Clinical trial NCT02672332
Conditions: Acne Vulgaris
Sponsor: Novan, Inc.
Start date: 2016-02-22; Completion date: 2016-12-21
Enrollment: 1307 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 12 week, multi-center, double-blinded, randomized, vehicle-controlled, parallel group, study to be conducted in approximately 1300 subjects with acne vulgaris in the US.

Detailed description:
This is a double-blind, placebo controlled study in subjects with moderate to severe acne. Subjects who satisfy the entry criteria will be randomized to SB204 4% QD or Vehicle Gel QD in a 1:1 ratio. Efficacy assessments will include Investigator Global Assessments (IGA) and inflammatory and non-inflammatory lesion counts. Subjects will return for post-Baseline evaluation at Weeks 2, 4, 8, and 12/Early Termination (ET).

Arms: arm 1: SB204 4% topically once daily arm 2: Vehicle Gel topically once daily
Interventions: intervention 1: SB204 4% intervention 2: Vehicle Gel
Intervention descriptions: intervention 1: Once daily intervention 2: Placebo comparator

Protocol documents:
Prot_000.pdf: 
 
Confidential and Proprietary, Novan, Inc. 
  
 
 
 
 
 
 
 
 
STUDY TITLE 
A Phase 3 Multi-Center, Randomized, Double-
Blinded, Vehicle-Controlled, Parallel Group Study 
Comparing the Efficacy, Tolerability and Safety of 
SB204 and Vehicle Gel Once Daily in the Treatment 
of Acne Vulgaris 
PROTOCOL NO. 
NI-AC301 
SPONSOR 
Novan, Inc. 
4222 Emperor Blvd., Suite 200 
Durham, NC 27703 
Tel.: 919-485-8080 
AMENDMENT 1 
06 January 2016 
VERSION 
2.0 
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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CONTACT INFORMATION PAGE 
 
Sponsor Contact Information: 
 
Novan, Inc. 
4222 Emperor Blvd., Suite 200 
Durham, NC 27703 
Tel:  919-485-8080 
Fax:  919-237-9212 
 
 
CRO Contact Information: 
 
Chiltern  
4000 CentreGreen Way 
Suite 300 
Cary, NC 27513 
Tel: 919-462-8867 
 
PROJECT MANAGER: 
Jamie Palmer 
Tel:  423-990-0276 
Mobile: 423-943-6163 
Fax:   423-968-3567 
E-mail: Jamie.Palmer@chiltern.com 
 
MEDICAL MONITOR: 
William R Welder, MD, MPH 
Tel: 423-990-0471 
Fax: 888-833-6865 
E-mail: Bill.Welder@Chiltern.com 
 
Serious Adverse Event (SAE) and Safety Contact Information: 
SAE Hotline: 1-888-SAE CHIL (1-888-723-2445) 
Email:GlobalSAEInbox@Chiltern.com 
Fax: 1-800-468-2288                             
 
 
 
 
 


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PROTOCOL AMENDMENT 
RATIONALE FOR AMENDMENT 
This protocol amendment is required to update the inclusion and exclusion criteria and the 
definition of subjects in the safety population. Eligible subjects are those age 9 and older.  Subjects 
with severe recalcitrant nodulocystic acne are excluded. The term “principal investigator (PI)” has 
been added to the list of abbreviations. The safety population will be comprised of all randomized 
subjects that received at least one dose of study medication. Edits to the clinical and non-clinical 
background sections update results from completed studies. Analysis specifics have been moved 
to the statistical analysis plan (SAP). Minor edits have been made to the document to ensure 
consistency. 
 
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. Minor administrative changes were made as well to correct grammar, 
punctuation, etc. 
Change 1: SYNOPSIS: Key Inclusion Criteria 
Be male or female, 9 to 40 years of age and older, inclusive and in good general health; 
Change 2: SYNOPSIS: Key Inclusion Criteria 
Have a minimum of 20 but not more than 40 inflammatory lesions (papules, pustules, nodules, 
and cysts) on the face; 
Change 3: SYNOPSIS: Key Exclusion Criteria 
Have any dermatological conditions on the face that could interfere with clinical evaluations 
such as severe recalcitrant nodulocystic acne, acne conglobata, acne fulminans, acne 
secondary to medications or other medical conditions, perioral dermatitis, clinically significant 
rosacea, or gram-negative folliculitis 
Change 4: SYNOPSIS: Primary Efficacy Analysis 
All three co-primary outcomes must show superiority over vehicle (p-value≤0.05) in order for 
efficacy to be demonstrated; therefore no adjustments for multiplicity will be made. 
The analysis of treatment differences in the absolute change in non-inflammatory lesion counts 
will be conducted using a repeated measures analysis of covariance with factors for treatment, site, 
sex, age, visit and treatment by visit interaction. The Baseline lesion count will be included as the 
covariate and subject nested within site will be the random repeated measure at each visit to adjust 
for the variability due to repeated visits. Change from Baseline lesion counts at each visit will be 
the dependent variable. Only the estimate of treatment differences at Week 12/ET will be evaluated 
for efficacy.   
 


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The analysis of the absolute change in inflammatory lesion counts will use the same method as the 
analysis of the non-inflammatory lesions. 
 
Subjects will be considered an IGA success if their IGA score is clear (0) or almost clear (1) at and 
is decreased by ≥ 2 grades from Baseline. 
 
Analysis of treatment differences in IGA success at Week 12/ET will be conducted using a logistic 
general linear covariance model with factors for treatment, site, sex and age, and with Baseline 
IGA score as a covariate. 
Change 5: SYNOPSIS: Secondary Efficacy Analysis 
Secondary efficacy outcomes include the percent change in inflammatory and non-inflammatory 
lesion counts at Week 12/ET, the median time to 35% improvement in inflammatory lesions, and 
the median time to a two or more grade improvement in IGA. The percent change in lesions will 
be analyzed for treatment differences using the same models as described in the co-primary 
efficacy analyses. Survival analysis methods will be used to sequentially estimate the treatment 
differences in the median time to 35% improvement in inflammatory lesions and the median time 
to a two or more grade improvement in the IGA. A subject will be censored if the endpoint is not 
realized. 
Change 6: LIST OF ABBREVIATIONS 
Added PI (Principal Investigator) to List of Abbreviations and Definitions 
Change 7: PROTOCOL BODY: Section 3.6, Study Population, Paragraph 1 
Approximately 1300 male and female subjects between the ages of 9 years of age and older 40 
(inclusive) with moderate to severe acne vulgaris on the face will be randomized to participate in 
the study. 
Change 8: PROTOCOL BODY: Section 1.1 
To date, approximately 400 500 subjects have been treated with NVN1000 Gel, including SB204, 
and approximately 200 275 subjects have been treated with the vehicle gel.  
Change 9: PROTOCOL BODY: Section 1.1, Background 
NVN1000 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) and in a human lymphocyte chromosome aberration assay.  
Change 10: PROTOCOL BODY: Section 3.6, Study Population 
Approximately 1300 male and female subjects between the ages of 9 and 40 (inclusive) years of 
age and older with moderate to severe acne vulgaris on the face will be randomized to participate 
in the study. Eligible subjects will have: at least 25 but no more than 70 non-inflammatory 
lesions (open and closed comedones); at least 20 but no more than 40 inflammatory lesions 
(papules, pustules, nodules, and cysts); at least 25 but no more than 70 non-inflammatory lesions 
(open and closed comedones); no more than two nodules or cysts; and an IGA of 3 (moderate) or 
4 (severe) on a 5-point IGA scale (Appendix 16.2). 
 


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Change 11: PROTOCOL BODY: Section 3.7.2, Inclusion Criteria 2 
Be male or female, 9 to 40 years of age and older, inclusive at Baseline and in good general 
health; 
Change 12: PROTOCOL BODY: Section 3.7.2, Inclusion Criteria 5 
Have a minimum of 20 but not more than 40 inflammatory lesions (papules, pustules, nodules, 
and cysts) on the face at Baseline; 
Change 13: PROTOCOL BODY: Section 3.7.3, Exclusion Criteria 1 
Have any dermatological conditions on the face that could interfere with clinical evaluations such 
as severe recalcitrant nodulocystic acne, acne conglobata, acne fulminans, acne secondary to 
medications or other medical conditions, perioral dermatitis, clinically significant rosacea, or 
gram-negative folliculitis; 
Change 14: PROTOCOL BODY: Section 7.2.2, Safety Population 
The safety (SAF) population will include all study randomized subjects that received at least 
one dose of study medication. who were and dispensed study medication and grouped by the 
treatment they were actually dispensed. All safety and tolerability analyses will be performed on 
the safety analysis population (SAF) population based on the treatments the subjects actually 
applied. 
Change 15: PROTOCOL BODY: Section 7.4.1, Primary Efficacy Analysis 
All three co-primary outcomes must show superiority over vehicle (p-value ≤0.05) in order for 
efficacy to be demonstrated; therefore no multiplicity adjustments will be made to the co-
primary outcome analyses. 
The analysis of treatment differences in the absolute change in non-inflammatory lesion counts 
will be conducted using a repeated measures analysis of covariance with factors for treatment, site, 
sex, age, visit and treatment by visit interaction. The Baseline lesion count will be included as the 
covariate and subject nested within site will be the random repeated measure at each visit to adjust 
for the variability due to repeated visits. Change from Baseline lesion counts at each visit will be 
the dependent variable. However, only the estimate of treatment differences at Week 12/ET will 
be evaluated for efficacy. 
The analysis of the absolute change in inflammatory lesion counts will use the same method as the 
analysis of the non-inflammatory lesions. 
Subjects will be considered an IGA success if their IGA score is clear (0) or almost clear (1) and 
is decreased by ≥ 2 grades from Baseline. 
Analysis of treatment differences in IGA success at Week 12/ET will be conducted using a logistic 
general linear covariance model with factors for treatment, site, sex and age, and with Baseline 
IGA score as a covariate. 
Prior to analysis of co-primary outcomes, missing post-Baseline lesion counts and IGA scores 
results at each visit will be imputed using a Markov chain Monte Carlo (MCMC) multiple 
imputation methodology. Missing lesion counts and missing IGA scores will be assumed to be 
missing at random at each visit (MAR). Therefore a Markov chain Monte Carlo (MCMC) 
imputation method will be employed to impute all missing lesion counts and IGA scores for all 


