A Phase 2, Multi-Center, Randomized, Evaluator-Blinded, Vehicle-Controlled Study Comparing the Efficacy, Tolerability, and Safety of SB204 Gel and Vehicle Gel Once or Twice Daily in the Treatment of Acne Vulgaris
Phase: PHASE2
Conditions: Acne Vulgaris
Sponsor: Novan, Inc.

  
 
STUDY TITLE 
A Phase 2, Multi-Center, Randomized, Evaluator-
Blinded, Vehicle-Controlled Study Comparing the 
Efficacy, Tolerability, and Safety of SB204 Gel and 
Vehicle Gel Once or Twice Daily in the Treatment of 
Acne Vulgaris 
PROTOCOL NO. 
NI-AC202 
SPONSOR 
Novan, Inc. 
4222 Emperor Blvd., Suite 200 
Durham, NC 27703 
Tel.: 919-485-8080 
AMENDMENT 1 
16 Oct 2014 
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. 
 
Confidential and Proprietary, Novan, Inc. 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
SPONSOR INFORMATION PAGE 
Sponsor Contact Information: 
 
Novan, Inc. 
4222 Emperor Blvd., Suite 200 
Durham, NC 27703 
Tel:  919-485-8080 
Fax:  919-237-9212 
 
QST Consultations Contact Information: 
 
Carol Houts 
QST Project Manager 
11275 Edgewater Dr. 
Allendale, MI  49401 
(616) 892-3703 Office 
(616) 892-4781 Fax 
 
 
Agi Buchanan, MD, PhD 
Medical Monitor 
11275 Edgewater Dr. 
Allendale, MI  49401 
(616) 892-3745 Office 
(616) 892-4781 Fax 
abuchanan@qstconsultations.com 
 
 
 
 
Sponsor Serious Adverse Event (SAE) and Safety Contact Information: 
Email: safety@qstconsultations.com  
 
 
Confidential and Proprietary, Novan, Inc. 
 
2 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
PROTOCOL AMENDMENT 
RATIONALE FOR AMENDMENT 
This protocol amendment is required due to a change in the calibration of the device employed in 
methemoglobin readings and increases the upper limit of methemoglobin for study enrollment 
from > 2.0% to > 3.0% and changes the criterion for subject discontinuation in the study due to 
elevated methemoglobin from > 3.0% to > 5.0%.  The change in methemoglobin levels 
permissible for study enrollment and continuation reflect this change in the calibration of the 
device. The amendment also increases the screening period from 28 days to 35 days to 
accommodate the washout period.  The protocol was edited to ensure consistency across 
sections. 
 
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. 
 
Change 1: SYNOPSIS: Diagnosis and Criteria for Inclusion, Exclusion Criterion # 12 
Have a methemoglobin value of > 3.0% at Screening or Baseline. 
 
Change 2:  PROTOCOL BODY: Section 1.5, Summary of Benefits and Risks, Paragraph 3 
Tolerability will be assessed during the planned study, and discontinuation criteria for 
intolerance by subjects is described in Section 6.7. 
 
Change 3: PROTOCOL BODY: Section 1.5, Summary of Benefits and Risks, Paragraph 4 
Methemoglobin will be monitored during the study and treatment stopped in any subject with a 
measured methemoglobin > 5.0%. 
 
Change 4: PROTOCOL BODY: Section 2.1, Study Rationale, Paragraph 1 
Novan is conducting this study to evaluate the efficacy, cutaneous tolerability and safety 
of SB204 2% Gel, SB204 4% Gel and Vehicle Gel administered once or twice daily to the face. 
 
Change 5: PROTOCOL BODY: Section 3, Study Design, Paragraph 1 
Subjects receiving current treatment for acne vulgaris may enter a wash out period after 
screening of up to 35 days prior to randomization. 
Confidential and Proprietary, Novan, Inc. 
 
3 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
 
Change 6: PROTOCOL BODY, Figure 1, Study Diagram 
 
Randomization 
 
 
 
 SB204 4% Gel BID 
(N=50) 
 
 
 
  
 
 SB204 4% Gel QD 
(N=50) 
 
 
 
  
 
 SB204 2% Gel BID 
(N=50) 
 
 
 
  
 
 Vehicle Gel BID 
(N=25) 
 
 
 
  
 
 Vehicle Gel QD 
(N=25) 
 
 
Visits 
 
Screening 
Baseline 
 
 
Day -35 to 
Day -1 
 
 (Day)        (0) 
 
(14) 
 
 
2 
 
 
(28) 
 
 
4 
 
 
 
(56) 
 
 
8 
 
 
(84) 
 
 
12/ET 
 
Study Week 
 
ET = Early termination 
 
Change 7:  PROTOCOL BODY: Section 3.3, Duration, Paragraph 1 
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. 
 
Change 8:  PROTOCOL BODY: Section 3.5, Visit Schedule, Paragraph 1 
The screening period will last up to 35 days.   
 
Change 9:  PROTOCOL BODY:  Section 3.7.3, Exclusion Critieria, Exclusion Critierion # 12 
Have a methemoglobin value of > 3.0% at Screening or Baseline. 
 
Change 10:  PROTOCOL BODY:  Section 4.1, Subject Entry Criteria, Paragraph 2 
Subjects with clinically significant anemia as determined by the Investigator or methemoglobin 
values > 3.0% will not be randomized. 
Confidential and Proprietary, Novan, Inc. 
 
4 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
 
Change 11:  PROTOCOL BODY: Table 2, Schedule of Visits and Procedures 
PROCEDURES 
Screening (Da
y -35 to Day -
1) 
Baseline 
(Day 0) 
Week 21 
±3 days 
(Day 14) 
Week 4 
±3 days 
(Day 28) 
Week 8 
±5 days 
(Day 56) 
Week 12/ET2 
±5 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 
X3 
 
 
 
X 
Chemistry, Hematology, 
PT/PTT 
X 
X3 
 
 
 
X 
Urine Pregnancy Test (all 
WOCBP) 
X 
X3 
 
X 
X 
X 
Methemoglobin  
X 
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 
X 
 
Study Drug and Diary 
Collected 
 
 
X 
X 
X 
X 
Subject Compliance 
Reviewed 
 
 
X 
X 
X 
X 
Photography 
 
X 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
¹ All visit dates are in reference to Baseline, e.g., Visit 2 occurs two weeks (14 days) after Baseline visit 
2All Week 12 procedures should be completed for subjects who prematurely discontinue. 
3 If the Baseline Visit is within 3 calendar days of the Screening visit, Physical Examination, Chemistry, Hematology, 
PT/PTT, and UPT do not need to be repeated. 
Confidential and Proprietary, Novan, Inc. 
 
5 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
 
Change 12:  PROTOCOL BODY: Header for Section 4.1.1, Screening (Day -35 to Day -1) 
 
Change 13:  PROTOCOL BODY:  Section 4.1.2, Baseline (Day 0) 
This visit can be combined with Screening.  The following procedures must be performed and 
recorded at the Baseline visit: 
1. Obtain any updated concomitant medication information. 
2. Update medical history. 
1. Update medication history and concomitant medication information. 
2. Perform a brief physical examination. 
 
Change 14:  PROTOCOL BODY:  Section 4.1.3, Week 2 (Day 14) 
9. Review subject diary for completion.   
10. Dispense new study drug and diary (if needed). 
 
Change 15: PROTOCOL BODY: Section 4.1.7, Discontinuation/Withdrawal Procedures, 
Paragraph 5 
Refer to Section 6.7 for a discussion of criteria for discontinuation of individual subjects 
from the study. 
Change 16:  PROTOCOL BODY:  Section 4.1.7, Discontinuation /Withdrawal Procedures, 
Paragraph 7 
Study completion or reason(s) for discontinuation as listed in the study record will be entered 
into the study database as follows: 
• Completed 
• Adverse Event  
• Lack of Efficacy  
• Withdrawal by Subject 
• Physician Decision  
• Protocol Violation  
• Lost to Follow-Up  
• Pregnancy  
Confidential and Proprietary, Novan, Inc. 
 
6 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
• Worsening of condition 
• Other  
 
Change 17:  PROTOCOL BODY:  Section 4.4.5, Methemoglobin, Paragraph 2 
Subjects with methemoglobin values of > 3.0% at Screening or Baseline will not be eligible to 
participate in the study.   
 
Change 18:  PROTOCOL BODY: Section 4.4.6, Pregnancy Testing, Paragraph 2 
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. 
 
Change 19:  PROTOCOL BODY:  Section 6.7, Discontinuation of Individual Subjects from the 
Study, Paragraph 2 
Subjects with > 5.0% methemoglobin at any post-baseline visit will 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. 
 
Change 20:  PROTOCOL BODY:  Section 9.1, Data Collection, Paragraph 2 
Only status of informed consent and assent signature, gender, date of birth, ethnicity, race, 
and reason for failure will be entered in the electronic data capture (EDC) system for screen 
failures. 
 
Confidential and Proprietary, Novan, Inc. 
 
7 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
 
INVESTIGATOR’S AGREEMENT 
I have carefully read the protocol entitled:  “A Phase 2, Multi-Center, Randomized, Evaluator-
Blinded, Vehicle-Controlled Study Comparing the Efficacy, Tolerability, and Safety of SB204 
Gel and Vehicle Gel Once or Twice 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 
Confidential and Proprietary, Novan, Inc. 
 
8 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
Title 
A Phase 2, Multi-Center, Randomized, Evaluator-Blinded, Vehicle-
Controlled Study Comparing the Efficacy, Tolerability, and Safety of 
SB204 Gel and Vehicle Gel Once or Twice Daily in the Treatment of 
Acne Vulgaris 
Study Objectives 
The primary objective of this study is to compare the efficacy, 
tolerability, and safety of two concentrations of SB204 Gel and Vehicle 
Gel once or twice daily for 12 weeks in subjects with moderate to 
severe acne vulgaris on the face. 
Treatment Regimens 
Eligible subjects at the Baseline visit will be randomized 2:2:2:1:1 to 
SB204 4% Gel BID, SB204 4% Gel QD, SB204 2% Gel BID, Vehicle 
Gel BID, or Vehicle Gel QD and treated for 12 weeks (84 days). 
Formulation 
Investigational Drug:  SB204 4% Gel  
Investigational Drug:  SB204 2% Gel  
Comparator Drug: Vehicle Gel  
Study Period 
Subjects will be dosed in the study for up to 12 weeks. 
Study Design 
This is a multi-center, evaluator-blinded, randomized, vehicle-
controlled, parallel-group study to be conducted in approximately 200 
subjects with acne vulgaris. 
Subjects who satisfy the entry criteria will be randomized to SB204 4% 
Gel BID, SB204 4% Gel QD, SB204 2% Gel BID, Vehicle Gel BID, or 
Vehicle Gel QD in a 2:2:2:1:1 ratio.  The SB204 Gel and Vehicle Gel 
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 5-10 seconds by the subject and applied to the entire 
face once or twice 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 and pulse rate, laboratory assessments including 
chemistry, hematology, methemoglobin, PT/ PTT measurements, and 
urine pregnancy tests (UPTs).  Subjects will return for post-baseline 
evaluation at Weeks 2, 4, 8, and 12. 
Confidential and Proprietary, Novan, Inc. 
 
