then apply to the 
surface of the warts and approximately 1 cm of surrounding skin (maximum of 1% TBSA to be 
treated).  Subjects will be randomized 3:1 to active:vehicle in four dose cohorts initiated at 
NVN1000 8% Gel.  Based on the previous human safety data with NVN1000 Gel at up to 16% as 
well as the nonclinical safety data, this dose is expected to be safe and well tolerated. The 
safety/tolerability of each cohort will be assessed by an independent DSMB after the first 12 
subjects of each cohort complete two weeks of dosing.   
2.2 STUDY OBJECTIVES 
The objectives of this study are to assess tolerability, safety and efficacy of topical NVN1000 Gel 
and Vehicle Gel for up to 12 weeks in subjects with EGW/PAW.  


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3. STUDY DESIGN 
Figure 1 depicts the study design for each cohort in this 12-week, variable dose, randomized, 
double blind study in subjects with EGW/PAW dosed with NVN1000 Gel or Vehicle Gel.  
Subjects receiving current treatment for EGW/PAW may enter a wash out period after screening 
of up to 35 days prior to randomization.  
Figure 1: Study Diagram (For Each Cohort) 
 
Randomization: 
3:1 
active:vehicle 
 Vehicle Gel to match cohort dosing 
 
 
 
  
 
 NVN1000 Gel 8% twice daily (Cohort 1) 
 
 
 
  
 
 NVN1000 Gel 8% once daily (Cohort 2) 
 
 
 
  
 
 NVN1000 Gel 16% once daily (Cohort 3) 
 
 
 
  
 
 NVN1000 Gel 24% once daily (Cohort 4) 
 
 
Visits 
  
Screening 
Baseline 
Visit 1 
Visit 2 
Visit 3 
Visit 4/ET 
Day -35 
to Day -1 
Day 0 
Day 14 
Day 28 
Day 56 
Day 84 
Study Week 
2 
4 
8 
12 
 
3.1 STUDY ENDPOINTS  
3.1.1 EFFICACY ENDPOINTS 
For the primary efficacy analyses, efficacy will be based on warts which are present at baseline.  
 
Selected summaries will be presented for total warts counts, including warts present at baseline 
and warts that arise during the treatment period.  Total wart counts will be based on any wart(s) 
observed at the given visit, including warts that were not present at baseline. 
3.1.1.1  PrimaryEndpoint 
The primary endpoint is the proportion of subjects with complete clearance of baseline  
EGW/PAW at or before Week 12 


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3.1.1.2 Secondary Endpoints 
Secondary endpoints include: 
 Proportion of subjects with complete clearance of total EGW/PAW at or before Week 12 
 Proportion of subjects with a complete or partial clearance of baseline  EGW/PAW  at or 
before Week 12. A partial clearance is defined as a reduction in the number of baseline 
warts 
 Proportion of subjects with complete clearance of baseline  EGW/PAW at Weeks 2, 4, 8 
and 12 
 Proportion of subjects with complete clearance of total EGW/PAW at Weeks 2, 4, 8 and 
12 
 Proportion of subjects with a complete or partial clearance of baseline  EGW/PAW at 
Weeks 2, 4, 8 and 12 
 Percent reduction in baseline EGW/PAW wart counts at Weeks 2, 4, 8 and 12 
 Count of baseline warts and count of total warts at Weeks 2, 4, 8 and 12  
 Time to complete clearance of baseline  warts 
 Recurrence of baseline warts cleared prior to Week 12   
3.1.2 TOLERABILITY ENDPOINTS 
The tolerability assessments include the Investigator’s assessment of erythema, edema, 
erosions/ulcers, and the subject’s report of burning/stinging based on the preceding 24 hours on a 
4-point (0-3) scale (Section 4.3). 
3.1.3 SAFETY ENDPOINTS 
Safety endpoints will include adverse events, labs including change from baseline in percent 
methemoglobin, chemistry, hematology, and PT/PTT values, change from baseline on physical 
examination including vital sign measurements.  Any clinically significant changes noted during 
the physical exam including the vital sign measurements, or safety laboratory assessments will be 
recorded as adverse events. 
3.2 STRUCTURE 
This is a variable dose, double-blind, multi-center, randomized, vehicle-controlled, 4-arm study.  
Dosing initiated at NVN1000 8% Gel twice daily. Amendement 1 modified Cohort 2 dosing to 
NVN1000 8% once daily based on local intolerability observed in two subjects randomized in 
Cohort 1.  Cohort 3 will be dosed with NVN1000 16% once daily and Cohort 4 will be dosed with 
NVN1000 24% once daily.  An independent Data Safety Monitoring Board (DSMB) will review 


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tolerability and safety data approximately 2 weeks after randomization of the 12th subject in each 
cohort to determine whether dosing shall change. Subjects will continue to enroll and accrue in the 
open dosing cohort pending the DSMB review. Upon completion of the DSMB review, the 
recommendations of the DSMB regarding dosing will be implemented. 
3.3 DURATION  
Subjects will be in the study for a maximum of 17 weeks including up to 35 days for screening 
followed by up to 84 (+5) days of treatment.   
3.4 DOSAGE/DOSE REGIMEN 
Approximately 250 mg of NVN1000 8% Gel, NVN1000 16% Gel, NVN1000 24% Gel, or Vehicle 
Gel will be mixed with an equal volume of hydrogel at each application.  The mixed gel will be 
applied to the surface of all external genital and perianal warts identified by the Investigator and 
to approximately 1 cm of surrounding normal skin, for a period of up to 84 (+ 5) days.  Subjects 
in Cohort 1 dosed twice daily.  The dose frequency for Cohort 2 and Cohort 3 is once daily.  Cohort 
4 will be implemented after review by the DSMB of safety and tolerability of Cohort 3. If dosing 
is well tolerated in Cohort 3, the DSMB may recommend increasing the strength of NVN1000 to 
24%. After reviewing the safety and tolerability results for Cohort 3, the DSMB may also 
recommend extending enrollment in Cohort 3 or decreasing the dose to Cohort 2.  A similar data 
review will occur after enrollment of 12 subjects in Cohort 4 (NVN1000 24% vs Vehicle). 
The test product and the hydrogel will be dispensed from 15 g aluminum tubes and stored by the 
subject at room temperature.  The NVN1000 Gel and Vehicle Gel will be opaque and the hydrogel 
will be clear.  The product should be mixed for 5-10 seconds until thoroughly combined with a 
uniform opaque appearance then applied. 
NVN1000 Gel and Vehicle Gel are similar in appearance, have similar mixing characteristics, and 
can not be differentiated by gross inspection.  
3.5 VISIT SCHEDULE 
The screening period will last up to 35 days.  At the end of the screening period, subjects will have 
their Baseline Visit.  Study visits will take place approximately every two weeks for the first four 
weeks, then every four weeks for the next eight weeks. 
3.6 STUDY POPULATION 
Approximately 120 otherwise healthy, non-immunocompromised male and female subjects 
between the ages of 18 and 50 (inclusive) with EGW/PAW will be randomized to participate in 
the study.  Eligible subjects will have at least 2 but no more than 20 EGW/PAW.  


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3.7 ELIGIBILITY CRITERIA 
3.7.1 INFORMED CONSENT AND AUTHORIZATION TO RELEASE HEALTH 
INFORMATION 
Written informed consent will be obtained from all subjects before any study-related procedures 
are performed.  The Investigator may discuss the study and the possibility for entry with a potential 
subject without first obtaining consent.  A subject willing to participate must give written informed 
consent prior to any study-related procedures being conducted, including those performed solely 
for the purpose of determining eligibility for study participation or withdrawal from current 
medication (if required prior to study entry).  The Investigator has both the ethical and legal 
responsibility to ensure that each subject being considered for inclusion in this study has been 
given a full explanation of the procedures and expectations for study participation.   
The site-specific informed consent must be forwarded to PPD for approval prior to submission to 
an Institutional Review Board (IRB) as appropriate.  An IRB approved informed consent form 
specific for this study will be provided to each subject to read and sign.  Each informed consent 
document must adhere to the ethical principles stated in the Declaration of Helsinki and will 
include the elements required by FDA regulations in 21 CFR as well as the International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable 
federal and local regulatory requirements.  The consent form(s) must also include a statement that 
Novan, their designees and auditing regulatory agencies will have direct access to the subject’s 
records and medical history.   
Once the appropriate essential information has been provided to the subject and legal 
representative (where applicable) and fully explained by the Investigator (or a qualified designee) 
and it is felt that the subject understands the implications and risks of participating in the study, 
the IRB approved consent  document(s) shall be signed and dated by both the subject and legal 
representative (where applicable) and the person obtaining consent (Investigator or designee), and 
by any other parties required by the IRB or other regulatory authorities.  The subject will be given 
a copy of the signed informed consent document with the original kept on file by the Investigator.  
All of the above activities must be completed before any study related procedures are conducted.  
3.7.2 INCLUSION CRITERIA 
Each subject must fulfill all of the following inclusion criteria to participate in the study: 
1. Have a signed written informed consent form (ICF); 
2. Be male or female, 18 to 50 years of age, inclusive and in good general health; 
3. Have a minimum of two but not more than 20 EGW/PAW with a maximum total wart 
surface area less than the area of the subject’s palm (approximately 1% BSA); 


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4. If currently receiving treatment for EGW/PAW at the time of screening, be willing to 
discontinue treatment for 28 days prior to randomization and during the study; 
5. Women of childbearing potential (WOCBP) must have a negative urine pregnancy test 
(UPT) prior to randomization; 
6. WOCBP must agree to use an effective method of birth control during the course of the 
study and for 30 days after their final study visit;  
7. Be willing and able to follow study instructions and likely to complete all study 
requirements. 
3.7.3 EXCLUSION CRITERIA 
Subjects will not be enrolled if they meet any of the following exclusion criteria: 
1. History of neoplasia including cervical intraepithelial neoplasia 2/3,  invasive cervical 
carcinoma, or other HPV associated malignancies within 5 years or current neoplasia 
(with the exception of non-melanoma skin cancer on non-genitals); 
2. Any recent (< 6 months) history of other genital infections, or other genital diseases 
including Bowens disease, Lichen Sclerosis et Atrophicus, Bowenoid papulosis, 
erythroplasia of Querat, verrucous carcinoma, lichen planus, and psoriasis thatrequires 
use of interfering topical or systemic therapy or makes evaluations and wart counting 
inconclusive; 
3. Have active HSV infection of the genitals as defined by initial outbreak within the 2 
weeks prior to screening or during the screening period or frequent recurrences (more 
than 4 events within one year prior to screening), if not receiving HSV suppressive 
therapy; 
4. Presence of broken or non-intact skin near the wart site; 
5. Have received treatment for EGW/PAW during the 28 days prior to baseline including 
podophyllotoxin, imiquimod, sinecatechins, or surgical procedures (cryotherapy, laser 
surgery, cold steel, electorfulgeration); 
6. Subjects using or requiring short- or long-acting nitrates, nitric oxide donor drugs or 
supplements (e.g., arginine, citrulline) or drugs associated with methemoglobinemia; 
7. Immunocompromised subjects including those who are known HIV positive or receiving 
current immunosuppressive treatment, including radiation therapy, non-inhaled 
corticosteroids (inhaled corticosteroid ≤ 1000 ug daily dose is acceptable), or 
chemotherapy; 
8. Treatment within 30 days or during the study with any immunosuppressant agents 
including corticosteroids or biologics that target the immune system; 
9. Have a history of hypersensitivity or allergic reactions to any of the ingredients in the 
NVN1000 Gel or Vehicle Gel as described in the Investigator’s Brochure; 


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10. Have a confirmed methemoglobin level of > 3.0% at Screening or Baseline per handheld 
pulse co-oximeter device; 
11. Have hemoglobin at Screening  < 10 g/dL;  
12. Subjects with warts solely involving the urethral meatus; peri-meatal warts will not be 
treated or counted; 
13. Subjects with known internal (vaginal, cervical, urethral, rectal) warts; 
14. Female subjects who are pregnant, nursing mothers, or planning to become pregnant 
during the study; 
15. Subjects scheduled to undergo endoscopy with use of topical anesthetics; 
16. Have any condition or situation which, in the Investigator’s opinion, puts the subject at 
significant risk, could confound the study results, or may interfere significantly with the 
subject’s participation in the study including clinically significant chronic medical or 
psychiatric conditions, or a recent (within two years) history of alcohol or substance 
abuse; 
17. Are unable to communicate or cooperate with the Investigator due to language problems, 
poor mental development, or impaired cerebral function; 
18. Have used an investigational drug or device within 30 days of Baseline or concurrent 
participation in a different interventional research study; 
19. Have participated in a previous study with NVN1000 Gel or SB204 Gel. 
4. STUDY PROCEDURES AND METHODS 
4.1 SUBJECT ENTRY PROCEDURES 
Prospective subjects as defined by the eligibility criteria in Sections 3.7.2 and 3.7.3 
(Inclusion/Exclusion Criteria) will be considered for entry into this study.  Subjects’ informed 
consent must be obtained prior to conducting any procedures. 
Some Baseline procedures (i.e., review of inclusion/exclusion criteria, brief physical exam, 
methemoglobin assessment, blood pressure and pulse rate, wart counts, adverse event assessment, 
concomitant medication review and UPT) must be completed prior to randomization.  Subjects 
with hemoglobin < 10 g/dL or methemoglobin values >3.0% will not be randomized.  
WOCBP having a positive UPT at Screening or Baseline may not be randomized into the study.  
Women of childbearing potential must agree to use an effective form of contraception during 
participation in the study and for 30 days after their final study visit.  Effective contraception 
includes oral contraceptives, IUD, implant, NuvaRing®, medroxyprogesterone injection, 
transdermal patch or abstinence with a documented second method of birth control should the 
subject become sexually active.  