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visits. Separate multiple imputation (MI) procedures will be used for each outcome, using 
Statistical Analysis Software (SAS) procedure MI. Details of PROC MI and options used in the 
imputation procedures will be provided in a statistical analysis plan. ITT subjects with only 
Baseline assessments will have the Baseline value carried forward across all visits. 
The primary analyses of the co-primary efficacy endpoints will be performed in the ITT population 
where missing data have been imputed as described above. Additional analyses of the co-primary 
outcomes will be performed using the PP population. To access the sensitivity of the primary 
efficacy results to imputation methods, each co-primary outcome will be analyzed as described 
above, but with missing data imputed by last observation carried forward (LOCF) and Baseline 
observation carried forward (BOCF) on the ITT population.  
Change 16: PROTOCOL BODY: Section 7.4.2, Secondary Efficacy Analyses 
Secondary efficacy outcomes include the percent change in inflammatory and non-inflammatory 
lesion counts at Week 12/ET, the median time to 35% improvement in inflammatory lesions and 
the time to a two or more grade improvement in the IGA. The percent change in lesions will be 
analyzed for treatment differences using the same models as described in the co-primary efficacy 
analyses. Survival analysis methods will be used to sequentially estimate the treatment differences 
in the median time to 35% improvement in inflammatory lesions and the median time to a two or 
more grade improvement in the IGA. A subject will be censored if the endpoint is not realized.   
Change 17: PROTOCOL BODY: Section 7.8, Sample Size and Power Consideration 
Approximately 1300 subjects will be randomized into the study in a 1:1 ratio (650 in each active 
arm) at approximately 50 sites in North America. 
 
 


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INVESTIGATOR’S AGREEMENT 
I have carefully read the protocol entitled: “A Phase 3 Multi-Center, Randomized, Double-
Blinded, Vehicle-Controlled, Parallel Group Study Comparing the Efficacy, Tolerability and 
Safety of SB204 and Vehicle Gel Once Daily in the Treatment of Acne Vulgaris” 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: 
SB204 
Name of Active Ingredient: 
NVN1000 
Title 
A Phase 3 Multi-Center, Randomized, Double-Blinded, Vehicle-Controlled, 
Parallel Group Study Comparing the Efficacy, Tolerability and Safety of SB204 
and Vehicle Gel Once Daily in the Treatment of Acne Vulgaris 
Study 
Objectives 
The objectives of this study are to compare efficacy, safety, and tolerability of 
SB204 and Vehicle Gel in subjects with acne vulgaris for 12 weeks. 
Treatment 
Regimens 
Eligible subjects at the Baseline visit will be randomized 1:1 to SB204 4% QD 
or Vehicle Gel QD and treated for up to 12 weeks (84 days). 
Formulation 
Investigational Drug:  SB204 4%  
Dosing:  Approximately 900 mg of SB204 Gel once daily to the face 
Duration of Treatment:  12 weeks 
Comparator Drug:  Vehicle Gel  
Dosing:  Approximately 900 mg of Vehicle Gel once daily to the face 
Duration of Treatment:  12 weeks 
Study Period 
Subjects will be dosed in the study for up to 12 weeks. 
Study Design This is a multi-center, double-blinded, randomized, vehicle-controlled, parallel 
group, study to be conducted in approximately 1300 subjects with acne vulgaris. 
 
Subjects who satisfy the entry criteria will be randomized to SB204 4% QD or 
Vehicle Gel QD in a 1:1 ratio. Investigational drug will be delivered from a 
double barrel single pump dispenser. The pump dispenses product from two 
chambers (NVN1000 Gel and a hydrogel or Vehicle Gel and a hydrogel) which 
will be mixed together in the palm for approximately 5 seconds by the subject 
and applied to the entire face once daily after washing. Efficacy assessments 
will include Investigator Global Assessments (IGA) and inflammatory and non-
inflammatory lesion counts. Tolerability and safety assessments include 
cutaneous tolerability evaluation (erythema, scaling, dryness, pruritus, 
burning/stinging), adverse event collection, physical exams, blood pressure, 
pulse rate, and urine pregnancy tests (UPTs). Subjects will return for post-
Baseline evaluation at Weeks 2, 4, 8, and 12/Early Termination (ET).  
Main 
Inclusion / 
Exclusion 
Criteria 
Key Inclusion Criteria: 
 Be male or female, 9 years of age and older and in good general health;  
 Have Baseline IGA score of 3 (moderate) or 4 (severe); 
 Have a minimum of 25 but not more than 70 non-inflammatory lesions 
(open and closed comedones) on the face; 


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 Have a minimum of 20 but not more than 40 inflammatory lesions 
(papules, pustules, nodules, and cysts) on the face; 
 Have no more than two nodules or cysts on the face. 
 
Key Exclusion Criteria: 
 Have any dermatological conditions on the face that could interfere with 
clinical evaluations such as severe recalcitrant nodulocystic acne, acne 
conglobata, acne fulminans, acne secondary to medications or other 
medical conditions, perioral dermatitis, clinically significant rosacea, or 
gram-negative folliculitis;  
 Have any underlying disease(s) or some other dermatological condition 
of the face that requires the use of interfering topical or systemic therapy 
or makes evaluations and lesion count inconclusive; 
 Have a history of experiencing significant burning or stinging when 
applying any facial treatment (e.g., make-up, soap, masks, washes, 
sunscreens, etc.) to their face; 
 Have used medications or vitamins which are reported to exacerbate 
acne during the 12 weeks immediately preceding Baseline (e.g., 
azathioprine, haloperidol, halogens such as iodides or bromides, 
lithium, anabolic steroids, systemic corticosteroids, phenytoin and 
phenobarbital). Daily use of a multi-vitamin is acceptable. 
 Have had a severe acne flare during the 12 weeks preceding Baseline. 
 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. 
Sample Size 
Approximately 1300 subjects will be randomized into the study in a 1:1 ratio 
(~650 in each arm).  
Efficacy 
Evaluation 
The same blinded evaluator should perform Investigator Global Assessments 
(IGA) and lesion counting at Screening, Baseline, and Weeks 2, 4, 8, and 12/ET. 
In the event that this is not possible due to unforeseen circumstances, a different 
blinded evaluator may evaluate the subject. However, the same evaluator 
should evaluate subjects at the Baseline and Week 12/ET evaluations. 
 
Investigator Global Assessment (IGA) 
The IGA score will be determined based on the evaluation of the overall signs 
and symptoms of acne vulgaris. IGA evaluations will be performed prior to the 
lesions counts, approximately three feet from the subject, and scored on a scale 
of 0 (clear) to 4 (severe). 
 
Lesion Counts 
At Screening, Baseline, and Weeks 2, 4, 8 and 12/ET, the evaluator will count 
the total number of non-inflammatory and inflammatory lesions on the subject’s 
face including the forehead, right and left cheeks, chin and nose. Non-
inflammatory lesion count will include the number of open and closed 
comedones. Inflammatory lesion count will include the number of papules and 


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pustules. The number of nodules and cysts will be recorded separately and 
included with the inflammatory lesion count.  
Tolerability  
Evaluation 
Subjects will be assessed at each visit from Baseline through Week 12/ET for 
cutaneous tolerability. Tolerability will be assessed on a scale of 0 to 3 where 
0=none, 1=mild, 2=moderate, and 3=severe for erythema, scaling, dryness, 
pruritus, and burning/stinging. 
Safety 
Evaluation 
Adverse events will be assessed and collected at each evaluation beginning at 
Screening. A brief physical exam will be collected at Screening, Baseline and 
Week 12/ET. Blood pressure and pulse will be collected at Screening, Baseline 
and each visit through Week 12/ET. Any clinically significant changes noted 
during the physical exam or vital sign measurements will be recorded as adverse 
events. Urine pregnancy tests in women of child-bearing potential will be 
conducted at Screening, Baseline, and Weeks 4, 8 and 12/ET. 
Additional 
Evaluations 
Photographs will be collected at Baseline, Week 4, Week 8, and Week 12/ET 
at a subset of sites.  
Endpoints 
Primary Efficacy Endpoints  
The co-primary efficacy endpoints are:  
 The absolute change in inflammatory lesion count from Baseline to 
Week 12/ET; 
 The absolute change in non-inflammatory lesion count from Baseline to 
Week 12/ET; 
 The proportion of subjects with IGA success at Week 12/ET.  A subject 
will be considered a success if the IGA score is clear (0) or almost clear 
(1) and ≥2 grades less than Baseline. 
 