9 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
Diagnosis and Criteria 
for Inclusion 
Male and female subjects between the ages of 12 and 40 (inclusive at 
Baseline) with acne vulgaris on the face, and at least 20 but no more 
than 40 inflammatory lesions (papules and pustules), 25 to 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 will be eligible for participation in the study.   
Inclusion criteria: 
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, 12 to 40 years of age, inclusive and in good 
general health; 
3. Have a Baseline IGA score of moderate (3) or severe (4); 
4. Have a minimum of 25 but not more than 70 non-inflammatory 
lesions (open and closed comedones) on the face; 
5. Have a minimum of 20 but no more than 40 inflammatory 
lesions (papules and pustules) on the face; 
6. Have no more than two nodules or cysts on the face; 
7. Women of childbearing potential (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. Males must agree to avoid fathering a child during the study 
and for 60 days after the last dose of the study drug by ensuring 
one of the acceptable methods of contraception listed is used 
and not donating sperm; and  
10. 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. 
 
Confidential and Proprietary, Novan, Inc. 
 
10 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
Exclusion Criteria: 
1. Have any dermatological conditions on the face that could 
interfere with clinical evaluations such as acne conglobata, acne 
fulminans, acne secondary to medications or other medical 
conditions, perioral dermatitis, clinically significant rosacea, or 
gram-negative folliculitis; 
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. Have used estrogens (e.g., Depogen, Depo-Testadiol, Gynogen, 
Valergen, etc.) or oral contraceptives for less than 12 weeks 
immediately preceding Baseline, discontinued use of estrogens 
or oral contraceptives less than 12 weeks prior to Baseline, or 
planning to begin or discontinue use of this therapy during the 
treatment period; 
6. Have used medications or vitamins which are reported to 
exacerbate acne during the 12 weeks immediately preceding 
Baseline (e.g. azothioprine, haloperidol, halogens such as 
iodides or bromides, lithium, anabolic steroids, systemic 
corticosteroids, phenytoin and phenobarbital).  The subject must 
not have had a severe acne flare for at least 12 weeks preceding 
Baseline.  Daily use of a multi-vitamin is acceptable. 
7. Have a history of hypersensitivity or allergic reactions to any of 
the ingredients in the SB204 Gel or Vehicle Gel as described in 
the Investigator’s Brochure; 
8. Subjects using or requiring short- or long-acting nitrates, nitric 
oxide donor drugs or supplements (eg; arginine, citrulline) or 
drugs associated with methemoglobinemia;  
9. Have used the following topical preparations within the time 
specified prior to Baseline or require the concurrent use of any 
of the following topical agents: 
 
 
Confidential and Proprietary, Novan, Inc. 
 
11 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
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 
Retinoids or retinol-containing 
products or corticosteroids 
4 weeks 
* Includes benzoyl peroxide, salicylic acid,  
dapsone, alpha-hydroxy acid, or glycolic 
acids 
10. 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 (≤10 days) of antibiotics if needed during the 
treatment phase of the study for non-acne related illnesses are 
allowed. 
* Intranasal and inhaled corticosteroids may be used throughout 
the trial if the subject is on a stable dose. 
11. Have had the following procedures on the face, including 
treatment area within the time specified prior to Baseline: 
 
 
 
Cryodestruction/Chemo-
destruction 
4 weeks 
Dermabrasion 
4 weeks 
Photodynamic Therapy 
4 weeks 
Acne Surgery 
4 weeks 
Intralesional Corticosteroids 
4 weeks 
X-ray, Laser Therapy, or Other 
Device 
4 weeks 
Confidential and Proprietary, Novan, Inc. 
 
12 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
12. Have a methemoglobin value of > 3.0% at Screening or 
Baseline; 
13. Have clinically significant anemia at Screening as determined 
by the Investigator; 
14. Intend to use a tanning booth or sunbathe during the study; 
15. 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.  Subjects scheduled for endoscopy 
with use of topical anesthetics should not be enrolled.   
16. Are unable to communicate or cooperate with the Investigator 
due to language problems, poor mental development, or 
impaired cerebral function; 
17. Have used an investigational drug or device within 30 days of 
Baseline or concurrent participation in a different research 
study; 
18. Have participated in a previous study with SB204 Gel or 
NVN1000 Gel. 
Sample Size 
Approximately 200 subjects will be randomized into the study in a 
2:2:2:1:1 ratio (~50 in each active arm and 25 in each vehicle arm).   
Efficacy Evaluation 
The same blinded evaluator will perform Investigator Global 
Assessments and lesion counting at Screening, Baseline, and Weeks 2, 
4, 8, and 12.  In the event that this is not possible due to unforeseen 
circumstances, a different blinded evaluator will evaluate the subject.  
However, the same evaluator should evaluate subjects at the Baseline 
and Week 12 evaluations. 
Investigator Global Assessment (IGA) 
The IGA score will be determined based on the Investigator evaluation 
of the overall signs and symptoms of acne vulgaris.  IGA evaluations 
will be performed prior to the lesion counts, approximately 3 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, the Investigator 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, which will be recorded separately.  
Confidential and Proprietary, Novan, Inc. 
 
13 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
Inflammatory lesion count will include the number of papules and 
pustules, which will be recorded separately.  The number of nodules 
and cysts will be reported separately and included with the 
inflammatory lesion counts.    
Tolerability 
Evaluation 
Subjects will be assessed at each visit from Baseline through Week 12 
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 performed at 
Screening, Baseline, and Week 12/Early Termination (ET).  Blood 
pressure and pulse will be measured at Screening, Baseline, and each 
visit through Week 12/ET.  Any clinically significant changes noted 
during the physical exam as well as from the change in vital sign 
measurements or safety laboratory assessments will be recorded as 
adverse events.  Methemoglobin will be measured with a pulse co-
oximeter and recorded at Screening, Baseline, and Weeks 2 and 12/ET.  
Chemistry, hematology, and PT/PTT will be assessed at Screening, 
Baseline, and Week 12.  Urine pregnancy tests in women of child-
bearing potential will be performed at Screening, Baseline, and Weeks 
4, 8, and 12/ET. 
Additional Evaluations Photographs of the face will be taken at Baseline and Week 12/ET.    
Confidential and Proprietary, Novan, Inc. 
 
14 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
Endpoints 
Primary Efficacy Endpoints The co-primary efficacy endpoints are:  
a.  The absolute change in inflammatory lesion count from Baseline 
to Week 12; 
b.  The absolute change in non-inflammatory lesion count from 
Baseline to Week 12; 
c.  The proportion of success according to the dichotomized IGA.  
A subject will be considered a success if the IGA at Week 12 is 
clear or almost clear and is at least 2 grades less than Baseline. 
Secondary Efficacy Endpoints The secondary endpoints include the 
following: 
a.  The percent change in inflammatory lesion count from Baseline 
to Week 12; 
b.  The percent change in non-inflammatory lesion count from 
Baseline to Week 12; 
c. The median time to improvement.  
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 each active treatment group 
to the combined Vehicle treatment group.  Comparisons will not be 
performed between active treatments.  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 population. 
For the dichotomized IGA, subjects will be considered a success if their 
IGA score is clear or almost clear and at least two grades less than 
Baseline. For those subjects for whom no Week 12 assessments are 
available, the last observation will be carried forward (LOCF) in order 
to provide a value for efficacy parameters that are missing, primarily 
due to missed visits.   Additionally, a sensitivity analysis to estimate 
missing efficacy data will be based on estimation using the method of 
Markov Chain Monte Carlo (MCMC) independently for each treatment 
group. All hypotheses will be two-sided at an alpha level of 0.05. 
Descriptive Statistics 
Descriptive statistics will be presented for the efficacy data at each 
evaluation for the ITT and PP populations.  Safety data will be 
summarized as indicated below for the safety population.  Continuous 
Confidential and Proprietary, Novan, Inc. 
 
15 

Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
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.  Descriptive 
statistics will be presented for the active treatment groups, each vehicle 
treatment group, and the vehicle treatment groups combined. 
Efficacy Analysis 
Lesion counts will be summarized at each evaluation from Baseline 
through Week 12.  Absolute and percent change in lesion counts will 
be summarized at Weeks 2, 4, 8, and 12.  IGA scores will be 
summarized from baseline through Week 12.  The dichotomized IGA 
scores will be summarized at Weeks 2, 4, 8, and 12. 
Primary Efficacy Analysis 
The analysis of the absolute change in non-inflammatory lesion counts 
at Week 12 will be conducted using an analysis of covariance with 
factor of treatment and baseline lesion count as the covariate.  The 
analysis of the absolute change in inflammatory lesion counts at Week 
12 will use the same method as the analysis of the non-inflammatory 
lesions. 
The analysis of the dichotomized IGA scores at Week 12 will be 
analyzed with a Cochran-Mantel-Haenszel test.  
Pairwise comparisons of each active treatment group to the combined 
vehicle treatment group will be computed without concern for 
controlling for multiplicity. 
Secondary Efficacy Analyses 
The analyses of percent change in inflammatory and non-inflammatory 
lesion counts at Week 12 will use the same method as the analysis of 
the non-inflammatory lesions. 
The time to improvement will be compared between each of the active 
treatment groups and the combined Vehicle treatment group using the 
Kaplan-Meier method.  An observation will be censored if 
improvement is not achieved by Week 12 (inclusive).  The log-rank test 
will be used to compare time to response between each active treatment 
group and the combined Vehicle treatment group.  
Confidential and Proprietary, Novan, Inc. 
 