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A female is considered to be of childbearing potential if she is sexually active with a non-sterilized 
partner UNLESS she is post-menopausal (no menses for 24 consecutive months), surgically 
sterilized, or without a uterus and/or both ovaries. 
After the required procedures are completed and study eligibility is confirmed, the subject will be 
randomized to treatment utilizing an Interactive Voice Response System/Interactive Web 
Response System (IVRS/IWRS) which will identify the study kit to be dispensed to the subject.  
The subject will be trained on the mixing, application, and storage of the study drug.  All study 
drug applications will be done at home.  
Study visits should occur at approximately the same time of day throughout the study.   
 


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Table 4: 
Schedule of Visits and Procedures 
SCHEDULE OF EVENTS 
PROCEDURES 
Screening 
(Day -35 
– 
 Day -1) 
Visit 1 
Baseline 
(Day 0) 
Visit 21 
Week 2 
±3 days 
(Day 14) 
Visit 3 
Week 4 
±5 days 
(Day 28) 
Visit 4 
Week 8 
±5 days 
(Day 56) 
Visit 5 
Week 
12/ET2 
±5 days 
(Day 84) 
Informed Consent 
X 
 
 
 
 
 
Demographics/Smoking 
X 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
Brief Physical 
Examination 
X 
X3 
 
 
 
X 
Chemistry, Hematology, 
PT/PTT 
X 
X3 
 
 
 
X 
Urine Pregnancy Test 
X 
X3 
 
X 
X 
X 
Methemoglobin4 
X 
X 
X 
 
 
X 
Blood Pressure and 
Pulse 
X 
X 
X 
X 
X 
X 
Wart Counts 
X 
X 
X 
X 
X 
X 
Tolerability Evaluation5 
 
X 
X 
X 
X 
X 
Instruct on Study Drug 
Application and Provide 
Subject Instructions 
 
X 
 
 
 
 
Dispense Dosing Diary 
 
X 
 
X 
X 
 
Collect Completed  
Dosing Diary 
 
 
 
X 
X 
X 
Study Drug Dispensed 
 
X 
 
X 
X 
 
Study Drug Collected 
 
 
 
X 
X 
X 
Subject Compliance 
 
 
X 
X 
X 
X 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
1   All visit dates are in reference to Baseline, e.g., Visit 2 occurs two weeks (14 days) after Baseline visit. 
2  All Week 12 procedures should be completed for subjects who prematurely discontinue. 
3  If the Baseline Visit is within 7 calendar days of the Screening visit, Physical Examination, Chemistry, Hematology, 
PT/PTT, and UPT do not need to be repeated. 
4 Collected via pulse co-oximetry at site. 
5  Tolerability Assessments are defined in Section 4.3 
 
 
 


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4.1.1 SCREENING (DAY -35 TO DAY – 1) 
The following procedures must be performed and recorded at the Screening visit: 
1. Review study procedures and information regarding the study including the potential risk 
and benefits of NVN1000 Gel with the subject and obtain written informed consent. 
2. Obtain demographic information and smoking history. 
3. Obtain subject’s medical history, medication history, and concomitant medication 
information. 
4. Verify appropriate contraception being used for WOCBP and male subjects per Section 
6.4. 
5. Measure percent methemoglobin using Masimo hand held pulse co-oximeter device and 
instructions provided by the sponsor.  
6. Collect blood pressure and pulse rate. 
7. Perform a brief physical examination. 
8. Obtain pregnancy test (WOCBP only) and evaluate results.  If pregnancy test is positive, 
the subject may not participate in the study. 
9. Perform wart counts.   
10. Collect chemistry, hematology, and PT/PTT. 
11. Confirm subjects meet eligibility criteria. 
12. Review prohibited medications, treatments, and supplements that should not be used 
prior to Baseline and during the trial. 
13. Collect AEs related to study procedures performed since signing of informed consent. 
14. Confirm the study schedule with the subject. 
4.1.2 BASELINE (DAY 0) 
The following procedures must be performed and recorded at the Baseline visit: 
1. Update medication history and concomitant medication information. 
2. Perform a brief physical examination. 
3. Obtain pregnancy test (WOBCP only) and evaluate results.  If pregnancy test is positive, 
the subject may not participate in the study. 
4. Measure percent methemoglobin using Masimo hand held co-oximeter device and 
instructions provided by the sponsor. 


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5. Collect blood pressure and pulse rate. 
6. Collect chemistry, hematology, and PT/PTT. 
7. Perform wart counts and mark all wart locations on source documents.  The EGW and 
PAW will be counted and recorded separately. 
8. Confirm eligibility and randomize subject. 
9. Perform tolerability assessment. 
10. Dispense subject diary and study drug.  Instruct subject on dispensing, mixing, and 
application of study product and diary completion. 
11. Update AE information for AEs reported at Screening and record any new AEs (e.g., AEs 
related to washout, AEs related to study procedures performed at visit, etc.). 
12. Confirm the study schedule with the subject. 
NOTE: If the Baseline Visit is within 7 calendar days of the Screening visit, Physical 
Examination, Chemistry, Hematology, PT/PTT, and UPT do not need to be repeated.   
4.1.3 WEEK 2 (DAY 14 ± 3) 
The following procedures must be performed and recorded at the Week 2 visit: 
1. Update concomitant medication information. 
2. Update AE information and record any new AEs if applicable. 
3. Measure percent methemoglobin using Masimo hand held pulse co-oximeter device and 
instructions provided by the sponsor. 
4. Collect blood pressure and pulse rate. 
5. Perform tolerability evaluation. 
6. Perform wart counts and mark location of all warts on  source documents. The EGW and 
PAW will be counted and recorded separately for baseline and total wart counts. 
7. Review study drug compliance, subject diary for completion; identify reasons for missed 
applications.   
8. Review study drug application instructions with subject, ensuring drug supply is 
sufficient and confirm areas to be treated.  
9. Review and confirm the study schedule with the subject. 


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4.1.4 WEEK 4 (DAY 28 ± 5) 
The following procedures must be performed and recorded at the Week 4 visit: 
1. Update concomitant medication information. 
2. Update AE information and record any new AEs if applicable. 
3. Obtain UPT (WOCBP only) and evaluate results. 
4. Collect blood pressure and pulse rate. 
5. Perform tolerability evaluation. 
6. Perform wart counts and mark location of all warts on source documents. The EGW 
and PAW will be counted and recorded separately for baseline and total wart counts. 
7. Collect returned study drug and diary, perform accountability, review study drug 
compliance and study drug application instructions with subject and confirm areas to be 
treated.  
8. Review subject diary for completion; identify reasons for missed applications. 
9. Dispense new study drug and diary.  
10. Review and confirm the study schedule with the subject. 
4.1.5 WEEK 8 (DAY 56 ± 5) 
The following procedures must be performed and recorded at the Week 8 visit: 
1. Update concomitant medication information. 
2. Update AE information and record any new AEs. 
3. Obtain UPT (WOCBP only) and evaluate results. 
4. Collect blood pressure and pulse rate. 
5. Perform tolerability evaluation. 
6. Perform wart counts and mark location of all warts on source documents. The EGW 
and PAW will be counted and recorded separatelyfor baseline and total wart counts.   
7. Collect returned study drug and diary, perform accountability, review study drug 
compliance and study drug application instructions with subject and confirm areas to be 
treated.  
8. Review subject diary for completion; identify reasons for missed applications.  
9. Dispense new supply of study drug and diary.  
10. Review and confirm the study schedule with the subject. 


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4.1.6 WEEK 12/ET (DAY 84 ± 5) 
The following procedures must be performed and recorded at the Week 12/ET visit: 
1. Update concomitant medication information. 
2. Perform a brief physical exam. 
3. Update AE information and record any new AEs. 
4. Obtain UPT (WOCBP only) and evaluate results. 
5. Measure percent methemoglobin using Masimo hand held pulse co-oximeter device 
and instructions provided by the sponsor. 
6. Collect blood pressure and pulse rate. 
7. Collect chemistry, hematology, and PT/PTT. 
8. Perform tolerability evaluation. 
9. Perform wart counts and mark location of all warts on source documents. The EGW 
and PAW will be counted and recorded separately for baseline and total wart counts.   
10. Collect returned study drug and diary, perform accountability, and review study drug 
compliance with subject.    
11. Review subject diary for completion; identify reasons for missed applications. 
4.1.7 DISCONTINUATION/WITHDRAWAL PROCEDURES 
A subject may voluntarily withdraw from study participation at any time, for any reason.  If the 
subject withdraws consent and discontinues from the study, the Investigator will attempt to 
determine the reason for discontinuation and record the reason in the subject’s study records and 
in the study database.  If a subject is withdrawn because of an AE, that AE should be indicated as 
the reason for withdrawal.  In the event of early discontinuation, (i.e., prior to Week 12/Day 84 
visit) and whenever possible, the subject should be asked to return to the study center to complete 
the Week 12/ET evaluations.  Subjects who withdraw from the study will not be replaced. 
If at any time during the study the Investigator determines that it is not in the best interest of the 
subject to continue, the subject will be discontinued from participation.  The Investigator can 
discontinue a subject at any time if medically necessary.  The Investigator may discontinue a 
subject’s participation if the subject has failed to follow study procedures or to keep follow-up 
appointments.  Appropriate documentation in the subject’s study record and the study database 
regarding the reason for discontinuation must be completed.   
All subjects who fail to return to the study center for the Week 12/ET visit will be contacted by 
telephone to determine the reason(s) why the subject failed to return for the necessary visit or 
elected to discontinue from the study.  If a subject is unreachable by telephone after a minimum of 


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two documented attempts (one attempt on two different days), a certified letter will be sent 
requesting that the subject contact the Investigator. 
Reasons for an Investigator’s withdrawal of a subject may include, but are not limited to, the 
following: 
 Safety (e.g., severe adverse reactions, pregnancy); 
 Lack of efficacy as determined by the Investigator;  
 When the requirements of the protocol are not adhered to  (e.g., significant issues with 
dosing compliance);  
 When a concomitant medication or treatment likely to interfere with the results of the 
study is reported, or required, by the subject (the Investigator will decide, in consultation 
with PPD, whether the subject is to be withdrawn);  
 When a subject is lost to follow-up.  The Investigator will try twice to reach the subject 
by telephone (one call, two separate days) and will send a certified follow-up letter before 
considering that the subject is lost-to-follow-up.  These actions will be reported on the 
subject’s study record and a copy of the follow-up letter maintained in the Investigator's 
file. 
Refer to Section 6.7 for a discussion of criteria for discontinuation of individual subjects from the 
study. 
All premature discontinuations and their causes must be carefully documented by the Investigator 
on the subject’s study record and in the study database.  In no case will a subject who has been 
assigned a study number and randomized into the study be replaced by another.  
All Week 12/ET evaluations should be performed at the time of premature discontinuation.  All 
data gathered on the subject prior to termination will be made available to PPD and Novan.  
Study completion or reason(s) for discontinuation as listed in the study record will be entered into 
the study database as follows: 
 Completed 
 Adverse Event  
 Lack of Efficacy  
 Withdrawal by Subject 
 Physician Decision  
 Protocol Violation  
 Lost to Follow-Up  


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 Pregnancy  
 Worsening of condition 
 Other  
Novan has the right to terminate or stop the study at any time.  Should this be necessary, both PPD 
and the Investigator will ensure that proper study discontinuation procedures are completed. 
4.2 
EFFICACY ASSESSMENTS 
The same blinded evaluator should perform EGW/PAW counting at Screening, Baseline and 
Weeks 2, 4, 8, and 12.  In the event that this is not possible due to unforeseen circumstances, a 
different blinded evaluator will evaluate the subject.  However, the same evaluator should evaluate 
subjects at the Baseline and Week 12/ET evaluations. 
The evaluator will count all EGW/PAW and identify baseline warts.  The location of all warts will 
be marked on source documents.  EGW/PAW will be counted and recorded separately for baseline 
and all warts.  At each study visit, the evaluator will note location of all warts, including new warts 
that have arisen since the last subject visit.   
4.2.1 WART COUNTS 
EGW/PAW counts will be captured separately and the location of the warts marked on source 
documents.  The baseline warts and the total wart counts will be counted at Baseline and all post-
treatment visits.  EGW/PAW that arise during the study will be identified, marked on source 
documents and reported separately for post-baseline visits.   
If an EGW/PAW clears during treatment, as determined by the Investigator, the subject will 
discontinue study drug application for that specific EGW/PAW, but other EGW/PAW will 
continue to be treated.  For baseline warts that clear during treatment, the Investigtor will assess 
recurrence of treated and cleared EGW/PAW on subsequent study visits.  
If all warts (those present at baseline and new warts that develop during the study) clear, as 
determined by the Investigator, the subject will not continue to apply study drug and will remain 
in the study for all scheduled post-baseline assessments to assess for wart recurrence.  
4.3 TOLERABILITY ASSESSMENTS 
The Investigator will evaluate the subject’s genital/perianal area prior to the first application of 
investigational product in addition to evaluating at each study visit.  The tolerability assessment 
for visits other than Baseline should be performed at least 30 minutes after study drug application 
and prior to wart counts.  Tolerability evaluations will include erythema, edema, 
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of local symptoms for the previous 24 hours.  The highest severity of each parameter will be 
recorded.  Tolerability endpoints will not be reported as an AE unless they reach severe and/or 
result in subject’s discontinuation from the study.  Tolerability assessments will be performed 
according to the following scales: 
Erythema 
Score 
Description 
0-None 
No evidence of erythema present 
1-Mild 
Slight pink coloration 
2-Moderate 
Definite redness 
3-Severe 
Marked erythema, bright red to dusky dark red in color 
Edema 
Score 
Description 
0-None 
No edema 
1-Mild 
Mild edema; barely perceptible 
2-Moderate 
Moderate swelling localized to the wart and immediately adjacent skin 
3-Severe 
Extensive edema that involves non-treatment sites adjacent to treatment area 
Erosions/Ulceration 
Score 
Description 
0-None 
No erosions 
1-Mild 
Slight erosions on some treated areas 
2-Moderate 
Erosions over half of the treated areas  
3-Severe 
Extensive full-thickness erosions over most treatment areas; or at least one 
area of ulceration 
Burning/Stinging 
Score 
Description 
0-None 
No burning/stinging 
1-Mild 
Slight warm, burning/stinging sensation; not very bothersome 
2-Moderate 
Definite warm, burning/stinging sensation that is somewhat bothersome 
3-Severe 
Hot, tingling/sensation that has caused definite discomfort and may have 
disturbed sleep 
4.4 SAFETY ASSESSMENTS 
4.4.1 ADVERSE EVENTS 
AEs will be collected starting after the subject has signed the informed consent and completed 
any study assessment until the end of the final study visit.  The date of onset, date ended, 
severity, relationship to study drug, therapy required, and action taken regarding study drug and 
study participation will be reported for each AE.  
See Section 6 for additional information regarding the evaluation of adverse events. 