Secondary Efficacy Endpoints  
The secondary endpoints include the following: 
1. The percent change in inflammatory lesion count from Baseline to 
Week 12/ET; 
2. The percent change in non-inflammatory lesion count from Baseline to 
Week 12/ET; 
3. The median time to a 35% reduction in the inflammatory lesion count; 
4. The median time to a two (2) or more grade improvement in IGA. 
Statistical 
Methods 
All statistical processing will be performed using SAS® 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 the active treatment group to the vehicle treatment group. 
Efficacy analyses will be performed using the intent-to-treat (ITT) and per-
protocol (PP) populations with the ITT population considered as primary. 
Safety analyses will be performed using the safety (SAF) population. 
 
Descriptive Statistics 
Descriptive statistics will be presented for the efficacy data at each evaluation 
visit. 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 of N. Descriptive 


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statistics will be presented for the active treatment group and vehicle treatment 
group. Summaries over both treatment groups will be presented for 
demographic and Baseline characteristics. 
 
Efficacy Analysis 
Efficacy of SB204 4% will be based on statistical superiority over vehicle for 
change from Baseline in lesion counts and IGA score improvement at Week 
12/ET. 
 
Primary Efficacy Analysis 
There are three co-primary efficacy outcomes:  
 change in inflammatory lesions counts at Week 12/ET  
 change in non-inflammatory lesions counts at Week 12/ET and  
  IGA success at Week 12/ET which is defined as an IGA score of clear 
(0) or almost clear (1) and ≥2 grades less than Baseline. 
 
All three co-primary outcomes must show superiority over vehicle  
(p-value≤0.05) in order for efficacy to be demonstrated; therefore no 
adjustments for multiplicity will be made. 
 
Secondary Efficacy Analyses 
Secondary efficacy outcomes include the percent change in inflammatory and 
non-inflammatory lesion counts at Week 12/ET, the median time to 35% 
improvement in inflammatory lesions, and the median time to a two or more 
grade improvement in IGA.  
Analysis of the secondary efficacy outcomes will be adjusted for multiplicity 
using a hierarchical step-down procedure. These endpoints will be tested in the 
specified order with the rule that once a p-value exceeds 0.05, endpoints further 
down in the order are not statistically significant.  
Tolerability Analyses 
Cutaneous tolerability assessments (erythema, scaling, dryness, pruritus, 
burning/stinging) will be summarized from Baseline to Week 12/ET. 
Additionally, change from Baseline in tolerability assessments will be 
summarized at Weeks 2, 4, 8, and 12/ET.  
Safety Analyses 
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.  
 


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All information pertaining to an AE noted during the study will be listed by 
subject, detailing verbatim term given by the PI or designee, preferred term 
(PT), 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.  
 
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.  
 
Physical Examinations 
Any clinically significant changes from Baseline will be documented as an AE. 
 
Vital Signs 
Blood pressure and pulse will be summarized by treatment group from Baseline 
through Week 12/ET. Additionally, change from Baseline in vital signs will be 
summarized at Weeks 2, 4, 8, and 12/ET. Any clinically significant changes 
from Baseline will be documented as an AE. 
Urine Pregnancy Tests 
Urine pregnancy test results for women of child-bearing potential (WOCBP) 
will be presented in data listings by subject. 
 
 


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LIST OF ABBREVIATIONS 
 
Definition 
AE 
Adverse Event 
BSA 
Body Surface Area 
BOCF 
Baseline Observation Carried Forward 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
ITT 
Intent to Treat population 
ITT 
Intent to Treat population 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NOVAN 
Novan, Inc. 
OTC 
Over-the-Counter 
PI 
Principal Investigator 


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PP 
Per-Protocol population 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Population 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Events 
UPT 
Urine Pregnancy Test 
WOCBP 
Women of Child-Bearing Potential 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ......................................................................................................................2 
CONTACT INFORMATION PAGE ...........................................................................................3 
PROTOCOL AMENDMENT.......................................................................................................4 
INVESTIGATOR’S AGREEMENT ............................................................................................8 
PROTOCOL SYNOPSIS ..............................................................................................................9 
LIST OF ABBREVIATIONS .....................................................................................................14 
TABLE OF CONTENTS ............................................................................................................16 
LIST OF FIGURES .....................................................................................................................19 
LIST OF TABLES .......................................................................................................................19 
1. INTRODUCTION..................................................................................................................20 
1.1 Background .....................................................................................................................20 
1.2 Investigational Product ...................................................................................................20 
1.3 Nonclinical Studies with NVN1000 ...............................................................................20 
1.4 Clinical Studies with NVN1000 Gel...............................................................................21 
1.5 Summary of Benefits and Risks ......................................................................................22 
2. RATIONALE AND OBJECTIVES .....................................................................................23 
2.1 Study Rationale ...............................................................................................................23 
2.2 Study Objectives .............................................................................................................23 
3. STUDY DESIGN ....................................................................................................................23 
3.1 Study Endpoints ..............................................................................................................24 
3.1.1 Efficacy Endpoints ..............................................................................................24 
3.1.2 Tolerability Endpoints ........................................................................................24 
3.1.3 Safety Endpoints .................................................................................................24 
3.2 Structure ..........................................................................................................................24 
3.3 Duration ..........................................................................................................................24 
3.4 Dosage/Dose Regimen ....................................................................................................24 
3.5 Visit Schedule .................................................................................................................25 
3.6 Study Population .............................................................................................................25 
3.7 Eligibility Criteria ...........................................................................................................25 
3.7.1 Informed Consent and Authorization to Release Health Information ................25 
3.7.2 Inclusion Criteria ................................................................................................26 
3.7.3 Exclusion Criteria ...............................................................................................26 
4. STUDY PROCEDURES AND METHODS ........................................................................29 


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4.1 Subject Entry Procedures ................................................................................................29 
4.1.1 Screening (Day -35 to Day 0) .............................................................................31 
4.1.2 Baseline (Day 0) .................................................................................................31 
4.1.3 Week 2 (Day 14) .................................................................................................32 
4.1.4 Weeks 4 and 8 (Days 28 and 56) ........................................................................32 
4.1.5 Week 12/ET (Day 84) .........................................................................................33 
4.1.6 Discontinuation/Withdrawal Procedures ............................................................33 
4.2 Efficacy Assessments......................................................................................................35 
4.2.1 Investigator Global Assessment..........................................................................35 
4.2.2 Lesion Counts .....................................................................................................36 
4.3 Tolerability Assessments ................................................................................................36 
4.4 Safety Assessments .........................................................................................................37 
4.4.1 Adverse Events ...................................................................................................37 
4.4.2 Physical Exam.....................................................................................................38 
4.4.3 Vital Signs...........................................................................................................38 
4.4.4 Pregnancy Testing...............................................................................................38 
4.5 Additional Assessments ..................................................................................................38 
4.5.1 Photography ........................................................................................................38 
4.6 Screen Failures ................................................................................................................38 
4.7 Protocol Deviations .........................................................................................................38 
5. PROHIBITED THERAPIES AND MEDICATIONS ........................................................39 
6. EVALUATION OF ADVERSE EVENTS ...........................................................................39 
6.1 Definitions.......................................................................................................................39 
6.1.1 Adverse Event Severity Grades ..........................................................................40 
6.1.2 Investigational Product Causality .......................................................................40 
6.2 Reporting Adverse Events ..............................................................................................41 
6.3 Immediately Reportable Events ......................................................................................41 
6.4 Pregnancy ........................................................................................................................42 
6.5 Follow-Up of Adverse Events ........................................................................................43 
6.5.1 Follow-Up of Non-Serious Adverse Events .......................................................43 
6.5.2 Follow-Up of Post Study Serious Adverse Events .............................................43 
6.6 Overdosage .....................................................................................................................43 
6.7 Discontinuation of Individual Subjects from the Study ..................................................44 
7. STATISTICAL ANALYSIS .................................................................................................44 
7.1 General Considerations ...................................................................................................44 
7.2 Populations ......................................................................................................................44 
7.2.1 Intent to Treat (ITT) Population .........................................................................44 