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Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
Tolerability Analyses 
Cutaneous tolerability assessments (erythema, scaling, dryness, 
pruritus, burning/stinging) will be summarized from Baseline to Week 
12.  Additionally, change from Baseline in tolerability assessments will 
be summarized at Weeks 2, 4, 8, and 12.  
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.  
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, 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 
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Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
Name of Sponsor/Company: 
Novan, Inc. 
Individual Study 
Table Referring to 
Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National 
Authority Use 
Only) 
Name of Finished Product: 
SB204 
Name of Active Ingredient: 
NVN1000 
Baseline through Week 12. Additionally, change from Baseline in vital 
signs will be summarized at Weeks 2, 4, 8, and 12. 
Laboratory Assessments 
Blood chemistry, hematology, and PT/PTT values will be reported 
individually at Screening, Baseline, and Week 12.  Laboratory test 
results will be summarized descriptively at Baseline and Week 12.  
Additionally, shifts from Baseline to Week 12 in laboratory test results 
based on normal ranges will be summarized with descriptive statistics.  
The last laboratory evaluation prior to the first dose of study drug will 
be used as Baseline for all laboratory analyses.  
Methemoglobin  
Methemoglobin will be reported as a percentage of hemoglobin.  
Methemoglobin will be summarized at Baseline and Weeks 2 and 
12/ET.  Additionally, the change from Baseline in methemoglobin at 
Weeks 2 and 12/ET will be summarized. 
Urine Pregnancy Tests 
Urine pregnancy test results for WOCBP will be presented in data 
listings by subject. 
 
Confidential and Proprietary, Novan, Inc. 
 
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Protocol NI-AC202, Protocol Amendment 1  
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Novan, Inc. 
 
 16 OCT 2014 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
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 
IUD 
Intrauterine Device 
LOCF 
Last Observation Carry Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOVAN 
Novan, Inc. 
OTC 
Over-the-Counter 
PP 
Per-Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TBSA 
Total Body Surface Area 
TEAE 
Treatment Emergent Adverse Events 
UPT 
Urine Pregnancy Test 
US 
United States 
WOCBP 
Women of Child-Bearing Potential 
 
Confidential and Proprietary, Novan, Inc. 
 
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Protocol NI-AC202, Protocol Amendment 1  
Version 2.0 
Novan, Inc. 
 
 16 OCT 2014 
TABLE OF CONTENTS 
SPONSOR INFORMATION PAGE ............................................................................................2 
PROTOCOL AMENDMENT.......................................................................................................3 
INVESTIGATOR’S AGREEMENT ............................................................................................8 
PROTOCOL SYNOPSIS ..............................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................19 
TABLE OF CONTENTS ............................................................................................................20 
1. INTRODUCTION..................................................................................................................24 
1.1 Background .....................................................................................................................24 
1.2 
Investigational Product ...................................................................................................24 
1.3 Nonclinical Studies with NVN1000 Gel.........................................................................25 
1.4 Clinical Studies with NVN1000 Gel...............................................................................25 
1.5 Summary of Benefits and Risks ......................................................................................28 
2. RATIONALE AND OBJECTIVES .....................................................................................29 
2.1 Study Rationale ...............................................................................................................29 
2.2 Study Objectives .............................................................................................................29 
3. STUDY DESIGN ....................................................................................................................29 
3.1 Study Endpoints ..............................................................................................................30 
3.1.1 Efficacy Endpoints ..............................................................................................30 
3.1.2 Tolerability Endpoints ........................................................................................31 
3.1.3 Safety Endpoints .................................................................................................31 
3.2 Structure ..........................................................................................................................31 
3.3 Duration ..........................................................................................................................31 
3.4 Dosage/Dose Regimen ....................................................................................................31 
3.5 Visit Schedule .................................................................................................................31 
3.6 Study Population .............................................................................................................31 
3.7 Eligibility Criteria ...........................................................................................................32 
3.7.1 
Informed Consent and Authorization to Release Health Information ................32 
3.7.2 
Inclusion Criteria ................................................................................................33 
3.7.3 Exclusion Criteria ...............................................................................................33 
4. STUDY PROCEDURES AND METHODS ........................................................................35 
4.1 Subject Entry Procedures ................................................................................................35 
4.1.1 Screening (Day -35 to Day – 1) ..........................................................................38 
4.1.2 Baseline (Day 0) .................................................................................................38 
4.1.3 Week 2 (Day 14) .................................................................................................39 
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4.1.4 Week 4 (Day 28) .................................................................................................39 
4.1.5 Week 8 (Day 56) .................................................................................................40 
4.1.6 Week 12/ET (Day 84) .........................................................................................40 
4.1.7 Discontinuation/Withdrawal Procedures ............................................................41 
4.2 Efficacy Assessments......................................................................................................43 
4.2.1 
Investigator Global Assessment..........................................................................43 
4.2.2 
Lesion Counts .....................................................................................................43 
4.3 Tolerability Assessments ................................................................................................44 
4.3.1 Cutaneous Tolerability Evaluations ....................................................................44 
4.4 Safety Assessments .........................................................................................................45 
4.4.1 Adverse Events ...................................................................................................45 
4.4.2 Physical Exam.....................................................................................................45 
4.4.3 Vital Signs...........................................................................................................45 
4.4.4 
Laboratory Assessments .....................................................................................46 
4.4.5 Methemoglobin ...................................................................................................46 
4.4.6 Pregnancy Testing...............................................................................................47 
4.5 Additional Assessments ..................................................................................................47 
4.5.1 Photography ........................................................................................................47 
4.6 Screen Failures ................................................................................................................47 
4.7 Protocol Deviations .........................................................................................................47 
5. PROHIBITED THERAPIES AND MEDICATIONS ........................................................47 
6. EVALUATION OF ADVERSE EVENTS ...........................................................................48 
6.1 Definitions.......................................................................................................................48 
6.1.1 Adverse Event Severity Grades ..........................................................................49 
6.1.2 
Investigational Product Causality .......................................................................50 
6.2 Reporting Adverse Events ..............................................................................................50 
6.3 
Immediately Reportable Events ......................................................................................50 
6.4 Pregnancy ........................................................................................................................51 
6.5 Follow-Up of Adverse Events ........................................................................................52 
6.5.1 Follow-Up of Non-Serious Adverse Events .......................................................52 
6.5.2 Follow-Up of Post Study Serious Adverse Events .............................................53 
6.6 Overdosage .....................................................................................................................53 
6.7 Discontinuation of Individual Subjects from the Study ..................................................53 
7. STATISTICAL ANALYSIS .................................................................................................53 
7.1 General Considerations ...................................................................................................53 
7.2 Populations ......................................................................................................................54 
7.2.1 
Intent to Treat (ITT) Population .........................................................................54 
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7.2.2 Safety Population ................................................................................................54 
7.2.3 Per-Protocol Population ......................................................................................54 
7.3 Demographic and Baseline Characteristics ....................................................................55 
7.4 Descriptive Statistics .......................................................................................................55 
7.5 Efficacy Analysis ............................................................................................................55 
7.5.1 Sensitivity Efficacy Analyses .............................................................................56 
7.6 Tolerability ......................................................................................................................57 
7.6.1 Cutaneous tolerability .........................................................................................57 
7.7 Safety ..............................................................................................................................57 
7.7.1 Adverse Events ...................................................................................................57 
7.7.2 Physical Examination .........................................................................................58 
7.7.3 Vital Signs...........................................................................................................58 
7.7.4 
Laboratory Assessments .....................................................................................58 
7.7.5 Methemoglobin ...................................................................................................58 
7.7.6 Urine Pregnancy Tests ........................................................................................58 
7.8 Sample Size and Power Considerations ..........................................................................58 
8. INVESTIGATIONAL PRODUCT MANAGEMENT .......................................................59 
8.1 Receipt of Investigational Product ..................................................................................59 
8.2 Storage of Investigational Product ..................................................................................59 
8.3 Treatment Assignment and Blinding ..............................................................................59 
8.4 Unblinding of Treatment Assignment ............................................................................59 
8.5 
Investigational Product Accountability ...........................................................................60 
8.6 Returns and Destruction ..................................................................................................60 
9. RECORDS MANAGEMENT ...............................................................................................60 
9.1 Data Collection ...............................................................................................................60 
9.2 File Management at the Study Site .................................................................................62 
9.3 Records Retention at the Study Site................................................................................62 
10. MONITORING, COMPLIANCE, AND QUALITY ..........................................................62 
10.1 Quality Assurance Audits and Quality Control ..............................................................63 
11. ETHICS AND RESPONSIBILITY ......................................................................................64 
12. CONFIDENTIALITY ...........................................................................................................64 
13. AMENDMENT POLICY ......................................................................................................64 
14. USE OF INFORMATION AND PUBLICATION..............................................................65 
15. REFERENCES .......................................................................................................................66 
16. APPENDICES ........................................................................................................................67 
16.1 APPENDIX 1:  List of Restricted Medications and Supplements:.................................67 
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16.2 APPENDIX 2:  Subject Instructions for Application of Study Drug .............................68 
16.3 APPENDIX 3:  Definitions for IGA Score .....................................................................69 
 
Confidential and Proprietary, Novan, Inc. 
 
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Protocol NI-AC202, Protocol Amendment 1  
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 16 OCT 2014 
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 to the skin after topical application.  SB204, comprising 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 240 subjects have been treated with NVN1000 Gel, including SB204, 
and 150 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% Gel or SB204 2% Gel 
Vehicle Gel  
Manufacturer 
Novan, Inc. 
Novan, Inc. 
Packaging 
Pump designed to deliver 1:1 Hydrogel: 
NVN1000 Gel to yield final 
concentration of SB204 4% Gel or 
SB204 2% Gel 
Pump designed to deliver 1:1 
Hydrogel: Vehicle Gel 
Storage Requirements 
Refrigerated, 2-8 °C  
Refrigerated, 2-8 °C  
Appearance Post-Mixing 
Opaque white gel  
Opaque white gel 
Dosing Schedule 
Once or twice daily 
Once or twice daily 
Route of Administration 
Topical Application 
Topical Application 
Confidential and Proprietary, Novan, Inc. 
 
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Novan, Inc. 
 