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4.4.2 PHYSICAL EXAM 
A brief physical exam will be performed at Screening, Baseline (Day 0) and Week 12/ET.  If 
clinically significant changes in the physical examination from Baseline are noted at the Week 
12/ET visit, these will be recorded as adverse events.  
4.4.3 VITAL SIGNS  
Blood pressure and pulse rate will be collected at Screening, Baseline, and at Weeks 2, 4, 8, and 
12.  Any clinically significant changes in vital signs from Baseline will be recorded as adverse 
events whether or not drug related. 
4.4.4 LABORATORY ASSESSMENTS 
Chemistry, hematology, and PT/PTT will be collected at Screening, Baseline, and Week 12/ET.  
Clinically significant changes in lab results post screening will be recorded as adverse events.  
Subjects with hemoglobin < 10 g/dL at Screening will not be eligible to participate. 
4.4.5 METHEMOGLOBIN  
Methemoglobin will be measured at Screening, Baseline, Week 2 and Week 12/ET using a 
Masimo Rainbow® SET® Rad-57™ pulse co-oximeter that analyzes methemoglobin levels.  The 
percent methemoglobin will be displayed on the pulse co-oximeter and recorded in the subject’s 
study record and in the study database.   
Subjects with confirmed methemoglobin values of > 3.0% at Screening or Baseline will not be 
eligible to participate in the study.  Subjects with confirmed values >5.0% during the study will be 
discontinued. A confirmed methemoglobin is defined as at least two readings within 0.5% of each 
other taken within a 30 minutes period. 
Clinically significant changes in methemoglobin will be recorded as adverse events.  The adverse 
event term should reflect the underlying diagnosis or symptoms and not the pulse co-oximeter 
result itself. 
Clinical symptoms and signs of methemoglobinemia in relation to the level of methemoglobin are 
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Table 5: 
Clinical Symptoms and Signs of Methemoglobinemia in Relation to the Level 
of Methemoglobin 
Level of Methemoglobin Clinical Symptoms and Signs 
<10% 
Frequently asymptomatic, occasionally grayish skin 
10%-20% 
Skin changes such as cyanosis 
20%-30% 
Dyspnea, headache, anxiety 
30%-50% 
Dizziness, palpitations, confusion, tachypnea 
50%-70% 
Seizures, cardiac arrhythmias, metabolic acidosis, coma 
>70% 
Death 
Source: (Boylston, 2002) 
4.4.6 PREGNANCY TESTING 
All WOCBP must have a UPT at Screening and Baseline and if the result is positive, the subject 
will not be allowed to participate in the study.  Refer to Section 6.4 for further information. 
A female is considered to be of childbearing potential UNLESS she is post-menopausal (no menses 
for 24 consecutive months), surgically sterilized, or without a uterus and/or both ovaries.  
Pregnancy tests will also be performed at Weeks 4, 8, and 12/ET.  If a subject is determined to be 
pregnant prior to or during Week 12/ET visit, the subject will be discontinued from the study but 
followed until term.  The outcome of the pregnancy, including status of the neonate, will be 
submitted. 
4.5 SCREEN FAILURES 
A screen failure subject will be a person from whom informed consent is obtained and is 
documented in writing (i.e., subject signs an informed consent form) but who does not meet the 
study eligibility requirements.  Subjects will be allowed to rescreen once within the 35-day 
screening period.  
4.6 PROTOCOL DEVIATIONS 
This study will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and well-being of the subject requires immediate intervention, based 
on the judgment of the Investigator (or a responsible, appropriately trained professional designated 
by the Investigator).  In the event of a significant deviation from the protocol due to an emergency, 
accident, or mistake, the Investigator or designee must contact PPD and the IRB, if applicable, at 


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the earliest possible time.  All deviations as well as actions taken as the result of the significant 
must be documented. 
5. PROHIBITED THERAPIES AND MEDICATIONS 
Concomitant medications are any prescription or OTC preparations.  Use of concomitant 
medications will be recorded on the concomitant medications study record and study database 
beginning at the Baseline Visit until the final evaluation (Week 12/ET).  
Subjects must not have used anti-wart treatments including topical treatments or procedures as 
described in Section 3.7.3 for at least 28 days prior to Baseline.  These medications/treatments are 
also prohibited during the trial.   
Subjects may not be concurrently on nitroglycerin, drugs associated with methemoglobinemia, 
drugs to treat EGW/PAW, or drugs/supplements that are nitric oxide releasers (Appendix 1).  
Subjects who have used an investigational drug or device within 30 days of Baseline should not 
be enrolled.  Subjects must not participate in a different interventional research study during the 
study period.  Any subject who has participated in a previous study with SB204 Gel/NVN1000 
Gel is ineligible for enrollment. 
Any medication/therapy used by the subject following first application of study product will be 
considered a concomitant medication/therapy (e.g., aspirin, acetaminophen, birth control pills, 
vitamins, etc.).  Every attempt should be made to keep concomitant medication/therapy dosing 
constant during the study.  Any change to concomitant medications/therapies should be noted on 
the subject’s study record and in the study database.  When applicable, an AE should be completed 
for any subject starting a concomitant medication/therapy after randomization into the study. 
6. EVALUATION OF ADVERSE EVENTS  
6.1 DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence (e.g., sign, symptom, disease, 
syndrome, intercurrent illness, clinically significant abnormal laboratory finding, injury or 
accident) whether or not considered drug related.  Any AE that emerges or worsens following 
administration of the informed consent and until the end of study participation will be collected.  
A pre-existing condition is one that is present prior to the start of the study and is to be reported as 
part of the subject’s medical history.  It should be reported as an AE only if the frequency, intensity, 
or the character of the condition worsens during the study. 


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An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed.  
 A serious adverse event (SAE) includes any event, if in the view of either the investigator or PPD 
Medical Monitor results in any of the following outcomes: 
 Death 
 Life-threatening event (i.e., the subject was, in the opinion of the Investigator, at immediate 
risk of death from the event as it occurred.  It does not apply to an AE that hypothetically 
might have caused death if it were more severe.) 
 Persistent or significant disability/incapacity (i.e., the AE results in a substantial disruption 
of the subject’s ability to carry out normal life functions) 
 Requires in-patient hospitalization or prolongs hospitalization (i.e., the AE required at least 
a 24-hour in-patient hospitalization or prolonged a hospitalization beyond the expected 
length of stay; hospitalizations for elective medical/surgical procedures, scheduled 
treatments, or routine check-ups are not SAEs by this criterion) 
 Congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a subject 
exposed to the molecule or investigational product before conception or during pregnancy) 
 Does not meet any of the above serious criteria but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above (i.e., 
is a significant or important medical event)  
6.1.1 ADVERSE EVENT SEVERITY GRADES 
The Investigator is responsible for evaluating all AEs and determining the severity of the event.  
Severity will be categorized according to the following definitions: 
 Mild:  Event may be noticeable to subject; does not influence daily activities; usually does 
not require intervention 
 Moderate:  Event may be of sufficient severity to make subject uncomfortable; 
performance of daily activities may be influenced; intervention may be needed  
 Severe:  Event may cause severe discomfort; usually interferes with daily activities; subject 
may not be able to continue in the study; treatment or other intervention usually needed  
The Investigator will follow all subjects who experience AEs as described in Section 6.5. 
6.1.2 INVESTIGATIONAL PRODUCT CAUSALITY 
Relationship of an AE to investigational product will be assessed as follows: 


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 Definite:  There is a clinically plausible time sequence between the onset of the AE and 
the application of investigational product; when the event responds to withdrawal of 
investigational product and recurs with re-administration of investigational product. 
 Probable:  There is a clinically plausible time sequence between the onset of the AE and 
the application of investigational product; the AE is unlikely to be caused by the 
concurrent/underlying illness, other drugs or procedures. 
 Possible:  There may or may not be a clinically plausible time sequence between the 
onset of the AE and the application of investigational product and a cause cannot be ruled 
out. 
 Unlikely:  There is no reasonable temporal association between the test material and the 
suspected event and the event could have been produced by the subject's clinical state or 
other modes of therapy administered to the Subject. 
 Unrelated:  This term should be reserved for those events that cannot be even remotely 
related to study participation. 
6.2 REPORTING ADVERSE EVENTS 
For the purpose of AE reporting the trial period is defined as the period after the subject signs the 
informed consent to the end of subject’s last visit.   
The Investigator will assess subjects at each scheduled study visit for the occurrence of AEs.  In 
order to avoid bias in eliciting AEs, subjects should be asked the following non-leading question:  
“How have you felt since your last visit?”  All AEs (serious and non-serious) reported by the 
subject must be recorded on the subject’s study record and entered into the study database.   
In addition, PPD must be notified within 24 hours of the Investigator’s knowledge of the event by 
telephone or email of any immediately reportable events according to the procedure outlined 
below.  Special attention should be paid to recording hospitalizations and concomitant therapies 
and medications. 
6.3 IMMEDIATELY REPORTABLE EVENTS 
Serious adverse events (SAEs) and pregnancy are considered immediately reportable events.  Any 
SAE, whether deemed drug-related or not, must be reported to PPD by telephone or FAX within 
24 hours after the Investigator or coordinator has become aware of its occurrence.  Within 24 hours 
of notification of the event, the Investigator/coordinator must complete a Serious Adverse Event 
(SAE) Form in the subject’s eCRF.  When appropriate, Novan will notify the appropriate 
regulatory body of drug related Serious Adverse Events. 
Serious Adverse Event (SAE) and Safety Contact Information:   
PPD PVG SAE Hotline:  1-888-483-7729 
PPD PVG SAE Fax:  1-888-529-3580 


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If a subject experiences an SAE or pregnancy the Investigator must:  
1. Report the SAE or pregnancy by telephone or fax (within 24 hours) to PPD PVG after the 
Investigator becomes aware of the event. 
2. Complete an SAE within the eCRF or fax Pregnancy Report Form to PPD PVG within 24 
hours of knowledge of the event.   
3. Obtain and maintain all pertinent medical records, information and medical judgments of 
medical personnel who assisted in subject’s treatment and follow-up and document as 
appropriate. 
4. Provide a more detailed report to both PPD and the IRB, if applicable, no later than seven 
days after the Investigator discovers the event as further information becomes available, 
and when necessary update the information with follow-up information including 
outcomes.  This report should include a statement as to whether the event was or was not 
related to the use of investigational product. 
5. The Investigator will notify the IRB of the SAE or pregnancy according to specific IRB 
requirements. 
The Investigator will collect information on SAEs until the subject’s health has returned to baseline 
status, until all parameters have returned to normal, or remaining health issues have otherwise been 
explained.   
6.4 PREGNANCY 
Women of child-bearing potential (WOCBP) must use an effective method of birth control during 
the course of the study and for 30 days following their final study visit.  Allowable methods of 
birth control include oral contraceptives, IUD, implant, NuvaRing®, injection, transdermal patch 
or abstinence with a documented second acceptable method of birth control should the subject 
become sexually active.   
A female is considered to be of childbearing potential unless she is post-menopausal (no menses 
for 24 consecutive months), surgically sterilized, or without a uterus and/or both ovaries.   
 
Before enrolling any subject in this clinical trial, the Investigator must review guidelines about 
study participation including the topics below: 
 Informed consent document 
 Pregnancy prevention information 
 Risks to unborn child(ren) 
 Any drug interactions with hormonal contraceptives 


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 Contraceptives in current use 
 Guidelines for the follow-up of a reported pregnancy 
Prior to study enrollment, all subjects must be advised of the importance of avoiding pregnancy 
during participation in this clinical study and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an informed consent document stating that the above-mentioned 
risk factors and the consequences were discussed. 
During the study, WOCBP should be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual cycle).  Subjects found to be 
pregnant prior to Week 12 will be discontinued from the study.  PPD PVG will ask the site to 
follow-up with the subject periodically during the pregnancy for ongoing health and safety 
information through term, as applicable.  Protocol-required procedures for the Week 12/ET 
evaluation must be performed for the subject. 
6.5 FOLLOW-UP OF ADVERSE EVENTS  
6.5.1 FOLLOW-UP OF NON-SERIOUS ADVERSE EVENTS 
Non-serious AEs that are not resolved at the time of the last scheduled study visit (Week 12/ET) 
must be recorded in the study database as not recovered/not resolved or ongoing.   
6.5.2 FOLLOW-UP OF POST STUDY SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) that are identified on the last scheduled contact (Week 12/ET) must 
be recorded in the study database and reported to PPD according to the reporting procedures 
outlined in Sections 6.2 and 6.3.  This may include unresolved previously reported SAEs, or new 
SAEs.  The Investigator should follow these SAEs until the events are resolved, or the subject’s 
health has returned to baseline status, until all parameters have returned to normal, remaining 
health issues have otherwise been explained, or the subject is lost to follow-up.  The Investigator 
should continue to report any significant follow-up information to PPD and the IRB up to the point 
the event has been resolved.  Resolution means the subject has returned to the baseline state of 
health, or the Investigator does not expect any further improvement or worsening of the subject’s 
condition.   
Any new SAEs reported by the subject to the Investigator that occur after the last scheduled contact 
and are determined by the Investigator to be reasonably associated with the application of 
investigational product should be reported to PPD and the IRB.   