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7.2.2 Safety Population ................................................................................................44 
7.2.3 Per-Protocol Population ......................................................................................44 
7.3 Demographic and Baseline Characteristics ....................................................................45 
7.4 Efficacy Analysis ............................................................................................................45 
7.4.1 Primary Efficacy Analyses .................................................................................45 
7.4.2 Secondary Efficacy Analyses .............................................................................46 
7.5 Drug Exposure and Compliance .....................................................................................46 
7.6 Tolerability ......................................................................................................................47 
7.7 Safety ..............................................................................................................................47 
7.7.1 Adverse Events ...................................................................................................47 
7.7.2 Physical Examination .........................................................................................47 
7.7.3 Vital Signs...........................................................................................................47 
7.7.4 Urine Pregnancy Tests ........................................................................................48 
7.8 Sample Size and Power Considerations ..........................................................................48 
8. INVESTIGATIONAL PRODUCT MANAGEMENT .......................................................48 
8.1 Receipt of Investigational Product ..................................................................................48 
8.2 Storage of Investigational Product ..................................................................................48 
8.3 Treatment Assignment and Blinding ..............................................................................49 
8.4 Unblinding of Treatment Assignment ............................................................................49 
8.5 Investigational Product Accountability ...........................................................................49 
8.6 Returns and Destruction ..................................................................................................49 
9. RECORDS MANAGEMENT ...............................................................................................50 
9.1 Data Collection ...............................................................................................................50 
9.2 File Management at the Study Site .................................................................................51 
9.3 Records Retention at the Study Site................................................................................51 
10. MONITORING, COMPLIANCE, AND QUALITY ..........................................................52 
10.1 Quality Assurance Audits and Quality Control ..............................................................53 
11. ETHICS AND RESPONSIBILITY ......................................................................................53 
12. CONFIDENTIALITY ...........................................................................................................53 
13. AMENDMENT POLICY ......................................................................................................53 
14. USE OF INFORMATION AND PUBLICATION..............................................................54 
15. REFERENCES .......................................................................................................................55 
16. APPENDICES ........................................................................................................................56 
16.1 APPENDIX 1:  List of Restricted Medications: .............................................................56 
16.2 APPENDIX 2:  Definitions for IGA Score .....................................................................57 
 


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LIST OF FIGURES 
 
Figure 1:  Study Diagram .................................................................................................23 
 
 
LIST OF TABLES 
 
Table 1: 
Schedule of Visits and Procedures ...................................................................30 
 


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1. INTRODUCTION 
1.1 BACKGROUND 
Acne vulgaris is a chronic skin disease characterized by open and closed comedones, papules, 
pustules, and cysts. Current acne therapies include oral and topical antibiotics, topical keratolytics, 
and oral contraceptives.   
Nitric oxide is a free radical gas naturally produced by the human body which has antimicrobial 
and anti-inflammatory activity. Novan, Inc. has developed a topical gel containing NVN1000, a 
drug which releases nitric oxide, for topical application. SB204, an admixture of an alcoholic 
NVN1000 Gel with an aqueous hydrogel, is in development for the treatment of acne vulgaris. In 
a randomized, double-blind, placebo-controlled, 12-week, Phase 2 study, SB204 decreased 
inflammatory and non-inflammatory lesion counts in subjects with acne and was well tolerated.   
To date, approximately 500 subjects have been treated with NVN1000 Gel, including SB204, and 
approximately 275 subjects have been treated with the vehicle gel.  
1.2 INVESTIGATIONAL PRODUCT  
NVN1000 has been developed to deliver controlled release of nitric oxide from micron sized 
polysiloxane macromolecules. The active agent is formulated into an alcohol-based topical gel and 
the formulation will be dispensed from a dual chamber pump.  
 
Investigational Products 
Name of Active 
Ingredient 
NVN1000 
None 
Drug Name/ 
Concentration 
SB204 4%  
Vehicle Gel  
Manufacturer 
Ei, LLC  
Ei, LLC  
Packaging 
Pump designed to deliver 1:1 
Hydrogel: NVN1000 Gel to yield 
final concentration of SB204 4%  
Pump designed to deliver 1:1 
Hydrogel: Vehicle Gel 
Storage 
Requirements 
Refrigerated until dispensing, 2-8 °C  Refrigerated until dispensing, 2-8 °C  
Appearance Post-
Mixing 
Opaque white gel  
Opaque white gel 
Dosing Schedule 
Once daily 
Once daily 
Route of 
Administration 
Topical Application 
Topical Application 
1.3 NONCLINICAL STUDIES WITH NVN1000  
Novan has completed over 30 nonclinical studies with NVN1000 to assess pharmacology, 
pharmacokinetics (ADME), and toxicology. In mini-pig and mouse studies, doses of SB204 far in 
excess both in concentration and applied surface area of projected clinical doses have not 


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demonstrated any significant toxicological effects. The most relevant and persistent finding has 
been a transient dermal erythema that is concentration dependent and believed to be a consequence 
of a vascular dilation, “flushing” effect. Oral administration of NVN1000 drug substance in a SEG 
I reproductive toxicology study in rats showed no adverse effects on fertility and mating behavior. 
Oral administration of NVN1000 drug substance in SEG II reproductive toxicology studies in rats 
and rabbits showed minor effects on fetal development at the highest doses. Dermal application 
has been safe and resulted in minimal exposure to nitrate or systemic silica when applied topically 
at supratherapeutic doses. In a 13-week GLP dermal toxicology study with SB204 in mini-pigs at 
doses of 48-fold (mg/kg) and 14-fold (mg/cm2) in excess of current maximum human dose, there 
was no increase in plasma nitrate concentrations, minimal systemic exposure (5-22 ng/mL) to the 
parent compound as measured by hMAP3, and no significant toxicologic findings (Study 14-NC-
001).  Cumulatively, these nonclinical data demonstrate that systemic absorption of NVN1000 
after dermal administration at supratherapeutic doses is minimal, with no major systemic organ 
toxicity.  
NVN1000 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) and in a human lymphocyte chromosome aberration assay.  
In nonclinical pharmacology studies conducted by Novan and outside laboratories, NVN1000 or 
related compounds demonstrated: 
 Bactericidal activity against P. acnes in vitro; 
 Anti-inflammatory activity in an allergic contact dermatitis ear swelling model; 
 Inhibition of lipogenesis by immortalized sebaceous cells. 
 
For additional information refer to the Investigator’s Brochure (IB). 
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 nine completed clinical 
studies, approximately 400 subjects have been treated with NVN1000 Gel or SB204 and 
approximately 200 subjects have been treated with Vehicle Gel. One unrelated serious adverse 
event (SAE) has been reported in the acne development program. The Adverse Event (AE profile 
has been similar in subjects treated with active (SB204) or Vehicle Gel. An asymptomatic, 
transient erythema has been observed in some subjects treated with SB204. There have been no 
clinically significant changes in laboratory results including methemoglobin, or in physical 
examinations. 
In a maximum use cross-over pharmacokinetic (PK) study conducted in 18 subjects with moderate 
to severe acne, there was no detectable exposure to the NVN1000 polysiloxane backbone assessed 
by measuring plasma concentrations of hydrolyzed N-Methylaminopropyl-trimethoxysilane 
(hMAP3) and no increase in plasma nitrate levels following topical administration of SB204. A 4 
period, double-dummy, cross-over study in subjects with moderate to severe acne is ongoing to 
assess effects of therapeutic and supratherapeutic doses of SB204 on ECG parameters. The 
thorough ECG study will be completed prior to dosing in the Phase 3 pivotal program. 


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In other development programs, local application-site reactions that led to treatment 
discontinuations were observed following application of alcoholic NVN1000 Gel or Vehicle Gel 
under occlusion in subjects with psoriasis or to the genital/perianal area in subjects with 
genital/perianal warts. 
Additional details regarding completed clinical studies are in the Investigator’s Brochure. 
1.5 SUMMARY OF BENEFITS AND RISKS 
The pathogenesis of acne vulgaris includes several mechanisms which are potential targets for 
nitric oxide. Nitric oxide has been demonstrated in vitro to decrease P. acnes, inhibit several 
inflammatory pathways relevant in acne, and to decrease sebum production. In two completed 
Phase 2 studies, subjects with acne treated with SB204 had lower inflammatory and non-
inflammatory lesion counts with greater ‘success’ on the dichotomized IGA score (‘clear/almost 
clear’ and at least a two grade change from Baseline) at the end of treatment when compared to 
subjects treated with Vehicle Gel. Once daily dosing was as effective as twice daily dosing. In the 
studies conducted to date, the systemic AE profile was similar between subjects treated with 
SB204 and subjects treated with Vehicle Gel. SB204 4% has been generally well tolerated and 
was not associated with a safety or tolerability signal. 
In the maximum use pharmacokinetic study, there was no observed hMAP3 in plasma and no 
change in nitrate levels after topical application of SB204 8% twice daily to approximately 17% 
body surface area (BSA).  
A transient (approximately 5-10 minutes), asymptomatic erythema has been observed in some 
subjects shortly after application of SB204 which is a physiologic response (vasodilation) to local 
nitric oxide release. In the most recently completed study, local application-site reactions were 
reported in approximately 5% of subjects treated with SB204. These local application-site 
reactions resolved after discontinuation of the product and by the end of the study. Topical 
application has been generally well-tolerated as assessed by scores for erythema, peeling, pruritus, 
and burning/stinging. Tolerability will be assessed during the planned study, and discontinuation 
criteria for intolerance by individual subjects is described in Section 6.7. 
Both SB204 and Vehicle Gel contain alcohol; 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.  
Based on the known mechanism of action of nitric oxide, theoretical risks from systemic exposure 
following topical administration of NVN1000 Gel or SB204 include hypotension and headache. 
The rate of headache has been comparable in subjects treated with NVN1000 or SB204 and 
Vehicle Gel.  Neither hypotension nor methemoglobinemia have been observed in nine completed 
studies that have enrolled over 400 subjects treated with NVN1000 Gel or SB204. 
Based on available data, Novan anticipates that the risks to subjects enrolling in this Phase 3 study 
at which the maximum strength of SB204 will be 4% once daily to approximately 3% body surface 
area are minimal, and that appropriate monitoring is in place to assess safety. Subjects randomized 
to treatment with SB204 4% once daily may have a clinical benefit from study participation.  