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1.3 
NONCLINICAL STUDIES WITH NVN1000 GEL 
The development program for NVN1000 Gel includes over 25 non-clinical studies to assess 
safety following topical application.  Studies performed to date with NVN1000 demonstrated the 
safety of the inert carrier silica particles and the lack of systemic silica particle bioavailability 
when applied topically.  Following daily topical administration of NVN1000 Gel to rats (at doses 
of 6, 12, and 20%) for five days or to miniature pigs (at doses of 6, 12, and 20%) for 28 days 
(10% TBSA), systemic exposure (blood levels) of nitrate and silicon were not statistically 
different from background levels.  The in-life portion of a 13-week dermal toxicity study in mini-
pigs has been completed; no significant findings have been noted to date.  In a 13-week dermal 
toxicity study in rats, local application events led to unscheduled study termination of all dose 
groups in a time-dependent manner. 
Pharmacokinetic studies to date in rats with the NVN1000 Gel have led to no appreciable 
systemic bioavailability (<2%) of NVN1000 or related compounds following repeated topical 
administration as assessed by nitrate as a marker for nitric oxide exposure and silicon as a marker 
for the polysiloxane backbone of NVN1000.  Silicon and nitrate were detected in blood only 
sporadically and at the same frequency and levels found in pre-dose blood samples.  Co-
administration of NVN1000 Gel with hydrogel did not impact the pharmacokinetics.  
NVN1000 Gel demonstrated mutagenicity in an Ames assay, but was not mutagenic in two in 
vivo genotoxicity tests in two tissue types: bone marrow via IP administration and skin via 
topical administration. 
For additional information refer to the Investigator’s Brochure. 
1.4 
CLINICAL STUDIES WITH NVN1000 GEL 
The topical administration of NVN1000 Gel to healthy volunteers or subjects with acne vulgaris 
has generally been well-tolerated with no safety concerns identified.  In seven completed clinical 
studies, approximately 240 subjects have been treated with NVN1000 Gel or SB204 Gel and 
approximately 150 subjects have been treated with Vehicle Gel.  No SAEs have been reported 
and the AE profile has been similar in subjects treated with active (NVN1000 or SB204 Gel) and 
vehicle.  Asymptomatic, transient erythema has been observed in some subjects treated with 
higher concentrations of NVN1000. There have been no clinically significant changes in 
laboratory results including methemoglobin, or changes in physical examinations.  A cross-over 
pharmacokinetic (PK) study was conducted in 18 subjects with moderate to severe acne. Subjects 
received nine applications of SB204 8% Gel or Vehicle Gel to the face, chest, upper back, and 
shoulders (~17% TBSA) over five days, had a nine day washout, then crossed over to the other 
treatment for nine applications over five days.  PK analysis of samples for nitrate and silicon is 
pending.  One subject withdrew during the second dosing period due to contact dermatitis.  In a 
psoriasis microplaque assay, local application-site reactions following application of alcoholic 
Confidential and Proprietary, Novan, Inc. 
 
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Protocol NI-AC202, Protocol Amendment 1  
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NVN1000 Gel or Vehicle Gel under occlusion were observed in some treated subjects that led to 
treatment discontinuations.   
Table 1 provides a listing of the clinical studies conducted to date in subjects with acne.  
Additional 
details 
regarding 
these 
studies 
are 
in 
the 
Investigator’s 
Brochure.
Confidential and Proprietary, Novan, Inc. 
 
26 

Protocol NI-AC202, Protocol Amendment 1  
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Novan, Inc. 
 
 16 OCT 2014 
Table 1: 
Clinical Studies Conducted to Date in Subjects with Acne 
Study 
Number 
Study Title 
Population 
Number 
Enrolled 
Treatment Groups 
Frequency / Duration 
of Treatment 
Phase 1 
 
 
 
 
NI-AC002 
[KGL 7563] 
A Phase I, Multiple-Dose, Single-Center, 
Observer-Blind, Randomized, 
Parallel-Group Study Evaluating the 
Safety and Cutaneous Tolerability of NVN1000 
Topical Gel in Healthy 
Volunteers 
Healthy volunteers 
≥ 18 years of age 
with elevated P. 
acnes counts  
60 
NVN1000 2 % Gel  
NVN1000 4 % Gel  
NVN1000 8 % Gel  
Vehicle Gel 
 
Once daily for 4 weeks 
(28 days) over entire 
face 
NI-AC004 
[KGL 7603] 
A Phase 1, 3-Day Study of Safety and 
Tolerability of NVN1000 Topical Gel in 
Healthy Volunteers 
Healthy volunteers 
≥ 18 years of age 
with elevated P. 
acnes counts  
15 
NVN1000 8% Gel 
NVN1000 Gel 8% and 
moisturizer 
Vehicle Gel 
Once daily for 3 days on 
forehead 
NI-AC006 
[KGL 7666] 
A Phase 1, Multiple-Dose, Evaluator-Blind, 
Randomized, Parallel-Group Study Evaluating the 
Safety and Cutaneous Tolerability of SB204 
(NVN1000 Gel with Hydrogel) in Healthy 
Volunteers 
Healthy volunteers 
≥ 18 years of age 
with elevated P. 
acnes counts  
30 
SB204 4% (NVN1000 
Gel with Hydrogel) 
Vehicle Gel with 
Hydrogel 
Twice daily for 14 days 
to face 
NI-AC101 
A Phase 1, Single-center, Double-Blind, 
Randomized, Cross-over Pharmacokinetic, 
Safety, and Tolerability Study of SB204 8% 
(NVN1000 Gel) and Vehicle Gel 
Subjects ≥ 18 years 
of age with 
moderate or severe 
acne vulgaris 
18 
SB204 8% Gel 
Vehicle Gel 
Twice daily for 4 days 
and once on the 5th day 
to upper back, upper 
chest, shoulders and face 
for two dosing periods 
Phase 2 
 
 
 
 
NI-AC001 
A Single-Center, Randomized, Double-Blind, 
Vehicle-Controlled, Parallel Group Comparison, 
POC Study Comparing the Tolerability, Safety 
and Efficacy of NVN1000 Topical Gel and Gel 
Vehicle in the Treatment of Moderate to Severe 
Acne Vulgaris 
Subjects 12-40 
years of age with 
moderate to severe 
acne vulgaris 
70 
NVN1000 2% Gel  
Vehicle Gel 
 
 
Once daily at bedtime 
for 8 weeks (56 days) 
over entire face 
NI-AC201 
A Multi-Center, Randomized, Evaluator-Blinded, 
Vehicle Controlled, Parallel Group, 3-arm Study 
Comparing the Efficacy, Tolerability, and  Safety 
of 2 Concentrations of SB204 (NVN1000 Gel and 
Vehicle Gel with Hydrogel) Twice Daily in the 
Treatment of Acne Vulgaris 
Subjects 12-40 
years of age with 
mild to severe acne 
vulgaris 
153 
SB204 4% Gel ; 
SB204 1% Gel ; 
Vehicle Gel with 
Hydrogel 
Twice daily for 12 weeks 
to face 
Confidential and Proprietary, Novan, Inc. 
 
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Protocol NI-AC202, Protocol Amendment 1  
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 16 OCT 2014 
  
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 sebum production, decrease 
P. acnes, alter keratinocyte differentiation, and inhibit inflammasome activation.  In a recently 
completed Phase 2 study, SB204 4% Gel administered twice daily in subjects with acne 
decreased inflammatory and non-inflammatory lesion counts at the end of treatment.  In the 
studies conducted to date, the AE profile was similar between subjects treated with NVN1000 
Gel, SB204 Gel, and subjects treated with Vehicle Gel.  NVN1000 Gel at 2%, 4%, and 8% 
concentrations was well tolerated and was not associated with a safety or tolerability signal. 
Nitric oxide released from NVN1000 is anticipated to be pharmacologically active in the skin.  
Any nitric oxide absorbed through the skin would be extremely short-lived (milliseconds) with 
rapid auto-oxidation to nitrite and nitrate.  Systemic bioavailability of NVN1000 or related 
compounds following repeated topical administration of NVN1000 Gel was < 2% in non-clinical 
pharmacokinetic studies conducted to date both with and without hydrogel.   
Dermal toxicology studies have demonstrated minimal evidence of toxicity in a 28 day miniature 
pig study dosed with 20% NVN1000 Gel across 10% TBSA, low dermal irritation in rabbits, and 
no dermal sensitization in guinea pigs.  A 13-week dermal toxicology study in mini-pigs with 
NVN1000 2%, 4%, and 8% Gel (10% TBSA) has completed the in-life period with no 
significant observed effects; histopathology and toxicokinetics data will be available prior to 
enrollment in the current study.  Local application site events in a 13 week dermal toxicology 
study in rats with NVN1000 2%, 4%, and 8% Gel (10% TBSA) led to premature discontinuation 
of all dose groups in a time-dependent manner.  These local adverse effects seen in the rat study 
are species specific and monitorable.  Tolerability will be assessed during the planned study, and 
discontinuation criteria for intolerance by subjects is described in Section 6.7. 
Based on the known mechanism of action of nitric oxide, theoretical risks from systemic 
exposure following topical administration of NVN1000 Gel or SB204 Gel include hypotension 
and headache.  Methemoglobinemia has been reported in patients treated with inhaled nitric 
oxide.  Methemoglobin will be monitored during the study and treatment stopped in any subject 
with a measured methemoglobin > 5.0%. 
Inadvertent administration to the eyes may result in ocular irritation and should be avoided.  
Should the product be accidently instilled in the eye(s), prompt flushing with copious amount of 
normal saline or water is recommended.  
A transient (approximately 5-10 minutes), asymptomatic erythema has been observed in some 
subjects shortly after application of NVN1000 Gel or SB204 Gel which is a physiologic response 
Confidential and Proprietary, Novan, Inc. 
 