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6.6 OVERDOSAGE 
There is no specific antidote for nitric oxide.  In the event of an overdose, best supportive care 
should be utilized.  Methylene blue may be used to treat subjects exhibiting methemoglobinemia 
(Boylston, 2002). 
6.7 DISCONTINUATION OF INDIVIDUAL SUBJECTS FROM THE STUDY  
Subjects who develop intolerance to the product as defined by scores of ‘severe’ (3) on 2 or more 
categories of tolerability (erythema, edema, erosions/ulcers, burning/stinging) shall be 
discontinued from the study.   
Subjects with a confirmed methemoglobin > 5.0% at any post-baseline visit will be discontinued 
from the study.  A confirmed methemoglobin is defined as at least 2 readings within 0.5% of each 
other taken within a 30 minutes period. 
If a subject is determined to be pregnant prior to Week 12, the subject will be discontinued from 
the study but followed until term. 
7. STATISTICAL ANALYSIS  
7.1 GENERAL CONSIDERATIONS 
All statistical processing will be performed using SAS® version 9.2 or higher unless otherwise 
stated.  Statistical significance will be based on two-tailed tests of the null hypothesis resulting in 
p-values of ≤0.05 unless stated otherwise.  Inferential testing will compare each active treatment 
group to the Vehicle treatment group.  Comparisons will not be performed between active 
treatments.  Efficacy analyses will be performed for the intent-to-treat (ITT) and per-protocol 
(PP) populations.  Safety analyses will be performed using the safety population. 
An interim analysis may be conducted upon completion of Cohorts 1 and 2.  A detailed description 
of the statistical methodology and data reporting for the interim and complete analysis for this 
study will be provided in the Statistical Analysis Plan (SAP).  The SAP will be finalized before 
the database is locked and released to Novan.  Any deviations from the SAP will be justified in 
the clinical study report.   
7.2 POPULATIONS 
7.2.1 INTENT TO TREAT (ITT) POPULATION 
The ITT population will include all study subjects who were randomized and dispensed study 
medication.   


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7.2.2 SAFETY POPULATION  
The safety population will include all randomized subjects with documented use of study 
medication (at least one application) and at least one post-baseline safety assessment.  
7.2.3 PER-PROTOCOL POPULATION 
The Per-Protocol (PP) population will include subjects who complete the Week 12 evaluation 
without noteworthy study protocol violations (e.g., any subject or investigator activity that could 
have possibly interfered with the therapeutic administration of the treatment or the precise 
evaluation of treatment efficacy).  The PP population will include subjects in the safety population 
who do not meet any of the following criteria: 
 Have taken any interfering concomitant medications 
 Have missed more than one interim study visit that they would have been eligible to attend 
as their EGW/PAW had not completely resolved 
 Have not been compliant with the dosing regimen (e.g., subjects must apply 80-120% of 
the expected applications of study medication during participation in the study) 
Prior to breaking the blind, other additional criteria may be added to the list to accommodate for 
unforeseen events that occurred during the conduct of the trial that result in noteworthy study 
protocol violations. 
7.3 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Subject demographic and baseline characteristics will be summarized by treatment group for the 
ITT, PP and safety populations.  For continuous variables (e.g., age), mean, median, standard 
deviation, minimum and maximum will be presented.  Categorical variables (e.g., ethnicity, race, 
smoking history) will be summarized with frequency count and percentage by treatment group.  
7.4 DESCRIPTIVE STATISTICS 
Descriptive statistics will be presented for the efficacy data at each evaluation for the ITT and PP 
populations.   Safety data will be summarized as indicated below for the safety population. 
Continuous data will be summarized with sample size (N), mean, median, standard deviation, 
minimum and maximum.  Categorical data will be summarized with N, frequency counts, and 
percentages. 
7.5 EFFICACY ANALYSIS  
Efficacy will be assessd based on wart counts at baseline and each evaluation through Week 12.  
Summaries based on baseline wart counts and counts for total warts will be presented.   


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7.5.1 PRIMARY EFFICACY ANALYSIS 
The number and proportion of subjects with complete clearance of baseline warts will be 
summarized by treatment group and each active dose group will be compared to vehicle using 
pairwise Pearson’s chi-square tests. The odds ratios and corresponding 95% CI will be presented.  
The pairwise comparisons of each active treatment group to the Vehicle Gel treatment group will 
be computed without concern for controlling for multiplicity. 
Percentages will be calculated out of the number of subjects in the analysis population.  Subjects 
who have a clearance of baseline warts at or before the Week 12 visit will be counted as cleared 
for the analysis.  Subjects who do not have a documented clearance by the end of study, including 
subjects with missing data at the Week 12 or other assessments, will be considered not cleared for 
the analysis. 
7.5.2 SECONDARY EFFICACY ANALYSES 
The number and proportion of subjects with complete clearance of total warts, and the number and 
proportion of subjects with complete or partial clearance of baseline warts at or by Week 12 will 
be assessed in a similar manner to the primary efficacy endpoint. The response over time will be 
similarly assessed for the proportion of subjects and total number of warts with complete clearance 
of baseline and total EGW/PAW.  The time to complete clearance of baseline warts will be 
summarized.  Each active dose group will be compared to vehicle using pairwise Pearson’s chi-
square tests and the odds ratios and corresponding 95% CIs will be presented. 
For those subjects in whom complete clearance of baseline warts is achieved prior to Week 12, 
recurrence of baseline warts will be assessed.   
Descriptive summaries will be provided for percent change in baseline wart counts and total wart 
counts.  Each active dose group will be compared to vehicle using pairwise t-tests and the 
corresponding 95% CIs for the differences in treatment means will be presented.  Subgroup 
analysis for gender and wart location (EGW/PAW) will also be performed.  
The secondary endpoints will include:  
 Proportion of subjects with complete clearance of total EGW/PAW at or before Week 12; 
 Proportion of subjects with a complete or partial clearance of baseline EGW/PAW  at or 
before Week 12. A partial clearance is defined as a reduction in the number of baseline 
warts; 
 Proportion of subjects with complete clearance of baseline EGW/PAW at Weeks 2, 4, 8 
and 12; 


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 Proportion of subjects with complete clearance of total EGW/PAW at Weeks 2, 4, 8 and 
12; 
 Proportion of subjects with a complete or partial clearance of baseline EGW/PAW at 
Weeks 2, 4, 8 and 12; 
 Percent reduction in baseline EGW/PAW wart counts at Weeks 2, 4, 8 and 12; 
 Count of baseline warts and count of total warts at Weeks 2, 4, 8 and 12; 
 Time to complete clearance of baseline warts; 
 Recurrence of baseline warts cleared prior to Week 12. 
7.6 TOLERABILITY ANALYSIS 
Tolerability assessments (erythema, edema, erosions/ulcerations, burning/stinging) will be 
summarized using frequency distributions at Baseline, Weeks 2, 4, 8, and 12/ET, as well as the 
worst post-baseline assessment.  The number and proportion of subjects with a severe assessment 
or a two step severity increase from baseline will be summarized by treatment group at Weeks 2, 
4, 8 and 12/ET for each assessment and for any assessment. In addition, shift tables will be 
presented. 
7.7 SAFETY ANALYSIS 
7.7.1 ADVERSE EVENTS 
All AEs that occur during the study will be recorded and classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-emergent AEs (TEAEs) 
are defined as AEs with an onset on or after the date of the first study drug dose. Adverse events 
noted prior to the first study drug administration that worsen after Baseline will also be reported 
as AEs and included in the summaries.  
All information pertaining to an AE noted during the study will be listed by subject, detailing 
verbatim term given by the Investigator or designee, preferred term, system organ class (SOC), 
onset date, resolution date, severity, seriousness, action taken, outcome, and drug relatedness. The 
event onset will also be shown relative (in number of days) to date of first dose.  
Treatment-emergent AEs will be summarized by treatment group, the number of subjects reporting 
a TEAE, SOC, preferred term, severity, relationship to study drug (causality), and seriousness.  
When summarizing AEs by severity and relationship, each subject will be counted only once 
within a system organ class or a preferred term by using the event with the highest severity and 
greatest relationship within each classification. 


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Serious AEs will be summarized by treatment group, severity, and relationship to study drug, and 
individual SAEs will be listed by subject. In addition, a list of subjects who prematurely 
discontinue from the study due to an AE will be provided. 
7.7.2 PHYSICAL EXAMINATION 
Changes in physical examination from baseline to end of treatment will be summarized.  Any 
clinically significant changes from Baseline will be documented as an AE. 
7.7.3  VITAL SIGNS  
Blood pressure and pulse will be summarized by treatment group from Baseline through Week 12.  
Additionally, change from Baseline in vital signs will be summarized at Week 2, 4, 8, and 12.  Any 
clinically significant changes from Baseline will be documented as an AE. 
7.7.4 LABORATORY ASSESSMENTS 
Blood chemistry, hematology, and PT/PTT values will be reported individually at Screening, 
Baseline, and Week 12.  Laboratory test results will be summarized descriptively at Baseline and 
Week 12.  Additionally, shifts from Baseline to Week 12 in laboratory test results based on normal 
ranges will be summarized with descriptive statistics.  The last laboratory evaluation prior to the 
first dose of study drug will be used as Baseline for all laboratory analyses.  Any clinically 
significant changes from Baseline will be documented as an AE. 
7.7.5 METHEMOGLOBIN  
Methemoglobin will be reported as a percentage of hemoglobin.  Methemoglobin will be 
summarized descriptively by treatment group at Baseline and Weeks 2 and 12.  Additionally, the 
change from baseline in methemoglobin will be summarized by treatment group at Weeks 2 and 
12. 
7.7.6 URINE PREGNANCY TESTS 
Urine pregnancy tests results for WOCBP will be presented in data listings by subject.   
7.8 SAMPLE SIZE AND POWER CONSIDERATIONS 
This study is not powered to detect a statistical difference in efficacy between treatment groups.  
Approximately 120 subjects will be randomized into the study in a 3:1 ratio at approximately 10 
sites in the US.  The number of subjects enrolled in any dosing cohort is dependent on the 
recommendations of the DSMB and enrollment rates.  The main objective of this study is to 
evaluate the tolerability, safety and efficacy of topical NVN1000.   


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8. INVESTIGATIONAL PRODUCT MANAGEMENT 
8.1 RECEIPT OF INVESTIGATIONAL PRODUCT 
Novan, or designee, will provide all investigational products to the study sites.   
8.2 STORAGE OF INVESTIGATIONAL PRODUCT 
Upon receipt from Novan, or Novan’s designee, a study staff member will place all study supplies 
in a temperature-controlled area.  The kits should be refrigerated (2-8 °C).  Access to study supplies 
should be strictly limited to the study staff.  Neither the Investigator nor any member of the study 
staff will distribute any of the study supplies to any person not participating in this study.  Study 
drug will be kept refrigerated up until the time it is dispensed to subjects.  After it is dispensed, it 
can be kept at room temperature. 
If a study staff member becomes aware that the study supplies have not been properly handled 
(i.e., supply arrives and was not placed in refrigerator upon receipt, the subject left study drug in 
hot vehicle over the weekend), Novan must be contacted immediately.  In such an event, study 
supplies should not be administered to any subject until Novan provides further direction. 
The investigational product will be dispensed at the discretion and by the direction of the 
Investigator in accordance with the conditions specified in this protocol.  It is the Investigator’s 
responsibility to ensure that accurate records of investigational product issuance and return are 
maintained. 
It is expected that the site staff will maintain refrigerator temperature logs in the investigational 
product storage area, recording the temperature at least once each working day.  Excursions in 
temperature during storage should be discussed with PPD personnel.  Other supplies will be stored 
at room temperature. 
8.3 TREATMENT ASSIGNMENT AND BLINDING 
Subjects will be randomized within each cohort to NVN1000 Gel or Vehicle Gel in a 3:1 ratio 
through utilization of the IVRS/IWRS.  The evaluator, Investigator, and subject will be blinded to 
the subject’s treatment. NVN1000 Gel and Vehicle Gel are similar in appearance and can not be 
differentiated.  
8.4 UNBLINDING OF TREATMENT ASSIGNMENT 
In the event that a subject should experience an adverse event for which it is medically required to 
break the blind in order to determine appropriate treatment, unblinding can be achieved by using 
the IVRS or IWRS.  A study subject for whom the blind is broken will discontinue study product 
and will be scheduled for a follow up safety visit and be encouraged to stay in the study until the 


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AE is resolved or stabilized.  Although not required, the Investigator should contact PPD Medical 
Monitor prior to breaking the blind.  
8.5 INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
A trained study staff member will maintain an inventory of investigational product components.  
This will include: 
 Dates and initials of person designated as responsible for the inventory of the 
investigational product 
 Amount received including date  
 Amount currently in refrigerator, 2-8 °C storage 
 Kits dispensed to each subject, identified by subject initials and a unique subject number 
 Amount transferred to another location within the study site or destroyed — this should 
not occur without prior notification to Novan 
 Non-study disposition (e.g., wasted,etc.) 
 Amount returned to Novan or designee, if applicable 
All investigational product accountability forms and treatment logs must be retained in the 
Investigator’s permanent study file.  These records must be available for inspection by Novan, 
PPD, or their designees or by regulatory agencies at any time. 
8.6 CLINICAL SUPPLIES RETURN AND DESTRUCTION 
Upon completion or termination of the study, the site will be instructed on return or destruction of 
clinical supplies.   
9. RECORDS MANAGEMENT 
9.1 DATA COLLECTION 
The full details of procedures for data handling will be documented in the Data Management Plan. 
Source study records will be collected for each study subject and a study database will be 
maintained for all randomized study subjects.   
Novan and PPD require that the study database be verifiable with the subject’s source study record.  
This requirement necessitates access to all original recordings and other records for each subject.  