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2. RATIONALE AND OBJECTIVES 
2.1 STUDY RATIONALE 
Novan is conducting this study to evaluate the efficacy, cutaneous tolerability and safety of SB204 
4% and Vehicle Gel administered once daily to the face. 
Subjects will dose once daily for up to 12 weeks (84 days) with SB204 4% or Vehicle Gel. 
Approximately 900 mg of gel (one pump stroke) will be applied evenly over the face (3% BSA). 
Based on the previous human safety data with SB204 and Vehicle Gel as well as the nonclinical 
safety data, this dose is expected to be safe and well tolerated. 
2.2 STUDY OBJECTIVES 
The primary objective of this study is to compare the efficacy, tolerability and safety of SB204 4% 
and Vehicle Gel once daily for 12 weeks in subjects with acne vulgaris.  
3. STUDY DESIGN 
Figure 1 depicts the overall study design for this 12-week, two arm, randomized, double-blinded 
study in subjects with moderate to severe acne vulgaris dosed once daily with SB204 or Vehicle 
Gel. Subjects receiving current treatment for acne vulgaris at the time of the Screening Visit may 
enter a wash out period of up to 35 days prior to randomization.  
Figure 1:  
Study Diagram 
 
Randomization 
 
 
 
 SB204 4% QD 
(N=650) 
 
 
 
  
 
 Vehicle Gel QD 
(N=650) 
 
 
Visits 
  
Screening 
Baseline 
 
 
Day -35 
to Day 0 
 
(Day)        
 
(14) 
 
 
2 
 
 
(28) 
 
 
4 
 
 
 
(56) 
 
 
8 
 
 
(84) 
 
 
12/ET 
 
Study Week 
 
ET = Early termination 
 


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3.1 STUDY ENDPOINTS  
3.1.1 Efficacy Endpoints 
Primary Efficacy Endpoints 
The co-primary efficacy endpoints are:  
 The absolute change in inflammatory lesion count from Baseline to Week 12/ET; 
 The absolute change in non-inflammatory lesion count from Baseline to Week 12/ET; 
 The proportion of subjects with IGA success at Week 12/ET. A subject will be considered 
a success if the IGA score is clear (0) or almost clear (1) and ≥2 grades less than Baseline 
 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints include the following: 
 The percent change in inflammatory lesion count from Baseline to Week 12/ET; 
 The percent change in non-inflammatory lesion count from Baseline to Week 12/ET; 
 The median time to a 35% reduction in inflammatory lesion counts; 
 The median time to a two (2) or more grade improvement in IGA. 
3.1.2 Tolerability Endpoints 
The cutaneous tolerability assessments include the evaluator’s assessment of erythema, scaling, 
dryness, and the subject’s report of pruritus and burning/stinging based on the preceding 24 hours. 
3.1.3 Safety Endpoints 
Safety endpoints will include the change from Baseline in vital sign measurements. Any clinically 
significant changes on physical exam or vital sign measurements will be recorded as AEs and 
included in the comparison. 
3.2 STRUCTURE 
This is a multi-center, randomized, double-blinded, vehicle-controlled, two arm study. 
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 days of treatment. Subjects who do not require washout from any current 
treatment may be screened and randomized on the same day. 
3.4 DOSAGE/DOSE REGIMEN 
Approximately 900 mg (1 ml) of SB204 4% or Vehicle Gel will be applied evenly over the entire 
face once a day for a period of up to 84 days. The product will be dispensed from a dual-chamber 
pump designed to deliver approximately equal amounts of NVN1000 Gel and hydrogel or Vehicle 
Gel and hydrogel. The NVN1000 Gel and Vehicle Gel will be opaque and the hydrogel will be 
clear. The subject will instantly mix the two substances in the palm of the hand and then 
immediately massage a thin layer over the entire face once daily after washing. The product should 


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be mixed for about 5 seconds until thoroughly combined with a uniform opaque appearance then 
applied with the fingertips. Application of study drug should occur prior to bedtime. 
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 1300 male and female subjects 9 years of age and older with moderate to severe 
acne vulgaris on the face will be randomized to participate in the study. Eligible subjects will have: 
at least 25 but no more than 70 non-inflammatory lesions (open and closed comedones); 20 but no 
more than 40 inflammatory lesions (papules, pustules, nodules, and cysts); no more than two 
nodules or cysts; and an IGA of 3 (moderate) or 4 (severe) on a 5-point IGA scale (Appendix 16.2). 
3.7 ELIGIBILITY CRITERIA 
3.7.1 Informed Consent and Authorization to Release Health Information 
Written informed consent/assent 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/assent. A subject wishing to participate must 
give written informed consent/assent 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 and assent forms must be forwarded to Chiltern for approval 
prior to submission to an Institutional Review Board (IRB) as appropriate. Each subject will sign 
the consent form that has been approved by the same IRB responsible for protocol approval. Each 
informed consent document must adhere to the ethical principles stated in the Declaration of 
Helsinki and will include the elements required by Food and Drug Administration (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 and Chiltern (or 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 parent or legal 
guardian (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 and assent (where applicable) document(s) shall be signed and dated by 
both the subject and parent or legal guardian (where applicable) and the person obtaining consent 
(Investigator or designee), and by any other parties required by the IRB or other regulatory 


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authorities. A subject under 18 years of age (or the age of majority in their state) must sign a written 
informed assent and be accompanied by the parent or legal guardian at the time of consent/assent 
signing. If a subject becomes 18 years of age during the study, the subject must provide written 
informed consent at the next study visit to continue study participation. 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). Subjects less than 18 years of age or 
the age of majority in their state must sign an assent form for the study and a parent or a 
legal guardian must sign the informed consent; 
2. Be male or female, 9 years of age and older at Baseline and in good general health; 
3. Have a Baseline IGA score of (3) moderate or (4) severe; 
4. Have a minimum of 25 but not more than 70 non-inflammatory lesions (open and closed 
comedones) on the face at Baseline; 
5. Have a minimum of 20 but not more than 40 inflammatory lesions (papules, pustules, 
nodules, and cysts) on the face at Baseline; 
6. Have no more than two nodules or cysts on the face at Baseline; 
7. WOCBP must have a negative urine pregnancy test (UPT) prior to randomization; 
8. 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; females taking hormonal contraceptives 
must have taken the same type for at least three months (90 days) prior to entering the study 
and must not change type during the study. Those who have used hormonal contraceptives 
in the past and stopped must have discontinued usage at least three months prior to the start 
of the study; and 
9. Be willing and able to follow study instructions and likely to complete all study 
requirements. Subjects under 18 years of age or age of majority must be accompanied by 
the parent or legal guardian at the time of assent/consent signing. 
3.7.3 Exclusion Criteria 
Subjects will not be enrolled if they meet any of the following exclusion criteria: 
1. Have any dermatological conditions on the face that could interfere with clinical 
evaluations such as severe recalcitrant nodulocystic acne, acne conglobata, acne fulminans, 
acne secondary to medications or other medical conditions, perioral dermatitis, clinically 
significant rosacea, or gram-negative folliculitis;  


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2. Have any underlying disease(s) or some other dermatological condition of the face that 
requires the use of interfering topical or systemic therapy or makes evaluations and lesion 
count inconclusive; 
3. Have a history of experiencing significant burning or stinging when applying any facial 
treatment (e.g., make-up, soap, masks, washes, sunscreens, etc.) to their face; 
4. Female subjects who are pregnant, nursing mothers, or planning to become pregnant during 
the study; 
5. Female subjects with known polycystic ovarian disease; 
6. Have used estrogens (e.g., Depogen, Depo-Testadiol, Gynogen, Valergen, etc.) or oral 
contraceptives for less than 3 months (90 days) immediately preceding Baseline, 
discontinued use of estrogens or oral contraceptives less than 3 months (90 days) prior to 
Baseline, or planning to begin or discontinue use of this therapy during the treatment 
period; 
7. Are transgender persons who are taking testosterone (female to male) or estrogen (male to 
female); 
8. Have facial hair, tattoos or other markings that could interfere with assessments or 
application of study drug; 
9. Have used medications or vitamins which are reported to exacerbate acne during the 12 
weeks immediately preceding Baseline (e.g., azathioprine, haloperidol, halogens such as 
iodides or bromides, lithium, anabolic steroids, systemic corticosteroids, phenytoin and 
phenobarbital). Daily use of a multi-vitamin is acceptable; 
10. Have had a severe acne flare in the 12 weeks preceding Baseline; 
11. Have a history of hypersensitivity or allergic reactions to any of the ingredients in the SB204 
or Vehicle Gel as described in the Investigator’s Brochure; 
12. Have used the following topical preparations on the face within the time specified prior to 
Baseline or require the concurrent use of any of the following topical agents on the face: 
Topical astringents/abrasives 
       1 week 
Other topical anti-acne medications* 
2 weeks 
Antibiotics 
2 weeks 
Moisturizers or sunscreens containing 
antibacterials 
2 weeks 
Anti-inflammatory products or 
corticosteroids 
4 weeks 
Topical corticosteroids 
4 weeks 
* Includes benzoyl peroxide, salicylic acid,  dapsone, alpha-hydroxy acid, 
glycolic acids, retinoids, or retinol-containing products 
 


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13. Have used the following systemic medications within the time specified prior to Baseline 
or require the concurrent use of any of the following systemic medications: 
 
Systemic antibiotics+ 
4 weeks 
Other systemic acne treatments 
4 weeks 
Corticosteroids 
12 weeks 
Systemic retinoids 
24 weeks 
Therapeutic Vitamin A Supplements  
> 10,000 IU/day 
24 weeks 
+Short courses (≤ approximately 14 days) of antibiotics are allowed if 
needed during the treatment phase of the study for non-acne related 
illnesses. 
*Intranasal and inhaled corticosteroids may be used throughout the trial if 
the subject is on a stable dose. 
 