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(vasodilation) to local nitric oxide release.  Topical application has been associated with local 
application-site reactions including erythema, peeling, desquamation, or burning/stinging.  These 
local application-site reactions may occur due to the active agent (NVN1000) or the vehicle.  
Local application-site events including erosions and contact dermatitis were reported in subjects 
with psoriasis treated with NVN1000 Gel and Vehicle Gel under occlusion.  These local 
application-site reactions resolved after discontinuation of the product and by the end of the 
study. 
Based on available data, Novan anticipates that the risks to subjects enrolling in this Phase 2 
study at which the maximum strength of SB204 Gel will be 4% twice daily to approximately 4 
percent total body surface area are minimal, and that appropriate monitoring is in place to assess 
safety.  At this stage of development, it is unknown if a clinical benefit will be observed in 
subjects with acne vulgaris following treatment for 12 weeks.   
2. RATIONALE AND OBJECTIVES 
2.1 
STUDY RATIONALE 
Novan is conducting this study to evaluate the efficacy, cutaneous tolerability and safety of      
SB 204 2% Gel, SB204 4% Gel and Vehicle Gel administered once or twice daily to the face. 
Subjects will dose once (in the evening) or twice daily (morning and evening) for up to 12 weeks 
(84 days) with SB204 4% Gel, twice daily with SB204 2% Gel, or once or twice daily with 
Vehicle Gel.  Approximately 0.9 g of gel (three (3) pump strokes) will be applied evenly over the 
face (4% TBSA).  Based on the previous human safety data with SB204 Gel at up to 8% and 
Vehicle Gel as well as the nonclinical safety data including dosing with and without hydrogel, 
this dose is expected to be safe and well tolerated. 
2.2 
STUDY OBJECTIVES 
The primary objective of this study is to compare efficacy, tolerability and safety of two 
concentrations of SB204 Gel and Vehicle Gel once or twice daily for 12 weeks in subjects with 
acne vulgaris.  
3. STUDY DESIGN 
Figure 1 depicts the overall study design for this 12 week, 5 arm, randomized, evaluator blinded 
study in subjects with moderate to severe acne vulgaris dosed once or twice daily with SB204 
and Gel Vehicle.  Subjects receiving current treatment for acne vulgaris may enter a wash out 
period after screening of up to 35 days prior to randomization.  
Confidential and Proprietary, Novan, Inc. 
 
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Figure 1: Study Diagram 
 
Randomization 
 
 
 
 SB204 4% Gel BID 
(N=50) 
 
 
 
  
 
 SB204 4% Gel QD 
(N=50) 
 
 
 
  
 
 SB204 2% Gel BID 
(N=50) 
 
 
 
  
 
 Vehicle Gel BID 
(N=25) 
 
 
 
  
 
 Vehicle Gel QD 
(N=25) 
 
 
Visits 
 
Screening 
Baseline 
 
 
Day 
-35 
to Day -1 
 
 (Day)        (0) 
 (14) 
 
 
2 
 
 (28) 
 
 
4 
 
 
 (56) 
 
 
8 
 
 
(84) 
 
 
12/ET 
 
Study Week 
 
ET = Early termination 
 
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; 
•  The absolute change in non-inflammatory lesion count from Baseline to Week 12; 
•  The proportion of success according to the dichotomized IGA.  A subject will be 
considered a success if the IGA at Week 12 is clear or almost clear and is at least 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; 
• The percent change in non-inflammatory lesion count from Baseline to Week 12; 
• The median time to improvement.  
 
Confidential and Proprietary, Novan, Inc. 
 
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3.1.2 TOLERABILITY ENDPOINTS 
The cutaneous tolerability assessments the investigator’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 percent methemoglobin, change from 
baseline vital sign measurements and in chemistry, hematology, and PT/PTT values, and the 
comparison of adverse events between groups.  Any clinically significant changes noted during 
the physical exam as well as from the vital sign measurements, or safety laboratory assessments 
will be recorded as adverse events and included in the comparison. 
3.2 
STRUCTURE 
This is a multi-center, randomized, evaluator-blinded, vehicle-controlled, 5-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.   
3.4 
DOSAGE/DOSE REGIMEN 
Approximately 0.9 g of SB204 2% Gel, SB204 4% Gel, or Vehicle Gel will be applied evenly 
over the entire face once or twice 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 or 
twice daily after washing.  The product should be mixed for 5-10 seconds until thoroughly 
combined with a uniform opaque appearance then applied with the fingertips (Appendix 2).  
Subjects assigned to once daily dosing should apply their dose at 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 200 healthy male and female subjects between the ages of 12 and 40 (inclusive) 
with moderate to severe acne vulgaris on the face will be randomized to participate in the study.  
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Eligible subjects will have:  at least 20 but no more than 40 inflammatory lesions (papules and 
pustules); 25 to 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 3). 
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 QST Consultations 
(QST) 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 FDA regulations in 21 
CFR as well as the International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, and applicable federal and local regulatory requirements.  The consent form(s) 
must also include a statement that Novan, their designees and auditing regulatory agencies will 
have direct access to the subject’s records and medical history.   
Once the appropriate essential information has been provided to the subject and 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 
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.  
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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, 12 to 40 years of age, inclusive and in good general health; 
3. Have a baseline IGA score of moderate (3) or severe (4); 
4. Have a minimum of 25 but not more than 70 non-inflammatory lesions (open and closed 
comedones) on the face; 
5. Have a minimum of 20 but no more than 40 inflammatory lesions (papules and pustules) 
on the face; 
6. Have no more than two nodules or cysts on the face; 
7. Women of childbearing potential (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;  
9. Males must agree to avoid fathering a child during the study and for 60 days after the last 
dose of the study drug by ensuring one of the acceptable methods of contraception listed 
is used and not donating sperm; and 
10. 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 acne conglobata, acne fulminans, acne secondary to medications or 
other medical conditions, perioral dermatitis, clinically significant rosacea, or gram-
negative folliculitis;  
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; 
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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. Have used estrogens (e.g., Depogen, Depo-Testadiol, Gynogen, Valergen, etc.) or oral 
contraceptives for less than 12 weeks immediately preceding Baseline, discontinued use 
of estrogens or oral contraceptives less than 12 weeks prior to Baseline, or planning to 
begin or discontinue use of this therapy during the treatment period; 
6. Have used medications or vitamins which are reported to exacerbate acne during the 12 
weeks immediately preceding Baseline (e.g. azothioprine, haloperidol, halogens such as 
iodides or bromides, lithium, anabolic steroids, systemic corticosteroids, phenytoin and 
phenobarbital).  The subject must not have had a severe acne flare for at least 12 weeks 
preceding Baseline.  Daily use of a multi-vitamin is acceptable. 
7. Have a history of hypersensitivity or allergic reactions to any of the ingredients in the 
SB204 Gel or Vehicle Gel as described in the Investigator’s Brochure; 
8. Subjects using or requiring short- or long-acting nitrates, nitric oxide donor drugs or 
supplements (eg; arginine, citrulline) or drugs associated with methemoglobinemia; 
9. Have used the following topical preparations within the time specified prior to Baseline or 
require the concurrent use of any of the following topical agents: 
 
 
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 
Retinoids or retinol-containing products or 
corticosteroids 
4 weeks 
* Includes benzoyl peroxide, salicylic acid,  dapsone, alpha-hydroxy 
acid, or glycolic acids 
 
10. 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 (≤10 days) of antibiotics if needed during the treatment phase of the study 
for non-acne related illnesses are allowed. 
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* Intranasal and inhaled corticosteroids may be used throughout the trial if the subject is 
on a stable dose. 
 
11. Have had the following procedures on the face, including treatment area within the time 
specified prior to Baseline: 
 
 
 
 
 
 
 
 
12. Have a methemoglobin value of > 3.0% at Screening or Baseline; 
 
13. Have clinically significant anemia at Screening as determined by the Investigator; 
 
14. Intend to use a tanning booth or sunbathe during the study; 
 
15. 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.  Subjects scheduled for endoscopy with use of topical 
anesthetics should not be enrolled.   
 
16. Are unable to communicate or cooperate with the Investigator due to language problems, 
poor mental development, or impaired cerebral function; 
 
17. Have used an investigational drug or device within 30 days of Baseline or concurrent 
participation in a different research study; 
 
18. Have participated in a previous study with SB204 Gel or NVN1000 Gel. 
4. STUDY PROCEDURES AND METHODS 
4.1 
SUBJECT ENTRY PROCEDURES 
Prospective subjects as defined by the eligibility criteria in Sections 3.7.2 and 3.7.3 
(Inclusion/Exclusion Criteria) will be considered for entry into this study.  Subjects’ informed 
consent/assent must be obtained prior to conducting any procedures. 
Some Baseline procedures (i.e., review of inclusion / exclusion criteria, brief physical exam, 
methemoglobin assessment, blood pressure and pulse rate, IGA, lesion counts, cutaneous 
tolerability, adverse event assessment, concomitant medication review and UPT) must be 
completed prior to randomization.  Subjects with clinically significant anemia as determined by 
the Investigator or methemoglobin values >3.0% will not be randomized.  
Cryodestruction/Chemo-destruction 
4 weeks 
Dermabrasion 
4 weeks 
Photodynamic Therapy 
4 weeks 
Acne Surgery 
4 weeks 
Intralesional Corticosteroids 
4 weeks 
X-ray, Laser Therapy, or Other Device 
4 weeks 
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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, 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.  Male subjects must agree to 
avoid fathering a child during the study and for 60 days after the last dose of the study drug by 
ensuring one of the acceptable methods of contraception is used and not donating sperm. 
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 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 home. 
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Table 2: 
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 -1) 
Baseline 
(Day 0) 
Week 21 
±3 days 
(Day 14) 
Week 4 
±3 days 
(Day 28) 
Week 8 
±5 days 
(Day 56) 
Week 12/ET2 
±5 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 
X3 
 
 
 
X 
Chemistry, Hematology, 
PT/PTT 
X 
X3 
 
 
 
X 
Urine Pregnancy Test (all 
WOCBP) 
X 
X3 
 
X 
X 
X 
Methemoglobin  
X 
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 
X 
 