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The Investigator must therefore agree to allow access to subjects’ records, and source data must 
be made available for all study data.  Subjects (or their legal representatives) must also allow access 
to the subject’s medical records.  Subjects will be informed of the importance of increased record 
access and permission granted by signature on the informed consent document prior to any study 
procedures being performed. 
Before the study database is formally submitted to Novan, the study monitor, PPD Medical 
Monitor or Novan may request copies of the subject’s source study record for preliminary medical 
review.   
The Investigator must keep written or electronic source documents for every subject participating 
in the clinical study.  These records must include:  
 Name 
 Contact information 
 Date of birth 
 Sex 
 Medical history 
 Concomitant diseases 
 Concomitant therapies/medication 
 Study visit dates 
 Performed examinations, evaluations, and clinical findings 
 Investigational product administration 
 AEs, SAEs, or pregnancy (as applicable) 
Additionally, any other documents with source data must be included in the subject’s source 
documents and must include the subject’s initials, study number and the date of the evaluation.   
The data recorded during the course of the study will be documented in the study database. 
Subjects will authorize the use of their protected health information during the informed consent 
process in accordance with the applicable privacy requirements.  Subjects who deny permission to 
use and disclose protected health information will not be eligible to participate in the study.  The 


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Investigator will ensure that the study records forwarded to PPD, Novan or their designees, and 
any other documents, contain no mention of subject names. 
Any amendments and corrections necessary will be undertaken in both the study records and the 
study database.   
Regulatory authorities, Investigational Review Boards, PPD or Novan may request access to all 
study records and other study documentation for on-site audit or inspection.  The Investigator must 
guarantee direct access to these documents.  The original set of study records will be kept by the 
site or an authorized designee in a secured area.  Clinical data will be recorded in an electronic 
format for subsequent statistical analyses.  Data files will be stored on electronic media with a final 
master data file kept by Novan after descriptive and statistical analyses and reports have been 
generated and are complete.  
9.2 FILE MANAGEMENT AT THE STUDY SITE 
It is the responsibility of the Investigator to ensure that the study center file is maintained in 
accordance with Section 8 – Essential Documents for the Conduct of a Clinical Trial of the ICH 
Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance and 21 CFR Part 312. 
9.3 RECORDS RETENTION AT THE STUDY SITE 
It is a Novan requirement that all Investigators participating in clinical studies maintain detailed 
clinical data for one of the following periods, whichever is longest: 
 Country-specific requirements; or 
 A period of at least two years following the last approval of a marketing application 
approved by a Regulatory Authority in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region; or, 
 A period of two years after Novan notifies the Investigator that the data will not be 
submitted for review by any Regulatory Authority. 
The Investigator must not dispose of any records or essential documents relevant to this study 
without either (1) written permission from Novan, or (2) providing an opportunity for Novan to 
collect such records.  The Investigator shall take responsibility for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated during 
this study.  Such documentation is subject to inspection by Novan and relevant regulatory agencies.  
If the Investigator withdraws from the study (e.g., relocation, retirement), all study-related records 
should be transferred to a mutually agreed-upon designee.  Notice of such transfer will be provided 
to Novan in writing.   


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10. MONITORING, COMPLIANCE, AND QUALITY 
All aspects of the study will be monitored by PPD or Novan according to Good Clinical Practices 
(GCP) and Standard Operating Procedures (SOPs) for compliance with applicable government 
regulations, (i.e., informed consent regulations, (21 C.F.R. § 50.20, 1999), and Institutional 
Review Board regulations, (21 C.F.R. § 56.103, 1981)).  Access to all records, both during the 
trial and after trial completion, should be made available to PPD and Novan at any time for review 
and audit to ensure the integrity of the data.  The Investigator must notify PPD immediately if the 
responsible IRB has been disqualified or if proceedings leading to disqualification have begun.   
The Investigator must conduct the protocol in accordance with applicable GCP regulations and 
guidelines, applicable informed consent regulations (21 C.F.R. § 50.20, 1999), and in compliance 
with the principles in the Declaration of Helsinki.  Every attempt must be made to follow the 
protocol and to obtain and record all data requested for each subject at the specified times.  If data 
is not recorded per protocol, the reason(s) must be clearly documented on the study records. 
Before study initiation, at a site initiation visit or at a meeting with the Investigator(s), a PPD or 
Novan representative will review the protocol and study records with the Investigator(s) and their 
staff.  During the study, the study monitor will visit the site regularly to check the completeness of 
subject records, the accuracy of entries into the study database, the adherence to the protocol and 
to GCP, the progress of enrollment, to ensure that consent is being sought and obtained in 
compliance with applicable regulations, and that the investigational product is being stored, 
dispensed and accounted for according to specifications.  The Investigator and key trial personnel 
must be available to assist the monitor during these visits. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the study database entries.  No information in these records about the 
identity of the subjects will leave the study center.  Monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs and the recording of primary efficacy and safety variables.  Additional checks of the 
consistency of the study records with the study database will be performed according to the study-
specific monitoring plan. 
The Investigator or designee must promptly enter the data into the study database after the subject’s 
visit.  The monitor is responsible for reviewing them and clarifying and resolving any data queries.  
A copy of the study records will be retained by the Investigator who must ensure that it is stored 
in a secure place with other study documents, such as the protocol, the Investigator’s Brochure and 
any protocol amendments. 
The Investigator must provide PPD and the responsible IRB with a study summary shortly after 
study completion. 


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10.1 QUALITY ASSURANCE AUDITS AND QUALITY CONTROL 
In addition to the routine monitoring procedures, audits of clinical research activities in accordance 
with SOPs may be performed to evaluate compliance with the principles of GCP.  A regulatory 
authority may also wish to conduct an inspection (during the study or even after its completion).  
If a regulatory authority requests an inspection, the Investigator must inform PPD immediately 
that this request has been made. 
Study conduct may be assessed during the course of the study by a Quality Assurance 
representative(s) to ensure that the study is conducted in compliance with the protocol and GCP.  
He/she will be permitted to inspect the study documents (study protocol, study records, 
investigational product, original, study-relevant medical records).  All subject data will be treated 
confidentially.   
11. ETHICS AND RESPONSIBILITY 
This study must be conducted in compliance with the protocol, the ICH Guidance for Industry E6 
Good Clinical Practice: Consolidated Guidance and the applicable regulatory requirements.  The 
Investigator must submit all essential regulatory documentation, as required by local and national 
regulations (including approval of the protocol and informed consent/assent form by an IRB) to 
PPD before investigational product will be shipped to the study site.  The Investigator will review 
the final study results to confirm that to the best of his knowledge, it accurately describes the 
conduct and results of the study.   
12. CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without written prior permission 
from Novan.  Authorized regulatory officials, PPD and Novan personnel (or their representatives) 
will be allowed full access to inspect and copy the records.  All study investigational products, 
subject bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol, unless otherwise agreed to in writing by Novan. 
Subjects will only be identified by unique subject numbers in the study database.   
13. AMENDMENT POLICY 
Only Novan may modify the protocol.  Amendments may be approved by all applicable national 
and local committees including, but not limited to, the government regulatory authorities and/or 
regional IRB before implementation.  The only exception is when an Investigator considers that a 
subject may be harmed and immediate action is necessary.  Under these circumstances, approval 
of the chairman of the IRB, or an authorized designee must be sought immediately.  The 
Investigator should inform PPD and the full IRB no later than five working days after the 


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emergency occurs.  Protocol-specified safety reporting requirements must be adhered to 
independent of any other variables.  All amendments that have an impact on subject risk, the study 
objectives or that require revision of the informed consent document must be approved by the IRB 
before implementation.  Administrative changes to the protocol and/or changes that do not impact 
subject safety, risk or comfort may be implemented prior to IRB approval if local institutional 
policy permits.  A copy of the written approval of the IRB, which becomes part of the essential 
study documents file, must be given to the study monitor.  Examples of amendments requiring 
such approval are: 
 A significant change in the study design 
 An increase in the number of invasive procedures to which subjects are exposed 
 An addition or deletion of a test procedure 
The Principal Investigator at each study site must sign the Investigator’s Agreement page of the 
amended protocol.   
14. USE OF INFORMATION AND PUBLICATION 
It is understood by the Investigator that the information generated in this study will be used by 
Novan in connection with the development of the product and therefore may be disclosed to 
government agencies in various countries.  To allow for the use of information derived from the 
study, it is understood that the Investigator is obliged to provide PPD and Novan with complete 
test results, all study data and access to all study records. 
Investigators may not report the results of this clinical study in any publication, poster or other 
public forum without express authorization from Novan.  
 
 


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15. REFERENCES  
Boylston, M.; Beer, D.  Methemoglobinemia:  A case study. Crit. Care Nurse, 2002.  22,  50-55. 
Coggin K, Balogh, K., Hollenbach, S., Christensen, N., Stasko, N. Antiviral Efficacy of Nitric 
Oxide-Releasing Drug Candidates In Vivo Utilizing the Cottontail Rabbit Papillomavirus Model. 
ICAAC Abstract, 2014, V-1822a. 
 
Guideline for Good Clinical Practice.  ICH Harmonised Tripartite Guideline, 1996.   
Protection of Human Subjects.  Code of Federal Regulations, Part 50, Title 21, Section 20, 1999.  
Institutional Review Boards.  Code of Federal Regulations, Part 56, Title 21, Section 103, 1981.  
 


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16. APPENDICES 
16.1 APPENDIX 1:  LIST OF RESTRICTED MEDICATIONS AND SUPPLEMENTS: 
 Anti-wart medications including but not limited to imiquimod, condylox, sinecatechins 
 Benzocaine & Cetacaine sprays 
 
 Corticosteroids (oral) 
 Dapsone 
 EMLA Creams  
 Chloroquine 
 Flutamide 
 L-arginine 
 L-citrulline 
 Lidocaine 
 Nitric oxide supplements 
 Nitrates 
 Nitric oxide 
 Nitroglycerin 
 Nitroprusside 
 Nitrous oxide 
 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
 
 
 
 
 
Novan Therapeutics 
 
NI-WA201 
 
A Phase 2 Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, 
Ascending Dose Study Assessing Tolerability, Safety, and Efficacy of Topical 
NVN1000 in Subjects with External Genital Warts and Perianal Warts 
 
30JAN2017 
 
Statistical Analysis Plan 
 
Version 2.2 
 
 
Prepared by: 
PPD 
3900 Paramount Parkway 
Morrisville, NC 27560 
 
 
 
 
 
 
 
 




Novan Therapeutics 
 
Statistical Analysis Plan, Version 2.2 
 
NI-WA201 
 
Date Issued: 30JAN2017 
 
  
 
 
 
3
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
1. 
INTRODUCTION ............................................................................................................ 7 
2. 
OBJECTIVES ................................................................................................................... 7 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 7 
3.1. 
OVERALL STUDY DESIGN AND PLAN ....................................................................... 7 
3.2. 
STUDY ENDPOINTS ........................................................................................................ 8 
3.2.1. PRIMARY EFFICACY ENDPOINT ................................................................................. 8 
3.2.2. SECONDARY EFFICACY ENDPOINTS ........................................................................ 8 
3.2.3. TOLERABILITY ENDPOINTS ........................................................................................ 9 
3.2.4. SAFETY ENDPOINTS ...................................................................................................... 9 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1. 
SAMPLE SIZE ................................................................................................................. 10 
4.2. 
RANDOMIZATION, STRATIFICATION, AND BLINDING ....................................... 10 
4.3. 
ANALYSIS POPULATIONS .......................................................................................... 11 
4.3.1. INTENT-TO-TREAT POPULATION ............................................................................. 11 
4.3.2. SAFETY POPULATION ................................................................................................. 11 
4.3.3. PER-PROTOCOL POPULATION ................................................................................... 11 
4.4. 
ASSESSMENT WINDOWS ............................................................................................ 12 
4.4.1. STUDY DAY ................................................................................................................... 12 
4.4.2. VISIT WINDOWS ........................................................................................................... 12 
5. 
SUBJECT DISPOSITION ............................................................................................. 13 
5.1. 
STUDY POPULATION ................................................................................................... 13 
5.2. 
DISPOSITION .................................................................................................................. 13 
5.3. 
PROTOCOL DEVIATIONS ............................................................................................ 13 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 13 
6.1. 
DEMOGRAPHICS ........................................................................................................... 13 
6.2. 
MEDICAL HISTORY ...................................................................................................... 14 
6.3. 
INCLUSION AND EXCLUSION CRITERIA ................................................................ 14 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 14 
7.1. 
CONCOMITANT MEDICATIONS ................................................................................ 14 
7.2. 
STUDY TREATMENTS .................................................................................................. 14 


Novan Therapeutics 
 
Statistical Analysis Plan, Version 2.2 
 
NI-WA201 
 
Date Issued: 30JAN2017 
 
  
 
 
 