14. Have had the following procedures on the face within the time specified prior to Baseline: 
 
Cryodestruction/Chemo-destruction 
4 weeks 
Dermabrasion 
4 weeks 
Photo / Photodynamic Therapy 
4 weeks 
Acne Surgery 
4 weeks 
Intralesional Corticosteroids 
4 weeks 
X-ray, Laser Therapy, or Other Device 
4 weeks 
 
15. Intend to use a tanning booth or sunbathe during the study; 
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;  
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. Are members of the same household where a subject is enrolled in NI-AC301, NI-AC302, 
or NI-AC303; 
20. Are immediate family members of study site personnel directly involved in NI-AC301, NI-
AC302, or NI-AC303; 
21. Have participated in a previous study with SB204 or NVN1000 Gel. 


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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/assent must be obtained prior to conducting any procedures. 
Some Baseline procedures (i.e., review of inclusion/exclusion criteria, brief physical exam, blood 
pressure and pulse rate, IGA, lesion counts, cutaneous tolerability, adverse event assessment, 
concomitant medication review and UPT) must be completed prior to randomization. Subjects who 
meet all eligibility criteria who do not require washout from any current treatment may be screened 
and randomized on the same day. 
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 is 
defined as stabilized on oral contraceptive for at least 3 months (90 days), intrauterine device 
(IUD), condom with spermicide, diaphragm with spermicide, implant, NuvaRing®, 
medroxyprogesterone injection, transdermal patch or abstinence with a documented second 
acceptable method of birth control should the subject become sexually active. Females taking 
hormonal contraceptives must have taken the same type for at least three months (90 days) prior 
to entering the study and must not change type during the study. Subjects who had used hormonal 
contraception and stopped must have stopped no less than three months prior to the start of the 
study. 
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. 
After the required procedures are completed and study eligibility is confirmed, the subject will be 
randomized to treatment utilizing an Interactive Web Response System (IWRS) which will 
identify the study drug pump 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 
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Table 1: 
Schedule of Visits and Procedures 
Study visits should occur at approximately the same time of day throughout the study.   
 
PROCEDURES 
Screening 
(Day -35 to 
Day 0) 1 
Baseline 
(Day 0) 
Week 22 
±3 days 
(Day 14) 
Week 4 
±5 days 
(Day 28) 
Week 8 
±5 days 
(Day 56) 
Week 
12/ET3 
±7 days 
(Day 84) 
Informed 
Consent/Assent 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
Brief Physical 
Examination 
X 
X4 
 
 
 
X 
Urine Pregnancy Test 
(all WOCBP) 
X 
X4 
 
X 
X 
X 
Blood Pressure and 
Pulse 
X 
X 
X 
X 
X 
X 
IGA 
X 
X 
X 
X 
X 
X 
Lesion Counts 
X 
X 
X 
X 
X 
X 
Cutaneous Tolerability 
Evaluation 
 
X 
X 
X 
X 
X 
Instruct on Study Drug 
Application and 
Provide Subject 
Instructions  
 
X 
 
 
 
 
Study Drug and Diary 
Dispensed 
 
X 
 
X 
X 
 
Study Drug and Diary 
Collected 
 
 
 
X 
X 
X 
Subject Compliance 
Reviewed 
 
 
X 
X 
X 
X 
Photography5 
 
X 
 
X 
X 
X 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
¹Subjects who meet all eligibility criteria at Screening and do not require a medication wash-out may complete all Baseline 
assessments and be randomized on the same day as the Screening visit. 
2All visit dates are in reference to Baseline, e.g., Visit 2 occurs two weeks (14 days) after Baseline visit. 
3All Week 12 procedures should be completed for subjects who prematurely discontinue. 
4If the Baseline Visit is within 7 calendar days of the Screening visit, Physical Examination and UPT do not need to be repeated. 
5Photography will be done at a subset of sites. 


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4.1.1 Screening (Day -35 to Day 0) 
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 SB204 with the subject and obtain written informed consent/assent. 
2. Obtain demographic information. 
3. Obtain subject’s medical history and medication history. 
4. Verify appropriate contraception being used for WOCBP per Section 6.4. 
5. Collect blood pressure and pulse rate after the subject has been sitting quietly for 5 minutes. 
6. Perform a brief physical examination. 
7. Obtain pregnancy test (WOCBP only) and evaluate results. If pregnancy test is positive, 
the subject may not participate in the study. 
8. Perform Investigator’s Global Assessment (IGA). 
9. Perform lesion counts. Inflammatory and non-inflammatory lesion counts will be 
performed on the entire face. 
10. Confirm subject meets eligibility criteria. 
11. Review prohibited medications, acne treatments, and supplements that should not be used 
prior to Baseline and during the trial. 
12. Collect AEs related to study procedures performed since signing of informed consent. 
13. 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 record concomitant medication information. 
2. Perform a brief physical examination. If the Baseline visit occurs within 7 calendar days 
of the Screening visit, the physical examination does not need to be repeated. 
3. Obtain pregnancy test (WOBCP only) and evaluate results. If pregnancy test is positive, 
the subject may not participate in the study. If the Baseline visit occurs within 7 calendar 
days of the Screening visit, the pregnancy test does not need to be repeated. 
4. Collect blood pressure and pulse rate after the subject has been sitting quietly for 5 minutes. 
5. Perform cutaneous tolerability assessment. 
6. Perform IGA.  
7. Perform lesion counts. 


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8. Have subject wash face and dry with lint free towel in preparation for photographs (if 
applicable). 
9. Collect photographs (if applicable). 
10. Confirm eligibility and randomize subject. 
11. Dispense subject diary and study drug. Instruct subject on dispensing, mixing, and 
application of study product and diary completion. 
12. 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.). 
13. Confirm the study schedule with the subject. 
4.1.3 Week 2 (Day 14) 
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. Collect blood pressure and pulse rate after the subject has been sitting quietly for 5 minutes. 
4. Perform cutaneous tolerability evaluation. 
5. Perform IGA. 
6. Perform lesion counts. 
7. Review diary completion and study drug compliance with subject.  
8. Review and confirm the study schedule with the subject. 
4.1.4 Weeks 4 and 8 (Days 28 and 56) 
The following procedures must be performed and recorded at the Week 4 and Week 8 visits: 
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 after the subject has been sitting quietly for 5 
minutes. 
5. Perform cutaneous tolerability evaluation. 
6. Perform IGA. 
7. Perform lesion counts. 


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8. Have subject wash face and dry with lint free towel in preparation for photographs (if 
applicable). 
9. Collect photographs (if applicable). 
10. Collect returned study drug and diary, perform accountability, and review diary completion 
and study drug compliance with subject.   
11. Dispense new study drug and diary. 
12. Review and confirm the study schedule with the subject. 
4.1.5 Week 12/ET (Day 84) 
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. Collect blood pressure and pulse rate after the subject has been sitting quietly for 5 
minutes. 
6. Perform cutaneous tolerability evaluation. 
7. Perform IGA. 
8. Perform lesion counts. 
9. Have subject wash face and dry with lint free towel in preparation for photographs (if 
applicable). 
10. Collect photographs (if applicable). 
11. Collect returned study drug and diary, perform accountability, and review diary 
completion and study drug compliance with subject.  
4.1.6 Discontinuation/Withdrawal Procedures 
A subject may voluntarily withdraw from study participation at any time. 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. 


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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 
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 respected (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 
Chiltern 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 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 using the same 
randomization number or treatment assignment.  
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 Chiltern.  
 
 


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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 as determined by the Investigator  
 Withdrawal by Subject 
 Physician Decision 
 Protocol Violation 
 Lost to Follow-Up 
 Pregnancy 
 Worsening of Condition 
 Other 
Novan has the right to terminate or stop the study at any time. Should this be necessary, the 
Investigator will ensure that proper study discontinuation procedures are completed. 
4.2 
EFFICACY ASSESSMENTS 
The same blinded evaluator should perform Investigator Global Assessments and lesion counts at 
Screening, Baseline and Weeks 2, 4, 8, and 12/ET. In the event that this is not possible due to 
unforeseen circumstances, a different blinded evaluator may evaluate the subject. However, the 
same evaluator should evaluate subjects at the Baseline and Week 12 (or early termination) 
evaluations. 
4.2.1 Investigator Global Assessment 
The Investigator’s Global Assessment Score will be a static assessment that is independent of the 
Baseline score. The evaluator will make the assessment without referring to the Baseline value and 
prior to performing lesion counts. The assessment should be made approximately three feet from 
the subject. The same evaluator should perform each study assessment for each study subject 
whenever possible, for consistency in evaluations. 
Subjects are eligible to participate in the study if they have a Baseline IGA score of 3 (moderate) 
or 4 (severe). 
 