Study Drug and Diary 
Collected 
 
 
X 
X 
X 
X 
Subject Compliance 
Reviewed 
 
 
X 
X 
X 
X 
Photography 
 
X 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
¹ All visit dates are in reference to Baseline, e.g., Visit 2 occurs two weeks (14 days) after Baseline visit 
2All Week 12 procedures should be completed for subjects who prematurely discontinue. 
3 If the Baseline Visit is within 3 calendar days of the Screening visit, Physical Examination, Chemistry, Hematology, 
PT/PTT, and UPT do not need to be repeated. 
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4.1.1 SCREENING (DAY -35 TO DAY – 1) 
The following procedures must be performed and recorded at the Screening visit: 
1. Review study procedures and information regarding the study including the potential risk 
and benefits of SB204 with the subject and obtain written informed consent/assent. 
2. Obtain demographic information. 
3. Obtain subject’s medical history, medication history, and concomitant medication 
information. 
4. Verify appropriate contraception being used for WOCBP and male subjects per Section 
6.4. 
5. Measure percent methemoglobin.  
6. Collect blood pressure and pulse rate. 
7. Perform a brief physical examination. 
8. Obtain pregnancy test (WOCBP only) and evaluate results.  If pregnancy test is positive, 
the subject may not participate in the study. 
9. Perform Investigator’s Global Assessment (IGA).  
10. Perform lesion counts.  Inflammatory and non-inflammatory lesion counts will be 
performed on the entire face.   
11. Collect chemistry, hematology, and PT/PTT. 
12. Confirm subjects meet eligibility criteria. 
13. Review prohibited medications, acne treatments, and supplements that should not be used 
prior to Baseline and during the trial. 
14. Collect AEs related to study procedures performed since signing of informed consent. 
15. Confirm the study schedule with the subject. 
4.1.2 BASELINE (DAY 0) 
The following procedures must be performed and recorded at the Baseline visit: 
1. 
Update medication history and concomitant medication information. 
2. 
Perform a brief physical examination. 
3. 
Obtain pregnancy test (WOBCP only) and evaluate results.  If pregnancy test is positive, 
the subject may not participate in the study. 
4. 
Measure percent methemoglobin. 
5. 
Collect blood pressure and pulse rate. 
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6. Collect chemistry, hematology, and PT/PTT. 
7. Perform IGA.  
8. Perform lesion counts. 
9. Perform cutaneous tolerability assessment. 
10. Have subject wash face and dry with lint free towel. 
11. Collect photographs. 
12. Confirm eligibility and randomize subject. 
13. Dispense subject diary and study drug.  Instruct subject on dispensing, mixing, and 
application of study product and diary completion. 
14. 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.). 
15. 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. Measure percent methemoglobin. 
4. Collect blood pressure and pulse rate. 
5. Perform IGA. 
6. Perform lesion counts. 
7. Perform cutaneous tolerability evaluation. 
8. Collect returned study drug and diary, perform accountability, and review study drug 
compliance with subject.  
9. Review subject diary for completion.   
10. Dispense new study drug and diary if needed.  
11. Review and confirm the study schedule with the subject. 
4.1.4 WEEK 4 (DAY 28) 
The following procedures must be performed and recorded at the Week 4 visit: 
1. Update concomitant medication information. 
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2. Update AE information and record any new AEs if applicable. 
3. Obtain UPT (WOCBP only) and evaluate results. 
4. Collect blood pressure and pulse rate. 
5. Perform IGA. 
6. Perform lesion counts. 
7. Perform cutaneous tolerability evaluation. 
8. Collect returned study drug and diary, perform accountability, and review study drug 
compliance with subject.   
9. Review subject diary for completion. 
10. Dispense new study drug and diary.  
11. Review and confirm the study schedule with the subject. 
4.1.5 WEEK 8 (DAY 56) 
The following procedures must be performed and recorded at the Week 8 visit: 
1.  Update concomitant medication information. 
2. Update AE information and record any new AEs. 
3. Obtain UPT (WOCBP only) and evaluate results. 
4. Collect blood pressure and pulse rate. 
5. Perform IGA. 
6. Perform lesion counts. 
7. Perform cutaneous tolerability evaluation. 
8. Collect returned study drug and diary, perform accountability, and review study drug 
compliance with subject.  
9. Review subject diary for completion.  
10. Dispense new supply of study drug and diary.  
11. Review and confirm the study schedule with the subject. 
4.1.6 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. 
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3. Update AE information and record any new AEs. 
4. Obtain UPT (WOCBP only) and evaluate results. 
5. Measure percent methemoglobin. 
6. Collect blood pressure and pulse rate. 
7. Collect chemistry, hematology, and PT/PTT. 
8. Perform IGA. 
9. Perform lesion counts. 
10. Perform cutaneous tolerability evaluation. 
11. Collect returned study drug and diary, perform accountability, and review study drug 
compliance with subject.   
12. Review subject diary for completion.  
13. Have subject wash face and dry with a lint-free towel.  
14. Collect photographs. 
4.1.7 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. 
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. 
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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 
QST, 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.  
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 QST and Novan.  
Study completion or reason(s) for discontinuation as listed in the study record will be entered 
into the study database as follows: 
• Completed 
• Adverse Event  
• Lack of Efficacy  
• Withdrawal by Subject 
• Physician Decision  
• Protocol Violation  
• Lost to Follow-Up  
• Pregnancy  
• Worsening of condition 
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• Other  
Novan has the right to terminate or stop the study at any time.  Should this be necessary, both 
QST and the Investigator will ensure that proper study discontinuation procedures are completed. 
4.2 
EFFICACY ASSESSMENTS 
The same blinded evaluator will perform Investigator Global Assessments and lesion counting at 
Screening, Baseline and Weeks 2, 4, 8, and 12.  In the event that this is not possible due to 
unforeseen circumstances, a different blinded evaluator will evaluate the subject.  However, the 
same evaluator should evaluate subjects at the Baseline and Week 12 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 Investigator 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 investigator will perform each study assessment for each 
study subject, 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).  
 
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: Few non-inflammatory lesions with no more than 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 nodular lesion. 
4 
Severe: Up to many non-inflammatory and inflammatory lesions, including nodular 
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 
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separately.  Non-inflammatory lesions (open and closed comedones) will be counted and 
recorded separately.  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 
4.3.1 CUTANEOUS TOLERABILITY EVALUATIONS 
The Investigator will evaluate the subject’s face prior to the first application of investigational 
product in addition to evaluating at 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 not be reported as an AE unless they 
reach severe and/or result in subject’s discontinuation 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 
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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.  
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.  Any clinically significant changes in vital signs from Baseline will be recorded as adverse 
events whether or not drug related. 
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4.4.4 LABORATORY ASSESSMENTS 
Chemistry, hematology, and PT/PTT will be collected at Screening, Baseline, and Week 12/ET.  
If clinically significant changes in lab results from Baseline are noted at the Week 12/ET visit, 
these will be recorded as adverse events.  Subjects with clinically significant anemia at Screening 
as determined by the Investigator will not be eligible to participate. 
4.4.5 METHEMOGLOBIN  
Methemoglobin will be measured at Screening, Baseline, Week 2 and Week 12/ET using a 
Masimo Rainbow® SET® Rad-57™ pulse co-oximeter that analyzes methemoglobin levels.  The 
percent methemoglobin will be displayed on the pulse co-oximeter and recorded in the subject’s 
study record and in the study database.   
Subjects with methemoglobin values of > 3.0% at Screening or Baseline will not be eligible to 
participate in the study.   
Clinically significant changes in methemoglobin will be recorded as adverse events.  The adverse 
event term should reflect the underlying diagnosis or symptoms and not the pulse co-oximeter 
result itself. 
Clinical symptoms and signs of methemoglobinemia in relation to the level of methemoglobin 
are listed in Table 3. 
Table 3: 
Clinical Symptoms and Signs of Methemoglobinemia in Relation to the Level 
of Methemoglobin 
Level of Methemoglobin Clinical Symptoms and Signs 
<10% 
Frequently asymptomatic, occasionally grayish skin 
10%-20% 
Skin changes such as cyanosis 
20%-30% 
Dyspnea, headache, anxiety 
30%-50% 
Dizziness, palpitations, confusion, tachypnea 
50%-70% 
Seizures, cardiac arrhythmias, metabolic acidosis, coma 
>70% 
Death 
Source: (Boylston, 2002) 
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4.4.6 PREGNANCY TESTING 
All WOCBP must have a UPT at Screening and Baseline and if the result is positive, the subject 
will not be allowed to participate in the study.  Refer to Section 6.4 for further information. 
A female is considered to be of childbearing potential UNLESS she is post-menopausal (no 
menses for 24 consecutive months), surgically sterilized, or without a uterus and/or both ovaries. 
Premenarchal subjects will be considered to be of childbearing potential. 
Pregnancy tests will also be performed at Weeks 4, 8, and 12.  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 Week 12/ET.  Baseline photographs may 
be reviewed by the sponsor or member of the study team to confirm appropriateness of enrolled 
subjects.  
4.6 
SCREEN FAILURES 
A screen failure subject will be a person from whom informed consent is obtained and is 
documented in writing (i.e., subject signs an informed consent form) but who does not meet the 
study eligibility requirements.  Subjects will not be allowed to rescreen.  
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 QST at the earliest 
possible time by telephone.  QST will contact Novan for confirmation on subject discontinuation 
decision prior to informing the site.  This will allow an early joint decision regarding the 
subject’s continuation in the study.  This decision will be documented by the Investigator and 
QST. 
5. PROHIBITED THERAPIES AND MEDICATIONS 
Concomitant medications are any prescription or OTC preparations.  Use of concomitant 
medications will be recorded on the concomitant medications study record and study database 
beginning at the Screening Visit until the final evaluation (Week 12/ET).  
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Subjects will be permitted to apply non-comedogenic moisturizer or sunscreen on an as-needed 
basis.  Moisturizer must not contain antibacterials and the subject must not change moisturizer 
and/or sunscreen used during the course of the study.  If used, moisturizers and sunscreen must 
be applied at least 30 minutes after study drug application.  Use of facial cleanser, moisturizers, 
and sunscreen will be considered concomitant medications; but these products will be recorded 
on a specific study record for facial cleansers, moisturizers and sunscreen. 
Subjects must not have used anti-acne treatments including topical or systemic antibiotics or 
retinoids as described in Section 3.7.3 prior to Baseline.  These medications are also prohibited 
during the trial.   
Subjects may not be concurrently on nitroglycerin, drugs associated with methemoglobinemia, 
drugs associated with exacerbating acne vulgaris, or drugs/supplements that are nitric oxide 
releasers (Appendix 1).  Subjects who have used an investigational drug or device within 30 days 
of Baseline should not be enrolled.  Subjects must not participate in a different research study 
during the study period.  Any subject who has participated in a previous study with SB204 
Gel/NVN1000 Gel must not participate. 
Any medication/therapy used by the subject following first application of study product will be 
considered a concomitant medication/therapy (e.g., aspirin, acetaminophen, birth control pills, 
vitamins, soap, moisturizer, sunscreen, 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 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 
QST 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  
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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 
Relationship of an AE to investigational product will be assessed as follows: 
• 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 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, QST 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 QST by telephone or email as soon as 
possible after the investigator or coordinator has become aware of its occurrence.  The 
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investigator/coordinator must complete a Serious Adverse Event (SAE) Form and email it to 
QST along with the subject’s Adverse Events Log and Concomitant Medications Log 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: 
Email: safety@qstconsultations.com 
 
If a subject experiences an SAE or pregnancy the Investigator must:  
1. Report the SAE or pregnancy by telephone or email immediately (within 24 hours) after the 
Investigator becomes aware of the event. 
2. Complete an SAE or Pregnancy Notification Form and email or overnight courier to QST 
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 QST and the IRB, if applicable, no later than seven 
days after the Investigator discovers the event as further information becomes available, 
and when necessary update the information with follow-up information including 
outcomes.  This report should include a statement as to whether the event was or was not 
related to the use of investigational product. 
5. The Investigator will notify the IRB of the SAE or pregnancy according to specific IRB 
requirements. 
The Investigator will collect information on SAEs until the subject’s health has returned to 
baseline status, until all parameters have returned to normal, or remaining health issues have 
otherwise been explained.   
6.4 
PREGNANCY 
Women of child-bearing potential (WOCBP) must use an effective method of birth control 
during the course of the study and for 30 days following their final study visit.  Allowable 
methods of birth control include 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.  
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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.   
 
Male subjects must agree to avoid fathering a child during the study and for 60 days after the last 
dose of study drug by ensuring one of the acceptable methods of contraception listed is used and 
by not donating sperm.  
Before enrolling any subject in this clinical trial, the Investigator must review guidelines about 
study participation including the topics below: 
• Informed consent document 
• Pregnancy prevention information 
• Risks to unborn child(ren) 
• Any drug interactions with hormonal contraceptives 
• 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).  Male subjects should be 
instructed to contact the investigator if their female partner becomes pregnant during the time the 
subject is enrolled through in the study through 60 days after the final visit.  The Investigator 
must immediately notify QST of any female subject or the female partner of a male subject who 
becomes pregnant any time during study participation, record the information on the Pregnancy 
Notification Form and email the form to QST.  Subjects found to be pregnant prior to Week 12 
will be discontinued from the study.  QST will ask the site to follow-up with the subject 
periodically during the pregnancy for ongoing health and safety information through term, as 
applicable.  Protocol-required procedures for the Week 12/ET evaluation must be performed for 
the subject. 
6.5 
FOLLOW-UP OF ADVERSE EVENTS  
6.5.1 FOLLOW-UP OF NON-SERIOUS ADVERSE EVENTS 
Non-serious AEs that are not resolved at the time of the last scheduled study visit (Week 12/ET) 
must be recorded in the study database as not recovered/not resolved.   
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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 QST 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 QST 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 QST 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 
(Boylston, 2002). 
6.7 
DISCONTINUATION OF INDIVIDUAL SUBJECTS FROM THE STUDY  
Subjects who develop intolerance to the product as defined by scores of ‘severe’ (3) on 2 or more 
categories of tolerability (erythema, scaling, dryness, pruritus, burning/stinging) shall be 
discontinued from the study.   
Subjects with > 5.0% methemoglobin at any post-baseline visit will 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® version 9.3 unless otherwise stated.  
Statistical significance will be based on two-tailed tests of the null hypothesis resulting in p-
values of ≤0.05 unless stated otherwise.  Inferential testing will compare each active treatment 
group to the combined Vehicle treatment group.  Comparisons will not be performed between 
active treatments.  Efficacy analyses will be performed for the intent-to-treat (ITT) and per-
protocol (PP) populations.  Safety analyses will be performed using the safety population. 
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For the dichotomized IGA, subjects will be considered a success if their IGA score is clear or 
almost clear and at least two grades less than Baseline.  
For those subjects for whom no Week 12 assessments are available, the last observation will be 
carried forward (LOCF) in order to provide a value for efficacy parameters that are missing, 
primarily due to missed visits.  Additionally, a sensitivity analysis to estimate missing efficacy 
data will be based on estimation using the method of Markov Chain Monte Carlo (MCMC) 
independently for each treatment group.  All hypotheses will be two-sided at an alpha level of 
0.05. 
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 ITT population will include all study subjects who were randomized and dispensed study 
medication.   
7.2.2 SAFETY POPULATION  
The safety population will include all randomized subjects with documented use of study 
medication (at least one application) and at least one post-baseline safety assessment.  
7.2.3 PER-PROTOCOL POPULATION 
The 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 evaluation 
of treatment efficacy).  The PP population will include subjects in the safety 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, with the exception of a discontinuation from the study due 
to an adverse event related to study treatment or documented lack of treatment effect; 
• Have missed more than one interim study visit; 
• Have not been compliant with the dosing regimen (i.e. subjects must apply 80-120% of the 
expected applications of study medication during participation in the study); 
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• Out of visit window at the Week 12 visit by ±5 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. 
7.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Subject demographic and baseline characteristics will be summarized by treatment group for the 
ITT, PP and safety populations.  For continuous variables (e.g. age), mean, median, standard 
deviation, minimum and maximum will be presented.  Categorical variables (e.g., ethnicity, race) 
will be summarized with frequency count and percentage by treatment group.  
7.4 
DESCRIPTIVE STATISTICS 
Descriptive statistics will be presented for the efficacy data at each evaluation for the ITT and PP 
populations.   Safety data will be summarized as indicated below for the safety population. 
Continuous data will be summarized with sample size (N), mean, median, standard deviation, 
minimum and maximum.  Categorical data will be summarized with N, frequency counts, and 
percentages. 
Descriptive statistics will be presented for the active treatment groups, each vehicle treatment 
group, and the vehicle treatment groups combined. 
7.5 
EFFICACY ANALYSIS  
Lesion counts will be summarized at each evaluation from Baseline through Week 12.  Absolute 
and percent change in lesion counts will be summarized at Weeks 2, 4, 8, and 12.  IGA scores 
will be summarized from Baseline through Week 12.  The dichotomized IGA scores will be 
summarized at Weeks 2, 4, 8, and 12.  
Primary Efficacy Analysis 
The analysis of the absolute change in non-inflammatory lesion counts at Week 12 will be 
conducted using an analysis of covariance with factor of treatment and baseline lesion count as 
the covariate.   
The analysis of the absolute change in inflammatory lesion counts at Week 12 will use the same 
method as the analysis of the non-inflammatory lesions. 
The analysis of the dichotomized IGA scores at Week 12 will be analyzed with a Cochran-
Mantel-Haenszel test.  
Pairwise comparisons of each active treatment group to the combined vehicle treatment group 
will be computed without concern for controlling for multiplicity. 
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Secondary Efficacy Analyses 
The analyses of percent change in inflammatory and non-inflammatory lesion counts at Week 12 
will use the same method as the analysis of the non-inflammatory lesions. 
 
The time to improvement will be compared between each of the active treatment groups and the 
combined Vehicle treatment group using the Kaplan-Meier method.  An observation will be 
censored if improvement is not achieved by Week 12 (inclusive).  The log-rank test will be used 
to compare time to response between each active treatment group and the combined Vehicle 
treatment group.   
7.5.1 SENSITIVITY EFFICACY ANALYSES 
A sensitivity analysis will use the method of Markov Chain Monte Carlo (MCMC) multiple 
imputation to impute missing data for the non-inflammatory and inflammatory lesion counts and 
IGA at Week 12.  This method does not rely on the assumption of data missing at random.  
Additionally, the pattern of missing observations in each treatment group cannot influence the 
missing value estimation in the other because the imputation is being conducted independently 
for each treatment group. 
 
Lesion Counts 
Multiple imputation and subsequent analysis will involve four distinct phases with these 
principal tasks: 
1. Calculate the number of missing values to be estimated by MCMC (nmiss) for 12 week 
value. 
2. Create a data set of subjects, one for each treatment group, with observed values and those 
needing estimation by MCMC. The missing lesion count values in each data set will be 
filled in using the MCMC method ‘5 x nmiss’ times to generate ‘5 x nmiss’ data sets.  
The resulting data sets for each treatment group will be combined into one complete data 
set for each imputation. 
Syntax: 
  
proc mi data=datain out=dataout seed=&seed. nimpute=5xnmiss;  
   where trtpn=(1, 2,, 3, 4, or 5); 
   mcmc chain=multiple; 
   var lescnt2-lescnt5; 
run; 
3. For each complete data set, the absolute change in non-inflammatory lesion counts and 
absolute change in inflammatory lesion counts for baseline minus the 12 week value will 
be computed.  Each complete data set will be analyzed as specified for the particular 
analysis. 
The results from these analyses will be combined into a single inference using SAS PROC 
MIANALYZE. 
IGA 
The sensitivity analysis for the IGA multiple imputation will involve four principal tasks: 
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1. Calculate the number of missing values, by treatment group, for IGA (total from 
Weeks 2, 4, 8, and 12). 
2. Missing values will be filled in `5 x nmiss` times to generate `5 x nmiss` complete 
data sets, where nmiss is the maximum number of missing values of both treatment 
groups.  The resulting imputed datasets for each treatment group will be combined 
into one complete dataset by imputation number. 
Syntax:   
proc mi data=datain out=dataout seed=&seed. nimpute=5 x nmiss;  
   where trtpn=(1, 2, 3, 4, or 5); 
   mcmc chain=multiple; 
   var IGA1 IGA2 IGA4 IGA8 IGA12; 
run; 
 
3. For each complete dataset, dichotomous endpoints (defined as IGA = 0 or 1 and at 
least a two-grade reduction from Baseline) will be computed.  The imputed IGA 
values will be rounded to the nearest integer value prior to computing the 
dichotomized endpoints.  Each complete data set will be analyzed with a Cochran-
Mantel-Haenszel test. 
Results from these analyses will be combined into a single inference using SAS® PROC 
MIANALYZE. 
7.6 
TOLERABILITY 
7.6.1 CUTANEOUS TOLERABILITY 
Cutaneous tolerability assessments (erythema, scaling, dryness, pruritus, burning/stinging) will 
be summarized from Baseline to Week 12 by treatment group. 
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 AEs and included in the summaries.  
All information pertaining to an AE noted during the study will be listed by subject, detailing 
verbatim term given by the PI or designee, preferred term, system organ class (SOC), onset date, 
resolution date, severity, seriousness, action taken, outcome, and drug relatedness. The event 
onset will also be shown relative (in number of days) to date of first dose.  
Treatment-emergent AEs will be summarized by treatment group, the number of subjects 
reporting a TEAE, SOC, preferred term, severity, relationship to study drug (causality), and 
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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.  Additionally, change from Baseline in vital signs will be summarized at Week 2, 4, 8, and 
12. 
7.7.4 LABORATORY ASSESSMENTS 
Blood chemistry, hematology, and PT/PTT values will be reported individually at Screening, 
Baseline, and Week 12.  Laboratory test results will be summarized descriptively at Baseline and 
Week 12.  Additionally, shifts from Baseline to Week 12 in laboratory test results based on 
normal ranges will be summarized with descriptive statistics.  The last laboratory evaluation 
prior to the first dose of study drug will be used as Baseline for all laboratory analyses. 
7.7.5 METHEMOGLOBIN  
Methemoglobin will be reported as a percentage of hemoglobin.  Methemoglobin will be 
summarized descriptively by treatment group at Baseline and Weeks 2 and 12.  Additionally, the 
change from baseline in methemoglobin will be summarized by treatment group at Weeks 2 and 
12. 
7.7.6 URINE PREGNANCY TESTS 
Urine pregnancy tests results for WOCBP will be presented in data listings by subject.   
7.8 
SAMPLE SIZE AND POWER CONSIDERATIONS 
Approximately 200 subjects will be randomized into the study in a 2:2:2:1:1 ratio (~ 50 in each 
active arm and ~25 in each vehicle arm) at approximately 20 sites in North America.  The main 
objective of this study is to evaluate the efficacy, tolerability and safety of SB204 with respect to 
vehicle.   
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8. INVESTIGATIONAL PRODUCT MANAGEMENT 
8.1 
RECEIPT OF INVESTIGATIONAL PRODUCT 
Novan, or designee, will provide all investigational products to the study sites.   
8.2 
STORAGE OF INVESTIGATIONAL PRODUCT 
Upon receipt from Novan, or Novan’s designee, a study staff member will place all study 
supplies in a temperature-controlled area.  The pumps should be refrigerated (2-8 °C).  Access to 
study supplies should be strictly limited to the study staff.  Neither the Investigator nor any 
member of the study staff will distribute any of the study supplies to any person not participating 
in this study. 
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), Novan must be contacted 
immediately.  In such an event, study supplies should not be administered to any subject until 
Novan provides further direction. 
The investigational product will be dispensed at the discretion and by the direction of the 
Investigator in accordance with the conditions specified in this protocol.  It is the Investigator’s 
responsibility to ensure that accurate records of investigational product issuance and return are 
maintained. 
It is expected that the site staff will maintain refrigerator temperature logs in the investigational 
product storage area, recording the temperature at least once each working day.  Excursions in 
temperature during storage should be discussed with QST personnel.  Other supplies will be 
stored at room temperature. 
8.3 
TREATMENT ASSIGNMENT AND BLINDING 
Subjects will be randomized to SB204 4% Gel, SB204 2% Gel, or Vehicle Gel on a 2:2:2:1:1 
through utilization of the IWRS.  The evaluator 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 
contacting the QST Medical Monitor who will arrange for the treatment assignment to be sent to 
the site by the unblinded IWRS administrator.  A study subject for whom the blind is broken will 
discontinue study product and will be scheduled for a follow up safety visit and be encouraged to 
stay in the study until the AE is resolved or stabilized.  
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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 and lot number 
• Amount currently in refrigerator, 2-8 °C storage 
• Pumps dispensed to each subject, identified by subject initials and a unique subject number  
• Amount transferred to another location within the study site or destroyed — this should not 
occur without prior notification to Novan 
• Non-study disposition (e.g., wasted, 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, 
QST, or 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.   
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 study subjects.  Only status of informed consent and assent signature, gender, 
date of birth, ethnicity, race, and reason for failure will be entered in the electronic data capture 
(EDC) system for screen failures.   
Novan and QST require that the study database be verifiable with the subject’s source study 
record.  This requirement necessitates access to all original recordings and other records for each 
subject.  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 
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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, QST Medical 
Monitor or Novan may request copies of the subject’s source study record for preliminary 
medical review.   
The Investigator must keep written or electronic source documents for every subject participating 
in the clinical study.  These records must include:  
• Name 
• Contact information 
• Date of birth 
• Sex 
• Medical history 
• Concomitant diseases 
• Concomitant therapies/medication 
• Study visit dates 
• Performed examinations, evaluations, and clinical findings 
• Investigational product administration 
• AEs, SAEs, or pregnancy (as applicable) 
Additionally, any other documents with source data must be included in the subject’s source 
documents and must include the subject’s initials, study number and the date of the evaluation.   
The data recorded during the course of the study will be documented in the study database. 
Subjects will authorize the use of their protected health information during the informed consent 
process in accordance with the applicable privacy requirements.  Subjects who deny permission 
to use and disclose protected health information will not be eligible to participate in the study.  
The Investigator will ensure that the study records forwarded to QST, Novan or their designees, 
and any other documents, contain no mention of subject names. 
Any amendments and corrections necessary will be undertaken in both the study records and the 
study database.   
Regulatory authorities, Investigational Review Boards, QST or Novan may request access to all 
study records and other study documentation for on-site audit or inspection.  The Investigator 
must guarantee direct access to these documents.  The original set of study records will be kept 
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by the site or an authorized designee in a secured area.  Clinical data will be recorded in an 
electronic format for subsequent statistical analyses.  Data files will be stored on electronic 
media with a final master data file kept by Novan after descriptive and statistical analyses and 
reports have been generated and are complete.  
9.2 
FILE MANAGEMENT AT THE STUDY SITE 
It is the responsibility of the Investigator to ensure that the study center file is maintained in 
accordance with Section 8 – Essential Documents for the Conduct of a Clinical Trial of the ICH 
Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance and 21 CFR Part 312. 
9.3 
RECORDS RETENTION AT THE STUDY SITE 
It is a Novan requirement that all Investigators participating in clinical studies maintain detailed 
clinical data for one of the following periods, whichever is longest: 
• Country-specific requirements; or 
• A period of at least two years following the last approval of a marketing application 
approved by a Regulatory Authority in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region; or, 
• A period of two years after Novan notifies the Investigator that the data will not be 
submitted for review by any Regulatory Authority. 
The Investigator must not dispose of any records or essential documents relevant to this study 
without either (1) written permission from Novan, or (2) providing an opportunity for Novan to 
collect such records.  The Investigator shall take responsibility for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated during 
this study.  Such documentation is subject to inspection by Novan and relevant regulatory 
agencies.  If the Investigator withdraws from the study (e.g., relocation, retirement), all study-
related records should be transferred to a mutually agreed-upon designee.  Notice of such 
transfer will be provided to Novan in writing.   
10. MONITORING, COMPLIANCE, AND QUALITY 
All aspects of the study will be monitored by QST or Novan according to Good Clinical 
Practices (GCP) and Standard Operating Procedures (SOPs) for compliance with applicable 
government regulations, (i.e., informed consent regulations, (21 C.F.R. § 50.20, 1999), and 
Institutional Review Board regulations, (21 C.F.R. § 56.103, 1981)).  Access to all records, both 
during the trial and after trial completion, should be made available to QST and Novan at any 
time for review and audit to ensure the integrity of the data.  The Investigator must notify QST 
immediately if the responsible IRB has been disqualified or if proceedings leading to 
disqualification have begun.   
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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 QST or 
Novan representative will review the protocol and study records with the Investigator(s) and 
their staff.  During the study, the study monitor will visit the site regularly to check the 
completeness of subject records, the accuracy of entries into the study database, the adherence to 
the protocol and to GCP, the progress of enrollment, to ensure that consent is being sought and 
obtained in compliance with applicable regulations, and that the investigational product is being 
stored, dispensed and accounted for according to specifications.  The Investigator and key trial 
personnel must be available to assist the monitor during these visits. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the study database entries.  No information in these records about the 
identity of the subjects will leave the study center.  Monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs and the recording of primary efficacy and safety variables.  Additional 
checks of the consistency of the study records with the study database will be performed 
according to the study-specific monitoring plan. 
The Investigator or designee must promptly enter the data into the study database after the 
subject’s visit.  The monitor is responsible for reviewing them and clarifying and resolving any 
data queries.  A copy of the study records will be retained by the Investigator who must ensure 
that it is stored in a secure place with other study documents, such as the protocol, the 
Investigator’s Brochure and any protocol amendments. 
The Investigator must provide QST and the responsible IRB with a study summary shortly after 
study completion. 
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 QST 
immediately that this request has been made. 
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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 QST 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, QST and Novan personnel (or their 
representatives) will be allowed full access to inspect and copy the records.  All study 
investigational products, subject bodily fluids, and/or other materials collected shall be used 
solely in accordance with this protocol, unless otherwise agreed to in writing by Novan. 
Subjects will only be identified by initials and 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 QST 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 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 
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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 QST and Novan with complete 
test results, all study data and access to all study records. 
Investigators may not report the results of this clinical study in any publication, poster or other 
public forum without express authorization from Novan.  
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15. REFERENCES  
Boylston, M.; Beer, D.  Methemoglobinemia:  A case study. Crit. Care Nurse, 2002.  22,  50-55. 
Guideline for Good Clinical Practice.  ICH Harmonised Tripartite Guideline, 1996.   
Protection of Human Subjects.  Code of Federal Regulations, Part 50, Title 21, Section 20, 1999.  
Institutional Review Boards.  Code of Federal Regulations, Part 56, Title 21, Section 103, 1981.  
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16. APPENDICES 
16.1 APPENDIX 1:  LIST OF RESTRICTED MEDICATIONS AND SUPPLEMENTS: 
• Anti-acne medications 
• Anabolic steroids 
• Azathioprine 
• Benzocaine & Cetacaine sprays  
• Bromides 
• Corticosteroids (oral) 
• Dapsone 
• EMLA Creams 
 
 
 
• Chloroquine 
• Flutamide 
• Halides 
• L-arginine 
• L-citrulline 
• Lidocaine 
• Lithium 
• Nitric oxide supplements 
• Nitrates 
• Nitric oxide 
• Nitroglycerin 
• Nitroprusside 
• Nitrous oxide 
• Phenobarbital 
• Phenytoin 
• Vitamin A (> 10,000 IU/day) 
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16.2 APPENDIX 2:  SUBJECT INSTRUCTIONS FOR APPLICATION OF STUDY 
DRUG     
 
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16.3 APPENDIX 3:  DEFINITIONS FOR IGA SCORE 
Grade 
Description 
0 
Clear: Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost clear: Few non-inflammatory lesions with no more than 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 nodular lesion. 
4 
Severe: Up to many non-inflammatory and inflammatory lesions, including nodular 
lesions 
 
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