4
7.2.1. EXPOSURE AND COMPLIANCE ................................................................................. 15 
8. 
EFFICACY ANALYSIS................................................................................................. 15 
8.1. 
PRIMARY EFFICACY ENDPOINT ............................................................................... 16 
8.1.1. PROPORTION OF SUBJECTS WITH COMPLETE CLEARANCE OF BASELINE 
EGW/PAW AT OR BEFORE WEEK 12 ......................................................................... 16 
8.2. 
SECONDARY EFFICACY ENDPOINTS ...................................................................... 16 
8.2.1. PROPORTION OF SUBJECTS WITH COMPLETE CLEARANCE OF TOTAL 
EGW/PAW AT OR BEFORE WEEK 12. ........................................................................ 17 
8.2.2. PROPORTION OF SUBJECTS WITH COMPLETE OR PARTIAL CLEARANCE OF 
BASELINE EGW/PAW AT OR BEFORE WEEK 12 .................................................... 17 
8.2.3. PROPORTION OF SUBJECTS WITH COMPLETE CLEARANCE OF BASELINE 
EGW/PAW AT WEEKS 2, 4, 8, AND 12 ........................................................................ 17 
8.2.4. PROPORTION OF SUBJECTS WITH COMPLETE CLEARANCE OF TOTAL 
EGW/PAW AT WEEKS 2, 4, 8, AND 12. ....................................................................... 18 
8.2.5. PROPORTION OF SUBJECTS WITH COMPLETE OR PARTIAL CLEARANCE OF 
BASELINE EGW/PAW AT WEEKS 2, 4, 8, AND 12. .................................................. 18 
8.2.6. PERCENT REDUCTION IN BASELINE EGW/PAW COUNTS AT WEEKS 2, 4, 8, 
AND 12. ............................................................................................................................ 18 
8.2.7. COUNT OF BASELINE WARTS AND COUNT OF TOTAL WARTS AT BASELINE 
AND WEEKS 2, 4, 8, AND 12 ........................................................................................ 18 
8.2.8. TIME TO COMPLETE CLEARANCE OF BASELINE WARTS .................................. 19 
8.2.9. RECURRENCE OF BASELINE WARTS CLEARED PRIOR TO WEEK 12 .............. 19 
8.3. 
TOLERABILITY ENDPOINTS ...................................................................................... 20 
9. 
SAFETY ANALYSIS ..................................................................................................... 21 
9.1. 
ADVERSE EVENTS ........................................................................................................ 21 
9.1.1. INCIDENCE OF ADVERSE EVENTS ........................................................................... 21 
9.1.2. RELATIONSHIP OF ADVERSE EVENTS TO STUDY DRUG ................................... 22 
9.1.3. SEVERITY OF ADVERSE EVENT ............................................................................... 22 
9.1.4. SERIOUS ADVERSE EVENTS ...................................................................................... 22 
9.1.5. SERIOUS TEAES, DEATHS AND ADVERSE EVENTS LEADING TO TREATMENT 
OR STUDY DISCONTINUATION ................................................................................. 23 
9.2. 
CLINICAL LABORATORY EVALUATIONS .............................................................. 23 
9.3. 
VITAL SIGN MEASUREMENTS .................................................................................. 24 
9.4. 
PHYSICAL EXAMINATION ......................................................................................... 24 
10. 
INTERIM ANALYSIS ................................................................................................... 24 


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11. 
APPENDICES ................................................................................................................. 26 
11.1. SCHEDULE OF STUDY PROCEDURES ...................................................................... 26 
 
LIST OF FIGURES 
Figure 3–1: Study Diagram ..............................................................................................................8 
 
 
LIST OF TABLES 
Table 1: Analysis Visit Windows ..................................................................................................12 
Table 2: Interim Analysis Outputs .................................................................................................24 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
CI 
confidence interval 
DSMB 
data safety monitoring board 
eCRF 
electronic case record form 
ET 
early termination 
EGW 
external genital warts 
FDA 
Food and Drug Administration 
HPV 
human papilloma virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ITT 
intent-to-treat 
IVRS/IWRS 
interactive voice response system/interactive web response system 
LOCF 
last observation carry forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOVAN 
Novan, Inc. 
PAW 
perianal warts 
PP 
per-protocol 
PT 
preferred term 
SAE 
serious adverse event 
SAS 
statistical analysis software 
SOC 
system organ class 
TEAE 
treatment-emergent adverse events 
TIW 
three times a week 
UPT 
urine pregnancy test 
WHODD 
World Health Organization Drug Dictionary 
WOCBP 
women of child-bearing potential 
 
 
 


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1. Introduction 
External genital warts (EGW) and perianal warts (PAW) are a common sexually 
transmitted disease due to infection with human papillomavirus (HPV). Current 
EGW/PAW treatments include local destructive procedures and topical treatments. These 
treatments are associated with local application site adverse reactions and wart recurrence 
rates of 10-30%.  
Nitric oxide is a free radical gas naturally produced by the human body which has 
anti-virucidal and anti-inflammatory activity. Novan, Inc. has developed a topical gel 
containing NVN1000, a drug which releases nitric oxide to the skin after application. In an 
animal model of skin papillomas, topical NVN1000 gel prevented wart growth in a dose 
responsive fashion.  
NVN1000 is also in development for the treatment of acne vulgaris. To date, 
approximately 400 subjects have been treated with NVN1000 Gel, and 200 subjects have 
been treated with the Vehicle Gel. In the completed studies for acne vulgaris, NVN1000 
Gel has been generally safe and well tolerated.  
Novan is conducting this Phase 2, variable dose, randomized, double-blind study to assess 
tolerability, safety and efficacy of topical NVN1000 in subjects with EGW/PAW.  
2. Objectives 
The objectives of this study are to assess tolerability, safety and efficacy of topical 
NVN1000 Gel and Vehicle Gel for up to 12 weeks in subjects with EGW/PAW.  
3. Investigational Plan 
3.1. Overall Study Design and Plan 
Subjects will dose for up to 12 weeks (84 days) with NVN1000 Gel or Vehicle Gel co-
administered with an equal volume of a carboxymethyl cellulose hydrogel. Subjects will be 
randomized 3:1 to active:vehicle in 4 dose cohorts initiated at NVN1000 8% Gel. The 
safety/tolerability of each cohort will be assessed by an independent data safety monitoring 
board (DSMB) after the first 12 subjects of each cohort complete 2 weeks of dosing.  
Figure 3–1 depicts the overall study design for this 12 week, variable dose, randomized, 
double blind study in subjects with EGW/PAW dosed with NVN1000 Gel or Vehicle Gel. 
Subjects receiving current treatment for EGW/PAW may enter a wash out period after 
screening of up to 35 days prior to randomization.  


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Subjects who are found to be cleared of all warts at a visit will discontinue treatment at that 
time. If warts recur at a subsequent visit prior to end of treatment, subjects will be 
dispensed a new kit of the same treatment they previously received. 
Figure 3–1: 
Study Diagram  
 
Randomization: 
3:1 
active:vehicle 
 Vehicle Gel to match cohort dosing 
 
 
 
  
 
 NVN1000 Gel 8% twice daily (Cohort 1) 
 
 
 
  
 
 NVN1000 Gel 8% once daily (Cohort 2) 
 
 
 
  
 
 NVN1000 Gel 16% once daily (Cohort 3) 
 
 
 
  
 
 NVN1000 Gel 24% once daily (Cohort 4) 
 
 
Visits 
  
Screening 
Baseline 
Visit 1 
Visit 2 
Visit 3 
Visit 4/ET 
Day –35 
to Day –1 
Day 0 
Day 14 
Day 28 
Day 56 
Day 84 
Study Week 
2 
4 
8 
12 
  
3.2. Study Endpoints 
3.2.1. Primary Efficacy Endpoint 
• Proportion of subjects with complete clearance of baseline EGW/PAW at or 
before Week 12 
3.2.2. Secondary Efficacy Endpoints 
The secondary endpoints will include: 
• Proportion of subjects with complete clearance of total EGW/PAW at or 
before Week 12 


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• Proportion of subjects with a complete or partial clearance of baseline 
EGW/PAW at or before Week 12. A partial clearance is defined as a 
reduction in the number of baseline warts. 
• Proportion of subjects with complete clearance of baseline EGW/PAW at 
Weeks 2, 4, 8, and 12 
• Proportion of subjects with complete clearance of total EGW/PAW at 
Weeks 2, 4, 8, and 12 
• Proportion of subjects with a complete or partial clearance of baseline 
EGW/PAW at Weeks 2, 4, 8, and 12 
• Count of baseline warts and count of total warts at Weeks 2, 4, 8, and 12 
• Percent and raw reduction in baseline EGW/PAW wart counts at Weeks 2, 
4, 8, and 12 
• Time to complete clearance of baseline warts 
• Recurrence of baseline warts cleared prior to Week 12 
3.2.3. Tolerability Endpoints 
The tolerability assessments include the investigator’s assessment of 
erythema, edema, erosions/ulcers, and the subject’s report of 
burning/stinging based on the preceding 24 hours on a 4 point (0-3) scale. 
3.2.4. Safety Endpoints 
Safety endpoints will include adverse events (AEs), laboratory tests 
including change from baseline in percent methemoglobin, chemistry, 
hematology, and prothrombin time (PT)/partial thromboplastin time (PTT) 
values, change from baseline on physical examination including vital sign 
measurements. Any clinically significant changes noted during the physical 
examination including the vital sign measurements, or safety laboratory 
assessments will be recorded as AEs. 
4. General Statistical Considerations 
All statistical processing will be performed using SAS® version 9.2 or higher unless 
otherwise stated. Statistical significance will be based on two-tailed tests of the null 
hypothesis resulting in p-values of ≤0.05 unless stated otherwise. Inferential testing will 
compare each active treatment group to the vehicle treatment group. Comparisons will not 
be performed between active treatments. All p-values will be reported without concern for 
controlling for multiplicity. Efficacy analyses will be performed for the intent-to-treat 
(ITT) and per-protocol (PP) populations. Safety analyses will be performed using the 
safety population as defined in section 4.3.2 
Continuous data will be summarized with sample size (N), mean, median, standard 


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deviation, minimum and maximum. Categorical data will be summarized with number of 
subjects N, frequency counts, and percentages. 
For analysis, baseline warts are defined as warts that are present at the baseline visit. Total 
warts include all warts present, even if they were not present at the baseline visit. Complete 
clearance is defined as zero warts present. Partial clearance is defined as a reduction in 
number of warts from baseline. 
The last evaluation for each endpoint prior to the first dose of study drug will be used as 
baseline for all analyses. 
For safety analyses including tolerability, summaries will be performed by treatment arm 
as well as “Pooled Active”, which is a total of all NVN1000 treatment arms. 
For disposition, demographics, efficacy, compliance and tolerability analyses, Vehicle Gel 
subjects will be summarized separately by dosing frequency (QD and BID). For other 
safety analyses, vehicle subjects will be combined. Subjects will be listed by actual 
treatment, with vehicle subjects listed separately by dosing frequency. 
For subjects who are taken off treatment due to complete clearance of warts and then later 
restart treatment due to recurrent warts, the date of last dose for analysis purposes will be 
the date of last dose for the second treatment interval. 
4.1. Sample Size 
This study is not powered to detect a statistical difference in efficacy between treatment 
groups. Approximately 120 subjects will be randomized into the study in a 3:1 ratio 
(active:vehicle) at approximately 15 sites in North America. The number of subjects 
enrolled in any dosing cohort is dependent on the recommendations of the DSMB and 
enrollment rates. The main objective of this study is to evaluate the tolerability, safety, and 
efficacy of topical NVN1000 Gel.  
4.2. Randomization, Stratification, and Blinding 
Subjects will be randomized to variable doses of NVN1000 or Vehicle Gel in a 3:1 ratio 
(active:vehicle) through utilization of the interactive voice response system/interactive web 
response system (IVRS/IWRS). The evaluator, Investigator, and subject will be blinded to 
the subject’s treatment. NVN1000 Gel and Vehicle Gel are similar in appearance and 
cannot be differentiated. 
In the event that a subject should experience an AE for which it is medically required to 
break the blind in order to determine appropriate treatment, unblinding can be achieved 
by using the IVRS/IWRS administrator. A study subject for whom the blind is broken 


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will discontinue study product and will be scheduled for a follow- up safety visit and be 
encouraged to stay in the study until the AE is resolved or stabilized. Although not 
required, the Investigator should contact PPD medical monitor prior to breaking the 
blind. 
Randomization treatment assignment and actual treatment received will be presented in a 
by subject listing. 
4.3. Analysis Populations 
4.3.1. Intent-to-Treat Population 
The ITT population will include all study subjects who were randomized and dispensed 
study medication.  
4.3.2. Safety Population 
The safety population will include all randomized subjects with documented use of study 
medication (at least one application) and at least one post-baseline safety assessment. The 
statement that a subject had no AEs constitutes a safety assessment.  
4.3.3. Per-Protocol Population 
The PP population will include subjects with no noteworthy study protocol deviations (i.e., 
any subject or investigator activity that could have possibly interfered with the therapeutic 
administration of the treatment or the precise evaluation of treatment efficacy) prior to 
initial clearance of baseline warts, or Week 12/early termination if the subject does not 
achieve complete clearance at any time during the study. The PP population will include 
subjects in the safety population who do not meet any of the following criteria: 
• Violated inclusion/exclusion criteria which have a potential impact on efficacy 
• Have taken any concomitant medications likely to impact efficacy 
• Have missed more than one interim study visit that they would have been eligible to 
attend as their EGW/PAW had not completely resolved 
• Have not been compliant with the dosing regimen (i.e., subjects must apply 80-120% 
of the expected applications of study medication during participation in the study) 
All significant protocol deviations will be documented in the Significant Protocol 
Deviations Rules document. Each significant deviation will be assigned a rule number and 
indication (yes/no) if the deviation will result in subject exclusion from the PP population. 
Prior to breaking the blind, other additional criteria may be added to the list to 
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in noteworthy study protocol deviations. A by subject listing will be presented including 
the reason subjects are not included in any analysis population. 
4.4. Assessment Windows 
4.4.1. Study Day 
When study day is used for display or in comparisons the following algorithm will be used: 
• study day = date of assessment - date of first dose of study medication +1,  
if date of assessment  first dose date. 
• study day = date of assessment - date of first dose of study medication, 
if date of assessment < first dose date. 
Note that this definition differs from the protocol in that the date of first dose of study 
medication is Day 1. The day before the date of first dose of study medication is Day -1. 
Study day for analysis is defined as per SDTM definition which does not include a study 
day Day 0.  
4.4.2.  Visit Windows 
By-visit analyses will be performed using the reported CRF visit. The one exception is the 
Week 12/ET visit. For safety endpoints that are not measured at every visit (e.g. lab values 
and vital signs), the Week 12/ET will be mapped to Week 12 but presented in 
tables/listings as Week 12/ET. For all other endpoints, for subjects who complete the 
study, the Week 12/ET visit will be mapped to “Week 12” and used in by visit analyses. 
For subjects who are early terminations, the Week 12/ET visit will be mapped to “ET” 
(early term and will not be included in the by visit analyses. The ET visit may be used for 
LOCF of missing data. The ET visit will be carried forward only to visits for which the ET 
visit occurred prior to on the last study day of the analysis visit window using the 
following windows: 
Table 1: Analysis Visit Windows 
Analysis Visit 
Visit Window (Based on Study Day) 
Week 2 
Day 2 to Day 22 
Week 4  
Day 23 to Day 45 
Week 8 
Day 46 to Day 71 
Week 12 
Day 72 + 


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5. Subject Disposition 
5.1. Study Population 
The number of subjects who were randomized and the number and percentage of subjects 
within each analysis population (ITT, safety, and PP) will be summarized for each 
treatment group for all randomized subjects. Vehicle Gel subjects will be separated into 
QD and BID groups. All percentages will be calculated based on the number of 
randomized subjects. A by subject list indicating subject’s inclusion in each analysis 
population and reason(s) that subject is excluded from an analysis population will be 
presented. 
5.2. Disposition 
The counts and percentages of subjects who completed or discontinued from the study will 
be presented based on the number of subjects in each treatment group and overall for all 
randomized subjects. Vehicle Gel subjects will be separated into QD and BID groups. The 
reasons for study discontinuation will also be summarized. All percentages will be based 
on the number of subjects randomized. Subject disposition data will be listed as well.  
5.3. Protocol Deviations 
Protocol deviations will be tracked by the clinical team on an on-going basis. Specific 
criteria for what constitutes a significant protocol deviation will be documented in the 
Significant Protocol Deviations Rules document as noted above in section 4.3.3. Subjects 
with significant protocol deviations and protocol deviations which result in exclusion from 
the PP population will be tabulated for each treatment group and listed by subject for all 
randomized subjects. Vehicle Gel subjects will be separated into QD and BID groups. All 
percentages will be based on the number of subjects randomized. 
6. Demographics and Baseline Characteristics 
6.1. Demographics 
Subject demographic and baseline characteristics will be summarized by treatment group 
and listed by subject for the ITT population. For continuous variables (e.g., age), mean, 
median, standard deviation, minimum and maximum will be presented. Categorical 
variables (e.g., ethnicity, race, smoking history, wart location at baseline [EGW only, 
PAW only, EGW and PAW]) will be summarized with frequency count and percentage by 
treatment group. Vehicle Gel subjects will be separated into QD and BID groups. 


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6.2. Medical History 
Medical history will be collected in the Electronic Case Report Form (eCRF) at the 
screening and baseline visits and verbatim terms will be coded classified on the basis of 
Medical Dictionary for Regulatory Activities (MedDRA) terminology, which will be 
updated whenever possible throughout the life of the study. Medical history will be 
summarized by the number and percentage of subjects with any medical history reported 
by coded system organ class, preferred term, and treatment group for the ITT population. 
Vehicle Gel subjects will be separated into QD and BID groups. A subject listing will also 
be included with start date and end date or ongoing status.  
6.3. Inclusion and Exclusion Criteria 
 
Inclusion and exclusion criteria deviations noted in the eCRF will be presented for the set 
of randomized subjects in a data listing. 
7. Treatments and Medications 
7.1. Concomitant Medications 
Any medicinal product, prescribed or over-the-counter (OTC), including herbal products, 
vitamins, and minerals is considered a concomitant medication. Any medications used 
during the study will be coded with the World Health Organization Drug Dictionary 
(WHODD), which will be updated whenever available throughout the life of the study.  
Concomitant medication use will be recorded in the eCRF beginning on baseline after the 
first dose of study medication until the final visit (Week 12/ET visit). Any changes in 
concomitant medications will also be recorded in the subject’s eCRF. 
Summary of concomitant medications by treatment group and preferred term will be 
provided. All concomitant medications will be presented in data listings. Concomitant 
medications will be summarized for the safety population. 
7.2. Study Treatments 
Approximately 250 mg of NVN1000 Gel or Vehicle Gel will be mixed with an equal 
volume of hydrogel at each application. The mixed gel will be applied to the surface of all 
external genital and perianal warts identified by the investigator and to approximately 1 cm 
of surrounding normal skin for a period of up to 84 days. The test product and the hydrogel 
will be dispensed from separate 15 g aluminum tubes and stored by the subject at room 
temperature. The NVN1000 Gel and Vehicle Gel will be opaque and the hydrogel will be 
clear. The product should be mixed for 5-10 seconds until thoroughly combined with a 
uniform opaque appearance then applied. 


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7.2.1. Exposure and Compliance 
Duration of exposure will be calculated in days as date of last dose of study medication– 
date of first dose of study medication+ 1. Percent compliance will be calculated as the 
number of total doses received divided by the number of planned doses times 100. The 
number of planned doses will be calculated as follows: 
2 times the duration (days) of exposure - 1 for cohorts dosing twice daily, 
and 
1 time the duration (days) of exposure for cohorts dosing once daily,  
The number of doses received will be calculated as the number of planned doses minus the 
total number of missed doses as indicated in the subject diaries. Descriptive statistics 
including the number of subjects, mean, standard deviation, median, minimum, and 
maximum for duration of study exposure and percent compliance will be provided by 
treatment group using the safety population. Vehicle Gel subjects will be separated into 
QD and BID groups for both exposure and compliance summaries. Compliance and 
treatment duration will also be listed by subject. 
In addition, number of missed doses for each subject based on subject diaries will be 
summarized in a frequency table and listed by subject. Doses missed specifically for 
tolerability reasons will likewise be summarized in a frequency table and listed by subject.  
For subjects who experience complete clearance, the number of missed doses and 
compliance will only be calculated up to and including the date of the first visit where the 
subject had a total wart count of 0. Any subsequent dosing due to recurrent warts will not 
be considered for analysis of missed doses or compliance. 
8. Efficacy Analysis 
 
Efficacy data is collected at each study visit. Wart count data including derived primary 
and secondary endpoint data such as complete clearance, time to complete clearance, time 
to recurrence, etc. will be presented in listings by subject. Subjects may receive more than 
one course of treatment if they experience complete clearing and subsequent recurrence of 
warts. Assessment of time to clearing, time to recurrence, and clearing at or before Week 
12 will be assessed based on the initial treatment course (i.e., first instance of 
clearing/recurrence only.) For efficacy assessments by visit (i.e., at Weeks 2, 4, 8 and 12), 
data will be summarized without regard to treatment course. (e.g., assessments at Week 8 
may include data for subjects still on their initial treatment course as they have not yet 
achieved clearance, subjects off treatment as they have previously cleared but not yet 


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experienced a recurrence, and subjects on a second course of treatment after prior 
clearance and recurrence.) 
 
Wart count data including derived primary and secondary endpoint data such as complete 
clearance, time to complete clearance, time to recurrence, etc. will be presented in data 
listings by subject. 
8.1. Primary Efficacy Endpoint 
8.1.1. Proportion of Subjects with Complete Clearance of Baseline 
EGW/PAW at or Before Week 12 
The primary efficacy endpoint is the proportion of subjects with complete clearance of 
baseline EGW/PAW at or before Week 12.  
 
The number and proportion of subjects with complete clearance of baseline warts will be 
summarized by treatment group and each active dose group will be compared to vehicle 
using pairwise Pearson’s chi-square tests. The Mantel-Haenszel odds ratios and 
corresponding 95% confidence interval (CI) will be presented. The Vehicle Gel arm will 
be separated into once-daily (QD) and twice-daily (BID) groups and compared pairwise to 
the corresponding active treatments. The three once-daily active treatment groups (8%, 
16%, and 24%) will be compared to the Vehicle Gel QD group and the NVN1000 8% BID 
group will be compared to the Vehicle Gel BID group. The pairwise comparisons will be 
computed without concern for controlling for multiplicity. The primary analysis will be 
performed for the ITT population.  
Percentages will be calculated based on the number of subjects in the ITT analysis 
population. Subjects who have clearance of baseline warts at or before the Week 12 visit 
will be counted as cleared for the analysis. Subjects who do not have a documented 
clearance by the end of study, including subjects with missing data at the Week 12 or other 
assessments, will be considered not cleared for the analysis.  
The primary analysis will be repeated for the PP population. Subgroup analysis for gender 
and wart location (EGW/PAW) will also be performed for the ITT population. The 
subgroup summaries will be descriptive only with no statistical hypothesis testing 
performed. 
8.2. Secondary Efficacy Endpoints 
The secondary efficacy analysis will be performed for both ITT and PP.  


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8.2.1. Proportion of Subjects with Complete Clearance of Total EGW/PAW 
at or Before Week 12. 
The number and proportion of subjects with complete clearance of total EGW/PAW will 
be summarized by treatment group and each active dose group will be compared to its 
corresponding vehicle group using pairwise Pearson’s chi-square tests. The Mantel-
Haenszel odds ratios and corresponding 95% CI will be presented.  
 
Subjects who have clearance of baseline warts at or before the Week 12 visit will be 
counted as cleared for the analysis. Subjects who do not have a documented clearance by 
the end of study, including subjects with missing data at the Week 12 or other assessments, 
will be considered not cleared for the analysis.  
Subgroup analysis for gender and wart location (EGW/PAW) will also be performed for 
the ITT populations. The subgroup summaries will be descriptive only with no statistical 
hypothesis testing performed.  
8.2.2. Proportion of Subjects with Complete or Partial Clearance of Baseline 
EGW/PAW at or Before Week 12 
The number and proportion of subjects with complete or partial clearance, defined as a 
reduction in the number of baseline EGW/PAW, will be summarized by treatment group 
and each active dose group will be compared to its corresponding vehicle group using 
pairwise Pearson’s chi-square tests. The Mantel-Haenszel odds ratios and corresponding 
95% CI will be presented.  
 
Subjects who have clearance, complete or partial, of baseline warts at or before the Week 
12 visit will be counted as cleared or partially cleared for the analysis. Subjects who do not 
have a documented clearance or partial clearance by the end of study, including subjects 
with missing data at the Week 12 or other assessments, will be considered not cleared or 
partially cleared for the analysis.  
8.2.3. Proportion of Subjects with Complete Clearance of baseline 
EGW/PAW at Weeks 2, 4, 8, and 12 
The number and proportion of subjects with complete clearance of baseline EGW/PAW at 
each post-baseline visit will be summarized by treatment group and each active dose group 
will be compared to its corresponding vehicle group using pairwise Pearson’s chi-square 
tests. The Mantel-Haenszel odds ratios and corresponding 95% CI will be presented.  
 
Imputation of missing data will be performed using a last-observation carried forward 
(LOCF) method where a missing assessment is replaced by the previous visit’s assessment.  


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8.2.4. Proportion of Subjects with Complete Clearance of Total EGW/PAW 
at Weeks 2, 4, 8, and 12. 
The number and proportion of subjects with complete clearance of total EGW/PAW at 
each visit will be summarized by treatment group and each active dose group will be 
compared to its corresponding vehicle group using pairwise Pearson’s chi-square tests. The 
Mantel-Haenszel odds ratios and corresponding 95% CI will be presented.  
 
Imputation of missing data will be performed using a last-observation carried forward 
(LOCF) method where a missing assessment is replaced by the previous visit’s assessment.  
8.2.5. Proportion of Subjects with Complete or Partial Clearance of Baseline 
EGW/PAW at Weeks 2, 4, 8, and 12. 
The number and proportion of subjects with complete or partial clearance, defined as a 
reduction in the number of warts, of baseline EGW/PAW at each post-baseline visit will be 
summarized by treatment group and each active dose group will be compared to its 
corresponding vehicle group using pairwise Pearson’s chi-square tests. The Mantel-
Haenszel odds ratios and corresponding 95% CI will be presented.  
 
Imputation of missing data will be performed using a last-observation carried forward 
(LOCF) method where a missing assessment is replaced by the previous visit’s assessment.  
8.2.6. Percent and Raw Reduction in Baseline EGW/PAW Counts at Weeks 
2, 4, 8, and 12. 
Descriptive summaries will be provided for percent and raw change in baseline wart counts 
at each visit. Raw change will be calculated as (post-baseline count – baseline count). 
Percent change will be calculated as (post baseline count – baseline count) divided by 
baseline count times 100. Each active dose group will be compared to its corresponding 
vehicle group using pairwise t-tests and the corresponding 95% CIs for the differences in 
treatment means will also be presented. 
 
Imputation of missing data will be performed using a last-observation carried forward 
(LOCF) method where a missing assessment is replaced by the previous visit’s assessment. 
 
8.2.7. Count of Baseline Warts and Count of Total Warts at Baseline and 
Weeks 2, 4, 8, and 12 
Descriptive summaries will be provided for count of baseline warts and count of total 
warts at each visit. Each active dose group will be compared to its corresponding vehicle 
group using pairwise t-tests and the corresponding 95% CIs for the differences in treatment 


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means will also be presented. The mean total number of baseline warts and total number of 
total warts by visit will also be graphically displayed.  
 
Imputation of missing data will be performed using a last-observation carried forward 
(LOCF) method where a missing assessment is replaced by the previous visit’s assessment. 
8.2.8. Time to Complete Clearance of Baseline Warts 
The time to complete clearance of baseline warts is calculated as the number of days 
between the date of first dose of study medication and the date that the baseline wart count 
is 0. Subjects who do not have clearing of baseline warts will be censored at the date of 
their last study assessment. 
Kaplan-Meier (KM) estimates of clearance rates at Week 2, Week 4, Week 8 and Week 12 
and their 95% CIs will be presented by treatment group. Vehicle Gel subjects will be 
separated into QD and BID groups. For estimates by week, week will be defined by the 
maximum day allowable by the visit windows (e.g., the summary for Week 2 will count all 
subjects with clearance on or before Day 18.) Because clearance is a positive outcome, 
clearance rates for each week will be calculated as (1 – the KM survival probability 
estimate). The median time to clearing and 95% CI for each treatment group will also be 
summarized. Inverse KM curves based on (1 – the KM survival probability estimates) will 
be plotted to describe the estimated proportion of subjects with clearance over time for 
each treatment group.  
8.2.9. Recurrence of Baseline Warts Cleared Prior to Week 12 
The time to recurrence of baseline warts which have previously cleared is calculated as the 
number of days between the first date that baseline wart count is 0 and the first date after 
that for which baseline wart count is > 0. Subjects who do not have recurrence of baseline 
warts after clearing will be censored at the date of their last study assessment. 
Kaplan-Meier estimates and plots will be presented for the time to recurrence in a similar 
manner to that described above for time to clearing; however as recurrence is negative 
outcome, the KM curves will be based on the KM survival probability estimates. Also, as 
clearing can occur at any visit, the KM estimates of recurrence will be based on 14 day 
intervals from the date of clearing: 2 Weeks (14 days), 4 Weeks (28 days), 6 Weeks (42 
days), 8 Weeks (56 days), and 10 Weeks (70 days) post clearing. KM curves will be 
presented for each treatment arm, with Vehicle Gel subjects separated into QD and BID 
groups.   


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8.3. Tolerability Endpoints  
Tolerability assessments will be performed according to the following scales: 
Erythema 
Score 
Description 
0-None 
No evidence of erythema present 
1-Mild 
Slight pink coloration 
2-Moderate 
Definite redness 
3-Severe 
Marked erythema, bright red to dusky dark red in color 
Edema 
Score 
Description 
0-None 
No edema 
1-Mild 
Mild edema; barely perceptible 
2-Moderate 
Moderate swelling localized to the wart and immediately adjacent skin 
3-Severe 
Extensive edema that involves non-treatment sites adjacent to treatment 
area 
Erosions/Ulceration 
Score 
Description 
0-None 
No erosions 
1-Mild 
Slight erosions on some treated areas 
2-Moderate 
Erosions over half of the treated areas  
3-Severe 
Extensive full-thickness erosions over most treatment areas; or at least 
one area of ulceration 
Burning/Stinging 
Score 
Description 
0-None 
No burning/stinging 
1-Mild 
Slight warm, burning/stinging sensation; not very bothersome 
2-Moderate 
Definite warm, burning/stinging sensation that is somewhat bothersome 
3-Severe 
Hot, tingling/sensation that has caused definite discomfort and may 
have disturbed sleep 
 
Tolerability assessments (erythema, edema, erosions/ulcerations, burning/stinging) will be 
summarized using frequency distributions at baseline, Weeks 2, 4, 8, and 12/ early 
termination (ET), as well as the worst post-baseline assessment. The worst post-baseline 
assessment will be determined individually for each tolerability parameter. (e.g., the worst 
assessment for erythema may occur at a different visit than the worst assessment for 
edema.) The number and proportion of subjects with a severe assessment or a two step 
severity increase from baseline will be summarized by treatment group at Weeks 2, 4, 8, 
and 12/ET for each assessment and for any assessment. Vehicle Gel subjects will be 
separated into QD and BID groups. Additionally, the number and percentage of subjects 


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who have 2 or more severe assessments at the same visit for any visit will be presented. A 
shift table will also be presented by tolerability parameter and treatment group, and all 
tolerability scores will be listed. 
9. Safety Analysis 
9.1. Adverse Events 
All AEs that occur during the study will be recorded and classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-emergent AEs 
(TEAEs) are defined as AEs with an onset on or after the date of the first study drug dose, 
and occur within 30 days of the last study drug dose. Adverse events noted prior to the first 
study drug administration that worsen after baseline will also be reported as TEAEs and 
included in the summaries.  
All information pertaining to an AE noted during the study will be listed by subject, 
detailing verbatim term given by the principal investigator or designee, preferred term, 
system organ class (SOC), onset date, resolution date, severity, seriousness, action taken, 
outcome, and drug relatedness. The event onset will also be shown relative to study drug 
initiation (in number of days). Listings will be provided for all TEAEs, adverse events 
prior to date of first treatment, and adverse events starting more than 30 days after last 
study drug use. 
9.1.1. Incidence of Adverse Events 
A TEAE is defined as any event not present before exposure to study drug or any event 
already present that worsens in either intensity or frequency after exposure to study drug. 
Adverse events will be deemed treatment emergent if the onset date is on or after the date 
of first treatment, Day 1. Events with onset date during the screening period are not 
treatment emergent and will be listed separately.  
The total number of TEAEs and the number and percentage of subjects with at least one 
TEAE in each SOC and having each individual TEAE based on the PT will be presented. 


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9.1.2. Relationship of Adverse Events to Study Drug 
A summary of TEAEs by relationship to study drug will be presented in a table by total 
number of TEAE and incidence of occurrence. The investigator will provide an assessment 
of the relationship of the event to the study drug as Unrelated, Unlikely, Possible, 
Probable, and Definite. The latter three categories would constitute “Related.” If a subject 
reports multiple occurrences of the same TEAE, only the most closely related occurrence 
will be presented in the incidence count. Treatment-emergent AEs that are missing a 
relationship will be presented in the summary table as “Related” but will be presented in 
the data listing with a missing relationship. Percentages will be calculated based on the 
number of subjects in the safety population. 
The TEAE data will be categorized and presented by SOC, PT, and relationship in a 
manner similar to that described in Section 9.1.1. 
9.1.3. Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table by total number of TEAE 
and incidence of occurrence. The severity that will be presented represents the most 
extreme severity captured on the eCRF page. The possible severities are “Mild,” 
“Moderate,” and “Severe.” In the TEAE severity table, if a subject reported multiple 
occurrences of the same TEAE, only the most severe will be presented in the incidence 
count. Treatment-emergent AEs that are missing severity will be presented in tables as 
“Severe” but will be presented in the data listing with a missing severity. Percentages will 
be calculated based on the number of subjects in the safety population.  
The TEAE data will be categorized and presented by SOC, PT, and severity in a manner 
similar to that described in Section 9.1.1. 
9.1.4. Serious Adverse Events 
Serious TEAEs will be presented in a table. At each level of subject summarization, a 
subject is counted once for the incidence if the subject reported one or more events. 
Percentages will be calculated based on the number of subjects in the safety population.  
The treatment-emergent SAE data will be categorized and presented by SOC and PT in a 
manner similar to that described in Section 9.1.1. 


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9.1.5. Serious TEAEs, Deaths and Adverse Events Leading to Treatment or 
Study Discontinuation 
A listing of all Serious TEAEs (including deaths) and/or AEs leading to treatment or study 
discontinuation will be presented. Additionally, a separate listing of any deaths will be 
presented. Deaths and discontinuations will be assessed based on data recorded in the AE 
eCRF page. Subject deaths will be identified as AEs where the outcome is “Fatal”. 
Adverse events leading to treatment discontinuation will be identified as AEs where the 
action taken with study drug is “Drug Withdrawn”. Adverse events leading to study 
discontinuation will be identified as AEs where the caused study discontinuation field is 
marked as “Yes”. 
9.2. Clinical Laboratory Evaluations 
The majority of laboratory assessments will be performed by a central laboratory. All 
summaries will be based on the units provided by the central laboratory and no conversion 
will be performed. Lab test names listed in the statistical analysis plan are the same as 
indicated in the protocol; however the tables and listings will report results using the test 
names based on CDISC controlled terminologies.  
Blood chemistry, hematology, and PT/PTT values will be reported individually at 
screening, baseline, and Week 12/ET. Laboratory test results will be summarized 
descriptively at baseline and Week 12/ET. Changes from baseline to Week 12/ET in 
laboratory test results based on normal ranges will be summarized with descriptive 
statistics. Any clinically significant changes from baseline will be documented as an AE. 
Blood chemistry, hematology, and PT/PTT data will also be presented in data listings by 
subject. 
Methemoglobin will be reported as a percentage of hemoglobin. Methemoglobin will be 
summarized descriptively by treatment group at baseline and Weeks 2 and 12/ET. 
Additionally, the change from baseline in methemoglobin will be summarized by treatment 
group at Weeks 2 and 12/ET. Methemoglobin data will also be presented in data listings by 
subject. 
For the above laboratory tests, ET visits will be summarized as Week 12/ET regardless of 
when the visit occurs as the tests are not performed at every visit. 
Urine pregnancy test results, performed at Screening, Baseline, and Weeks 4, 8, and 12, for 
women of child-bearing potential (WOCBP) will be presented in data listings by subject.  


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9.3. Vital Sign Measurements 
Blood pressure and pulse will be summarized by treatment group from baseline through 
Week 12. Additionally, change from baseline in vital signs will be summarized at Weeks 
2, 4, 8, and 12. Any clinically significant changes from baseline will be documented as an 
AE. All visit sign measurement data will be listed.  
9.4. Physical Examination 
Any clinically significant changes from baseline will be documented as an AE. All 
physical examination data will be listed. 
10. Interim Analysis 
There will be 4 Data Safety Monitoring Board (DSMB) meetings during the conduct of 
this study to evaluate safety and tolerability prior to dose modification. A subset of the 
final safety and tolerability tables and listings, will be provided to the DSMB for review. 
Outputs to be provided to the DSMB are documented in the DSMB charter. No inferential 
statistics or hypothesis testing is planned for the DSMB analyses. DSMB analyses will be 
unblinded to actual treatment. The analyses for the DSMB will be performed by a separate, 
independent statistics team.   
In addition, an Interim Analysis including efficacy summaries will be conducted upon 
completion of Cohorts 1 and 2 to assist in the planning of future trials. No stopping rules 
for futility or early efficacy assessment will be applied as part of the interim analysis. The 
analysis will only be conducted on the subjects in cohorts 1 and 2, and a subset of tables 
from the primary analysis will be presented. Pairwise comparisons will be done between 
each active treatment in the cohorts and Vehicle Gel and nominal p-values will be 
presented without adjustment. Additionally, no adjustments will be made to p-values in the 
final analysis as a result of the interim analysis.  
The analysis set for the interim analysis will be subjects randomized into one of the first 
two cohorts. All subjects randomized on or prior to the last randomization date entered into 
IVRS for Cohort 2 will be included. 
 
 
 
Table 2: Interim Analysis Outputs 
Table 
Population 
Table 14.1-1 Subject Disposition 
All Randomized Subjects 


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Table 14.1-2 Demographics and Baseline Characteristics 
Intent-to-Treat Population 
Table 14.2-1.1 Complete Clearance of Baseline EGW/PAW at 
or Before Week 12 
Intent-to-Treat Population 
Table 14.2-1.3 Complete Clearance of Baseline EGW/PAW at 
or Before Week 12 by Gender 
Intent-to-Treat Population 
Table 14.2-7.1 Percent Change in Baseline EGW/PAW at 
Weeks 2, 4, 8, and 12 
Intent-to-Treat Population 
Table 14.2-9.1 Count of Total Warts at Weeks 2, 4, 8, and 12 
Intent-to-Treat Population 
Table 14.3-1 Study Drug Exposure (Days) and Missed Doses 
Safety Population 
Table 14.3-3.1 Summary of Tolerability Evaluations 
Safety Population 
Table 14.3.1-2 Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Population 
 


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11. Appendices 
11.1. 
 Schedule of Study Procedures 
 
PROCEDURES 
Screening 
(Day -35 – 
Day -1) 
Visit 1 
Baseline 
(Day 0) 
Visit 21 
Week 2 
±3 days 
(Day 14) 
Visit 3 
Week 4 
±5 days 
(Day 28) 
Visit 4 
Week 8 
±5 days 
(Day 56) 
Visit 5 
Week 
12/ET2 
±5 days 
(Day 84) 
Informed Consent 
X 
Demographics/Smoking 
X 
Medical History 
X 
X 
Medication History 
X 
X 
Inclusion/Exclusion 
X 
X 
Brief Pi hysical 
Examination 
X 
X
3 
X 
Chemistry, 
Hematology, PT/PTT 
X 
X
3 
X 
Urine Pregnancy Test 
X 
X3
X 
X 
X 
Methemoglobin4 
X 
X 
X 
X 
Blood Pressure and 
Pulse 
X 
X 
X 
X 
X 
X 
Wart Counts 
X 
X 
X 
X 
X 
X 
Tolerability Evaluation5 
X 
X 
X 
X 
X 
Instruct on Study Drug 
Application and Provide 
Subject Instructions 
X 
Dispense Dosing Diary 
X 
X 
X 
Collect Completed 
Dosing Diary 
X 
X 
X 
Study Drug Dispensed 
X 
X 
X 
Study Drug Collected 
X 
X 
X 
Subject Compliance 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
1  All visit dates are in reference to Baseline, e.g., Visit 2 occurs two weeks (14 days) after Baseline visit. 
2  All Week 12 procedures should be completed for subjects who prematurely discontinue. 
3  If the Baseline Visit is within 7 calendar days of the Screening visit, Physical Examination, Chemistry, 
Hematology, PT/PTT, and UPT do not need to be repeated. 
4 
Collected via pulse co-oximetry at site. 
5 
Tolerability Assessments are defined in Section 4.3 of the protocol