 
 


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The following scores will be used to assign IGA scores: 
Grade 
Description 
0 
Clear: Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost clear: Rare non-inflammatory lesions with rare papules 
(papules may be resolving and hyperpigmented, though not pink-red). 
2 
Mild: Some non-inflammatory lesions with no more than a few 
inflammatory lesions. 
3 
Moderate: Up to many non-inflammatory lesions and may have some 
inflammatory lesions, but no more than one nodulocystic lesion. 
4 
Severe: Up to many non-inflammatory and inflammatory lesions, but 
no more than a few nodulocystic lesions 
4.2.2 Lesion Counts 
The facial area lesion counts will be taken from the forehead, right and left cheeks, chin and nose. 
The lesion count groups will be inflammatory and non-inflammatory. Facial inflammatory lesions 
(pustules, papules, nodules and cysts) will be counted and recorded. Non-inflammatory lesions 
(open and closed comedones) will be counted and recorded. The following are definitions of each 
lesion type:  
Inflammatory lesions are defined as follows: 
 
Papule - A small, superficial, circumscribed, palpable lesion elevated above the skin surface, less 
than 10 mm in diameter 
Pustule - A superficial elevated lesion that contains yellow fluid (pus) within or beneath the 
epidermis  
Nodule - A firm (indurated) lesion greater than 10 mm in diameter and that is thicker or deeper 
than the average papule 
Cyst - Spherical swelling that contains fluid or semisolid material 
 
Non-inflammatory lesions are defined as follows: 
 
Open comedones (blackhead) - Plugged follicular units with brown/black central debris 
Closed comedones (whitehead) - Plugged follicular units with white central debris 
4.3 TOLERABILITY ASSESSMENTS 
The evaluator will assess the subject’s face at Baseline and each study visit. The cutaneous 
tolerability assessment for visits other than Baseline should be performed at least 30 minutes after 
study drug application. Cutaneous tolerability evaluations will include erythema, scaling, dryness, 
pruritus and burning/stinging. Pruritus and burning/stinging will be based on the subject’s report 
for the previous 24 hours. Cutaneous tolerability endpoints will be reported as an AE if they reach 
severe and/or result in subject’s discontinuation from the study. Subjects who develop intolerance 
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(erythema, scaling, dryness, pruritus, burning/stinging) shall be discontinued from the study. 
Cutaneous 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 
Scaling 
Score 
Description 
0-None 
No scaling 
1-Mild 
Fine scales present to limited areas of the face, barely perceptible 
2-Moderate 
Fine scale generalized to all areas of the face 
3-Severe 
Scaling and peeling of skin over all areas of the face 
Dryness 
Score 
Description 
0-None 
No dryness 
1-Mild 
Slight but definite roughness 
2-Moderate 
Moderate roughness 
3-Severe 
Marked roughness 
Pruritus 
Score 
Description 
0-None 
No itching 
1-Mild 
Slight itching, not very bothersome 
2-Moderate 
Moderate amount of itching, somewhat bothersome 
3-Severe 
Severe amount of itching, definite discomfort and sleep may be disturbed 
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. 


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See Section 6 for additional information regarding the evaluation of adverse events. 
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/ET. Any clinically significant changes in vital signs from Baseline will be recorded as adverse 
events whether or not drug related. 
4.4.4 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. 
Premenarchal subjects will be considered to be of childbearing potential for this study. 
Pregnancy tests will also be performed at Weeks 4, 8, and 12/ET. If a subject is determined to be 
pregnant prior to Week 12, the subject will be discontinued from the study but followed until term. 
4.5 ADDITIONAL ASSESSMENTS  
4.5.1 Photography 
Photographs of the face will be taken at Baseline and Weeks 4, 8, and 12/ET at a subset of sites. 
Baseline photographs may be reviewed by the sponsor or members of the study team to confirm 
appropriateness of enrolled subjects. 
4.6 SCREEN FAILURES 
A subject is considered screened once they have signed the ICF and completed one screening 
assessment. A screen failure subject will be any screened subject who does not meet the study 
eligibility requirements. Subjects will not be allowed to rescreen. Screen failures will not be 
recorded in the case report form (CRF). 
4.7 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 Chiltern at the earliest possible time 


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by telephone. This will allow an early joint decision regarding the subject’s continuation in the 
study. This decision will be documented by the Investigator and Chiltern. 
5. PROHIBITED THERAPIES AND MEDICATIONS 
Concomitant medications are any prescription or over-the-counter (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 will be permitted to apply non-comedogenic moisturizer or sunscreen on an as-needed 
basis. Moisturizer must not contain antibacterials and the subject should not change moisturizer 
and/or sunscreen used during the course of the study. If used, moisturizers and sunscreen should 
be applied at least 30 minutes after study drug application. 
Subjects must not have used anti-acne treatments including topical agents to the face, systemic 
antibiotics or procedures that may impact acne (as described in Section 3.7.3) prior to Baseline. 
These medications and procedures are also prohibited during the trial. Topical anti-acne agents 
may be used to treat acne on the chest, back or upper shoulders in this study. 
Subjects may not be concurrently on drugs associated with exacerbating acne vulgaris. (Appendix 
16.1). 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 or NVN1000 
Gel must not participate. 
Any medication/therapy used by the subject following first application of study product will be 
considered a concomitant medication (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 enrollment 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’s 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 
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 until there is a return to the subject’s 
Baseline condition or until a clinically satisfactory resolution is achieved or the subject is lost to 
follow-up. 
6.1.2 Investigational Product Causality 
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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/assent and completed one study assessment 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, Chiltern 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) are considered immediately reportable events. Any SAE, whether 
deemed drug-related or not, must be reported to Chiltern by telephone, email, or fax as soon as 
possible after the Investigator or coordinator has become aware of its occurrence. The 
Investigator/coordinator must complete a Serious Adverse Event (SAE) Form and fax/email it to 
Chiltern within 24 hours of notification of the event. When appropriate, Novan will notify the 
appropriate regulatory body of drug related Serious Adverse Events. 
Serious Adverse Event (SAE) and Safety Contact Information: 
Phone: SAE Hotline: 1-888-SAE CHIL (1-888-723-2445) 
Email: GlobalSAEInbox@chiltern.com 
Fax: 1-800-468-2288 


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If a subject experiences an SAE or pregnancy the Investigator must:  
1. Report the SAE or pregnancy by telephone, fax, or email immediately (within 24 hours) 
after the Investigator becomes aware of the event. 
2. Complete an SAE or Pregnancy Notification Form and fax/email or overnight courier to 
Chiltern 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 Chiltern 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. 
6. 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 stabilized on oral contraceptive for at least three months, IUD, condom with 
spermicide, diaphragm with spermicide, implant, NuvaRing®, injection, transdermal patch or 
abstinence with a documented second acceptable method of birth control should the subject 
become sexually active. Females taking hormonal contraceptives must have taken the same type 
for at least three months (90 days) prior to entering the study and must not change type during the 
study. Those who have used birth control pills or hormonal contraception in the past and stopped 
must have discontinued usage at least three months prior to the start of the study. 
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) 


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 Any drug interactions with hormonal contraceptives 
 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). The Investigator must 
immediately notify Chiltern of any female subject who becomes pregnant any time during study 
participation, record the information on the Pregnancy Notification Form and email the form to 
Chiltern. Subjects found to be pregnant prior to Week 12 will be discontinued from the study. 
Chiltern 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 ongoing/not recovered/not resolved. 
6.5.2 Follow-Up of Post Study Serious Adverse Events 
Serious adverse events that are identified on the last scheduled contact (Week 12/ET) must be 
recorded in the study database and reported to Chiltern 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 is 
lost to follow-up. The Investigator should continue to report any significant follow-up information 
to Chiltern 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 Chiltern and the IRB. 
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. 


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6.7 DISCONTINUATION OF INDIVIDUAL SUBJECTS FROM THE STUDY 
Subjects who develop intolerance to the product as defined by scores of 3 (severe) on 2 or more 
categories of tolerability (erythema, scaling, dryness, pruritus, burning/stinging) shall be 
discontinued from the study. 
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® 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. 
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, based on N. Data will be presented for the active treatment group and vehicle 
treatment group. Demographic and Baseline data will also be presented over both treatment 
groups. 
A detailed description of the statistical methodology and data reporting 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 intent to treat (ITT) population will include all study subjects who were randomized and 
dispensed study medication and grouped by the treatment to which they were assigned at 
randomization. All efficacy analyses will be performed on the ITT population. 
7.2.2 Safety Population  
The safety (SAF) population will include all randomized subjects who received at least one dose 
of study medication. All safety and tolerability analyses will be performed on the safety analysis 
population (SAF) population based on the treatments the subjects actually applied.  
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 (i.e., any subject or investigator activity that could 
have possibly interfered with the therapeutic administration of the treatment or the precise 


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evaluation of treatment efficacy). The PP population will include subjects in the SAF population 
who do not meet any of the following criteria: 
 Violated the inclusion/exclusion criteria; 
 Have taken any interfering concomitant medications; 
 Did not attend the Week 12 visit; 
 Have not been compliant with the dosing regimen; 
 Out of visit window at the Week 12 visit by ±7 days. 
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. To determine dosing non-compliance criteria, the data will be reviewed in a 
blinded manner and a cut-point will be determined. 
7.3 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Subject demographic and Baseline characteristics will be summarized by treatment group and 
overall for the ITT, PP and SAF populations. For continuous variables (e.g., age), mean, median, 
standard deviation, minimum and maximum will be presented. Categorical variables (e.g., 
ethnicity, race) will be summarized with frequency count and percentage by treatment group. Age 
will also be categorized and summarized as proportion of adults (age≥18) and juvenile (age<18). 
7.4 EFFICACY ANALYSIS  
Efficacy of SB204 4% will be based on statistical superiority over vehicle for change from 
Baseline in lesion counts and improvement in IGA score at Week 12/ET. 
7.4.1 Primary Efficacy Analyses 
There are three co-primary efficacy outcomes:  
 change in inflammatory lesions counts at Week 12/ET 
 change in non-inflammatory lesions counts at Week 12/ET and 
 IGA success at Week 12/ET which is defined as an IGA score of clear (0) or almost clear 
(1) and ≥2 grades less than Baseline 
All three co-primary outcomes must show superiority over vehicle (p-value ≤0.05) in order for 
efficacy to be demonstrated; therefore no multiplicity adjustments will be made to the co-primary 
outcome analyses.. 
Prior to analysis of co-primary outcomes, missing post-Baseline lesion counts and IGA scores 
results at each visit will be imputed using a Markov chain Monte Carlo (MCMC) multiple 
imputation methodology. Separate multiple imputation (MI) procedures will be used for each 
outcome, using Statistical Analysis Software (SAS) procedure MI. Details of PROC MI and 
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subjects with only Baseline assessments will have the Baseline value carried forward across all 
visits. 
The primary analyses of the co-primary efficacy endpoints will be performed in the ITT population 
where missing data have been imputed as described above. Additional analyses of the co-primary 
outcomes will be performed using the PP population. To access the sensitivity of the primary 
efficacy results to imputation methods, each co-primary outcome will be analyzed as described 
above, but with missing data imputed by last observation carried forward (LOCF) and Baseline 
observation carried forward (BOCF) on the ITT population.  
7.4.2 Secondary Efficacy Analyses 
Secondary efficacy outcomes include the percent change in inflammatory and non-inflammatory 
lesion counts at Week 12/ET, the median time to 35% improvement in inflammatory lesions and 
the time to a two or more grade improvement in the IGA.  
Analysis of the secondary efficacy outcomes will be adjusted for multiplicity using a hierarchical 
step-down procedure. These endpoints will be tested in the specified order with the rule that once 
a p-value exceeds 0.05, endpoints further down in the order are not statistically significant. The 
order will be as follows: 
1) Percent change in inflammatory lesions at Week 12/ET 
2) Percent change in non-inflammatory lesions at Week 12/ET 
3) Median time to achieve 35% reduction in inflammatory lesions 
4) Median time to a two or more grade improvement in the IGA. 
7.5 DRUG EXPOSURE AND COMPLIANCE 
Drug exposure and compliance will be performed on Safety Population. The number of days that 
study drug was taken and study drug compliance will be summarized by treatment group.  
Duration of exposure will be defined as: 
(Date of Last Drug Administration – Date of First Drug Administration + 1 day) / 7 days, rounded 
down to an integer. 
The percent compliance for SB204 will be calculated as follows and presented as follows: 
% Compliance = (Number of Doses Expected– Number of Doses Missed)/(Number of Doses 
Expected)*100 
 
Where the number of doses expected is the defined as the number of days from Baseline to the 
Week 12/ET visit.  Subject’s diaries will be reviewed at each visit to report the number of doses 
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Percent compliance will be summarized by frequency count and percentage of subjects with 
compliance as defined in the SAP. Percent compliance will also be summarized as a continuous 
variable using descriptive statistics. 
7.6 TOLERABILITY 
Cutaneous tolerability assessments (erythema, scaling, dryness, pruritus, burning/stinging) will be 
summarized by visit from Baseline to Week 12/ET by treatment group.  The proportion of subjects 
in each treatment group who shift scores from Baseline at each visit will also be summarized. 
7.7 SAFETY 
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 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 Investigator or designee, preferred term, 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. 
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 
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/ET. Additionally, change from Baseline in vital signs will be summarized at Week 2, 4, 8, 
and 12/ET. Any clinically significant changes from Baseline will be documented as an AE. 


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7.7.4 Urine Pregnancy Tests 
Urine pregnancy tests results for WOCBP will be presented in data listings by subject.   
7.8 SAMPLE SIZE AND POWER CONSIDERATIONS 
Approximately 1300 subjects will be randomized into the study in a 1:1 ratio (650 in each arm) at 
approximately 50 sites in North America. In the previous phase 2 study, the pooled vehicle IGA 
‘success’ rate was 7.1% and the pooled SB204 IGA success rate was 13.4%. Using NQuery 
Advisor v7 (Statistical Solutions, Ltd) to estimate sample size and statistical power, based on a 
vehicle IGA success rate of 7% and a 6% difference for the SB204 arm, a sample size of 1294 was 
estimated to have at least 95% power for a two-sided test at the alpha=0.05 level using the 
continuity corrected chi-square test. 
The statistical power for detecting treatment differences in inflammatory or non-inflammatory 
lesions exceeds 99% once at least 256 subjects are treated in each group.  This is based on the 
following assumptions: 
 For inflammatory lesions: vehicle mean change = -7.6, SB204 mean change = -14.1, and a 
common standard deviation = 17.1 
 For non-inflammatory lesions: vehicle mean change = -5.8, SB204 mean change = -11.3, 
and common standard deviation = 11.8 
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 pumps should be refrigerated (2-8 °C) until dispensed to a 
subject. 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. 
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 Chiltern CRA must be 
contacted immediately. In such an event, study supplies should be quarantined and 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 
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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 the Chiltern CRA immediately and study 
supplies should be quarantined and not administered until Novan provides approval for use. Other 
supplies will be stored at room temperature. 
8.3 TREATMENT ASSIGNMENT AND BLINDING 
Subjects will be randomized to SB204 4% or Vehicle Gel on a 1:1 basis through utilization of the 
IWRS. The evaluator and subject will be blinded to the subject’s treatment. 
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 IWRS. A study subject for whom the blind is broken will be discontinued from the study. 
Although not required, the Investigator should contact the Chiltern 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 
 Pumps dispensed to each subject, identified at a minimum by a unique subject number  
 Amount transferred to another location within the study site or destroyed — this should 
not occur without prior notification to Chiltern 
 Non-study disposition (e.g., wasted, broken) 
 Amount returned to Novan or designee, if applicable 
 Amount destroyed, 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 and 
Chiltern, their designees or by regulatory agencies at any time. 
8.6 RETURNS AND DESTRUCTION 
Upon completion or termination of the study, the site will be instructed on return or destruction of 
clinical supplies. 


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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 requires 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. 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, the Chiltern Medical 
Monitor or other Novan staff 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 at a minimum 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. 
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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 
Investigator will ensure that the study records and any other documents forwarded to Chiltern 
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, Novan and Chiltern or their designees, 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, their designees, 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 
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10. MONITORING, COMPLIANCE, AND QUALITY 
All aspects of the study will be monitored by Chiltern 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 Chiltern at any time for review and audit 
to ensure the integrity of the data. The Investigator must notify Chiltern 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 Novan or 
Chiltern 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. A reduced source data 
verification model will be deployed for this study in order to focus on the critical data for analysis 
and this will be executed per the study specific monitoring plan. 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 CRO 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 Chiltern 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 
Chiltern 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, Chiltern, 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 at a minimum 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 Chiltern and the full IRB no later than five working days after the 
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 


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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 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  
Guideline for Good Clinical Practice.  ICH Harmonised Tripartite Guideline. 1996.   
Protection of Human Subjects.  Code of Federal Regulations. 1999.Part 50, Title 21, Section 20.  
Institutional Review Boards.  Code of Federal Regulations. 1981. Part 56, Title 21, Section 103. 


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16. APPENDICES 
16.1 APPENDIX 1:  LIST OF RESTRICTED MEDICATIONS: 
 Anti-acne medications  
 Anabolic steroids 
 Azathioprine 
 Bromides 
 Corticosteroids (oral) 
 Chloroquine 
 Flutamide 
 Halides 
 Lithium 
 Phenobarbital 
 Phenytoin 
 Vitamin A (> 10,000 IU/day) 
 


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16.2 APPENDIX 2:  DEFINITIONS FOR IGA SCORE 
Grade 
Description 
0 
Clear: Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost clear: Rare non-inflammatory lesions with rare papules 
(papules may be resolving and hyperpigmented, though not pink-
red). 
2 
Mild: Some non-inflammatory lesions with no more than a few 
inflammatory lesions. 
3 
Moderate: Up to many non-inflammatory lesions and may have some 
inflammatory lesions, but no more than one nodulocystic lesion. 
4 
Severe: Up to many non-inflammatory and inflammatory lesions, but 
no more than a few nodulocystic lesions 
 
 

SAP_001.pdf: