Clinical trial NCT03927703
Conditions: Molluscum Contagiosum
Sponsor: Novan, Inc.
Start date: 2019-06-13; Completion date: 2020-02-03
Enrollment: 355 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 multi-center, randomized, double-blind, vehicle-controlled, parallel group study to be conducted in up to approximately 340 subjects ≥6 months of age with MC. Subjects or their caregivers will apply SB206 12% or Vehicle Gel once daily for a minimum of 4 weeks and up to 12 weeks to all lesions identified at Baseline and new treatable lesions that arise during the course of the study.

Detailed description:
This is a Phase 3 multi-center, randomized, double-blind, vehicle-controlled, parallel group study to be conducted in approximately 340 subjects with MC. After obtaining informed consent/assent, subjects who satisfy entry criteria will be randomized 2:1 (active:vehicle). Subjects receiving current treatment for MC at the time of the Screening Visit will enter a wash out period of up to 14 days prior to randomization.

Subjects or their caregivers will apply SB206 12% or Vehicle Gel once daily for a minimum of 4 weeks and up to 12 weeks to all lesions identified at Baseline and new treatable lesions that arise during the course of the study. Subjects or their caregivers will continue to treat the area until the next scheduled visit even if the lesion(s) clear. If the investigator determines all lesions are cleared at a clinic visit, the treatment may stop. Subjects will visit the clinic at Screening/Baseline, Week 2, Week 4, Week 8, Week 12. In addition, subjects will be seen in the clinic for a safety follow-up at Week 24.

Arms: arm 1: SB206 12% topically once daily arm 2: Placebo topically once daily
Interventions: intervention 1: SB206 12% intervention 2: Placebo
Intervention descriptions: intervention 1: Topically once daily intervention 2: Topically once daily

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
NI-MC302 Clinical Study Report 
 
 
16.1.1 Protocol and Protocol Amendments 
 
Confidential 
16  
APPENDICES 
16.1  
STUDY INFORMATION 
16.1.1 
PROTOCOL AND PROTOCOL AMENDMENTS  
 
This appendix includes 
 
Document 
Version, Date 
NI-MC302 Protocol  
Version 1.0, 26 March 2019 
 
Page 1/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium gel 
 
 
 
 
 
DRUG: 
SB206/NVN1000 
 
STUDY NUMBER(S): 
NI-MC302 
 
PROTOCOL(S) TITLE: 
A Phase 3 Multi-Center, Randomized, Double-Blind, 
Vehicle-Controlled, Parallel Group Study Comparing 
the Efficacy and Safety of SB206 and Vehicle Gel Once 
Daily in the Treatment of Molluscum Contagiosum 
IND NUMBER: 
137015 
 
SPONSOR: 
Novan, Inc. 
 
ORIGINAL PROTOCOL DATE: 
26 March 2019  
 
VERSION NUMBER: 
Version 1.0 
 
 
 
Page 2/70


Page 3/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 3 of 69
 
 
NI-MC302 
A Phase 3 Multi-Center, Randomized, Double-Blind, Vehicle-Controlled, Parallel Group 
Study Comparing the Efficacy and Safety of SB206 and Vehicle Gel Once Daily in the 
Treatment of Molluscum Contagiosum 
CONFIDENTIALITY AND INVESTIGATOR’S STATEMENT 
The information contained in this protocol and all other information relevant to SB206 are the 
confidential and proprietary information of Novan, Inc. (Novan), and except as may be required 
by federal, state or local laws or regulation, may not be disclosed to others without prior written 
permission of Novan, Inc. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations (CFR) 
for Good Clinical Practices (GCP) and International Conference on Harmonization (ICH) 
guidelines and will make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Novan, Inc. or specified designees. I will 
discuss the material with them to ensure that they are fully informed about SB206 and the study. 
 
 
___________________________________  
_________________________________ 
Principal Investigator Name (printed) 
 
Signature 
 
__________________________________  
_________________________________ 
Date 
 
 
 
 
 
 
Site Number 
Page 4/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 4 of 69
 
 
STUDY SYNOPSIS 
Title:  
A Phase 3 Multi-Center, Randomized, Double-Blind, Vehicle-Controlled, Parallel 
Group Study Comparing the Efficacy and Safety of SB206 and Vehicle Gel Once 
Daily in the Treatment of Molluscum Contagiosum 
Rationale:  
Molluscum contagiosum (MC) is spread easily by close contact and 
autoinoculation from scratching or trauma. Although a single lesion of molluscum 
contagiosum is benign and generally self-limiting to about 2 months, many cases 
have an extended infection period, up to 2 years, due to autoinoculation. There is 
a significant unmet medical need to treat MC, considering most patients with MC 
are healthy young children and the disease is highly contagious. Ablative treatment 
often causes fear in children and may interfere in physician-patient relationships; 
repeated ablative treatments are difficult. Topical application of SB206 may 
accelerate resolution of MC without causing pain and/or scarring, decrease the 
need for ablative treatment and provide an effective, safe and convenient treatment 
option for MC. 
Target 
Population
: 
Males and females, 6 months of age and older, with a minimum of 3 and a 
maximum of 70 MC lesions at Baseline. 
Number of 
Subjects: 
Approximately 340 subjects randomized. 
Objectives:  This study is being conducted to evaluate the efficacy and safety of SB206 12% 
QD for the treatment of MC.   
Dosing 
Regimen 
Subjects will apply treatment once daily to all lesions identified at Baseline and 
new lesions that arise during treatment for a minimum of 4 weeks and up to 12 
weeks. If the investigator determines all lesions are cleared at a clinic visit, the 
treatment may stop. If treatment is stopped due to clearance, subjects will continue 
regularly scheduled visits through Week 24/ET2. Each dose of SB206 will consist 
of hydrogel thoroughly mixed with berdazimer sodium gel. Each dose of vehicle 
will consist of hydrogel thoroughly mixed with vehicle gel. The subject or 
caregiver will apply to the lesions and approximately 1 cm surrounding each 
lesion. 
Periocular lesions will be treated if the lesions are at least 2 cm from the edge of 
the eye.      
Page 5/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 5 of 69
 
 
Study 
Design: 
This is a Phase 3 multi-center, randomized, double-blind, vehicle-controlled, 
parallel group study to be conducted in up to approximately 340 subjects ≥6 
months of age with MC. After obtaining informed consent/assent, subjects who 
satisfy entry criteria will be randomized 2:1 (active:vehicle). Subjects receiving 
current treatment for MC at the time of the Screening Visit will enter a wash out 
period of up to 14 days prior to randomization. In the event no wash out period is 
required, Screening and Baseline visit activities may be combined into a single 
visit. At randomization, subjects will be stratified into four strata corresponding to 
the cross-classification of household number of randomized subjects (1 subject per 
household vs 2 subjects per household) and investigator type (dermatologist vs 
other).  Households randomizing 2 subjects would receive the same treatment 
assignment for both subjects.   
Subjects or their caregivers will apply SB206 12% or Vehicle Gel once daily for 
a minimum of 4 weeks and up to 12 weeks to all lesions identified at Baseline and 
new treatable lesions that arise during the course of the study. Subjects or their 
caregivers will continue to treat the area until the next scheduled visit even if the 
lesion(s) clear. If the investigator determines all lesions are cleared at a clinic visit, 
the treatment may stop. If treatment is stopped due to clearance, subjects will 
continue regularly scheduled visits through Week 24/ET2. At Weeks 2, 4, and 8, 
the investigator will count and record the number of active (raised, treatable) 
molluscum lesions per body area. At Weeks 2, 4, and 8, the investigator will 
determine if new lesions have occurred since the last visit, and the subject or 
caregiver will be instructed by the investigator to re-initiate treatment.  
Subjects will visit the clinic at Screening/Baseline, Week 2, Week 4, Week 8, 
Week 12, and Week 24. Subjects will be contacted via phone on Day 2 to collect 
subject information on early dose reactions. At Weeks 16 and 20, subjects will be 
contacted via phone to capture information regarding MC recurrence and AEs; at 
Week 24, the subject will be seen at the site for a final study visit to assess scarring, 
keloid, and MC recurrence. Subjects who discontinue the study prior to the Week 
12 visit due to adverse events (AEs) or other reasons will be asked to complete the 
Week 12 visit assessments; this will be recorded as an Early Termination (ET1) 
visit. No study drug treatment will be provided after the Week 12 visit. Subjects 
who discontinue from the study after Week 12 but prior to Week 24 will be asked 
to come to the site to complete Week 24 assessments; this visit will be recorded as 
an ET2 visit. 
Page 6/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 6 of 69
 
 
Safety assessments include Beginning of the End (BOTE) Inflammation Scores, 
Local Skin Reactions (LSRs), adverse event collection, including scarring/keloid, 
and urine pregnancy tests (UPTs). Safety assessments will be completed at 
specified site visits through Week 12. After Week 12, safety information for 
ongoing AEs and new AEs will be collected, along with information regarding 
household MC occurrence. 
Inflammatory reactions around the MC have been associated with imminent 
resolution of MC (sometimes referred to as “beginning-of-the-end” [“BOTE”] 
sign). In most cases, clinical features can differentiate between BOTE and LSR. 
BOTE may be associated with itch, but not pain. BOTE is usually asymptomatic, 
self-limited, localized to individual MC lesions, and does not require 
discontinuation of study treatment or additional treatment. LSR is generally more 
diffuse, associated with significant itch or tenderness, may necessitate 
discontinuation of study treatment and may need treatment for symptomatic relief 
(e.g. a topical corticosteroid or topical anesthetic). For very severe LSR, systemic 
corticosteroids may be considered. Investigators will assess the treatment area at 
each scheduled visit and use their medical judgement to differentiate between 
BOTE and LSRs. BOTE Inflammation Score and LSR score will be recorded at 
each visit. BOTE should not be considered an AE. When LSRs are clinically 
significant, the Investigator should report the condition as AE(s). At Baseline (30 
min. post-dose) and Weeks 2 through Week 12, the Investigators will rate LSRs 
on individual features including erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration.  
BOTE Inflammation Score 
Score 
Global Assessment 
Description 
0 
No inflammation 
No evidence of local inflammation 
1 
Mild 
Minimal erythema and/or edema 
2 
Moderate 
Definite erythema and/or edema 
with 
or without hemorrhagic 
crusting 
3 
Severe 
Erythema and edema with definite 
hemorrhagic crusting 
Page 7/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 7 of 69
 
 
4 
Very Severe 
Strong reaction spreading beyond 
the treated area, bullous reaction, 
erosions 
LSR Score 
 
Erythema 
Flaking/ 
Scaling 
Crusting 
Swelling 
Vesiculation/ 
Pustulation 
Erosion/ 
Ulceration 
0 
Not 
present 
Not 
present 
Not 
present 
Not 
present 
Not present 
Not present 
1 
Slightly 
pink  
Mild, 
limited  
Isolated 
crusting 
Minimal, 
limited 
Fine vesicles  
Superficial 
erosion 
2 
Pink 
or 
light red 
Moderate  
Crusting    
< 50% 
Mild, 
palpable  
Scant 
transudate or 
exudate  
Moderate 
erosion 
3 
Red, 
restricted 
to 
treatment 
area 
Coarse 
Crusting    
> 50% 
Moderate 
Moderate 
transudate or 
exudate  
Marked, 
extensive 
4 
Red 
extending 
outside 
treatment 
area 
Scaling 
extending 
outside 
treatment 
area 
Crusting 
extending 
outside 
treatment 
area 
Marked 
swelling 
extending 
outside 
treatment 
area 
Marked 
transudate or 
exudate  
Black 
eschar 
or 
ulceration 
Clinically significant LSRs that are reported as adverse events and/or subject 
reported intolerability (i.e. itching, pain) may result in an investigator directed 
temporary treatment hold (drug holiday), and topical corticosteroids may be used 
to treat LSRs for up to 2 weeks. The subject may re-initiate study drug treatment 
prior to the next scheduled visit. Upon re-initiation of study drug treatment, if a 
subject develops worsening LSRs, allergic contact dermatitis may be suspected. 
The investigator may take photographs of the suspected allergic contact dermatitis 
and discuss possible confirmation of allergic contact dermatitis with the CRO 
medical monitor. The investigator should also discuss necessity of patch testing 
with the subject/caregiver. The investigator will then discontinue the subject from 
study drug treatment and treat the area(s) with corticosteroids for up to 2 weeks. 
If the subject provides consent/assent, the investigator will consult the contract 
Page 8/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 8 of 69
 
 
research organization (CRO) medical monitor to implement the process for patch 
testing.  
Adverse events will be assessed and collected after the initiation of study drug 
treatment through the end of the subject’s last visit. Treatment related adverse 
events will be followed up until resolution or up to one year after last treatment, 
whichever is sooner.  
Scar formation will be assessed starting at the Week 4 visit through Week 12 and 
again at Week 24. The investigator will map locations of the molluscum lesions at 
Baseline. Additional lesions identified through Week 12 will be added to the map. 
Using the map as a guidance, the investigator will assess the treated areas for 
scar/keloid formation. The investigator will count and record the number of active 
(raised, treatable) molluscum lesions per body area. If a scar is larger than 5mm in 
diameter and/or larger than 1 mm deep, this will be considered an adverse event 
for the purposes of this study. In addition, keloid/hypertrophic scars will also be 
recorded as adverse events. Any scars <5mm in diameter and/or <1mm deep will 
not be considered AEs since these are considered part of the normal healing. 
If a subject’s treatment is discontinued by the investigator or the subject because 
of an AE, that AE should be indicated as the reason for treatment discontinuation. 
All subjects will be encouraged to remain in the study throughout the 24-week 
study duration. 
In the event of suspected allergic contact dermatitis, photographs may be taken of 
the affected area(s) and transmitted to the CRO medical monitor for review prior 
to initiating patch testing. Photography is not a protocol requirement and subjects 
must have documented consent for photographs to be taken.  
When approximately 200 subjects (cumulative across studies MC301 and MC302) 
have completed 4 weeks of treatment, a Data Safety Monitoring Board (DSMB) 
will review all available unblinded safety data (including patch testing). 
Inclusion / 
Exclusion 
Criteria: 
Inclusion Criteria: 
1. Be 6 months of age or older, and in good general health; 
2. Have a written informed consent form signed by subject or a parent or legal 
guardian and an assent form as required;  
3. Have between 3 and 70 treatable MC at Baseline; 
Page 9/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 9 of 69
 
 
4. Female subjects age 9 and above must have a negative UPT at Baseline; 
5. Female subjects age 9 and above must agree to practice a medically 
acceptable form of birth control during the study and for 30 days after 
Week 12/ET1; 
6. Be willing and able to follow study instructions and likely to complete all 
study requirements. 
Exclusion Criteria: 
1. Have strongly suggested sexually transmitted MC and do not agree to 
refrain from sexual activities throughout the study period. 
2. Are immunosuppressed, have immunodeficiency disorder, or are on 
immunosuppressive treatment; 
3. Have significant injury on and/or surrounding MC that may impact ability 
to treat and count lesions; 
4. Have received treatment with topical calcineurin inhibitors or steroids on 
MC or within 2 cm of MC lesions within 14 days prior to Baseline; 
5. Have received treatment for MC during the 14 days prior to Baseline with 
podophyllotoxin, imiquimod, cantharidin, sinecatechins, topical retinoids, 
oral or topical zinc, or other homeopathic or over the counter (OTC) 
products including, but not limited to, ZymaDerm and tea tree oil, 
cimetidine and other histamine H2 receptor antagonists (including Zantac);  
6. Have received surgical procedures related to MC (cryotherapy, curettage, 
other) within 14 days prior to Baseline; 
7. Have MC only in periocular area; 
8. Female subjects who are pregnant, planning a pregnancy or breastfeeding; 
9. Have known hypersensitivity to any ingredients of SB206 or Vehicle Gel 
including excipients; 
10. Have participated in a previous study with a berdazimer sodium product 
(SB204, SB206, SB208, SB414); 
Page 10/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 10 of 69
 
 
11. Have more than 1 family member currently participating in a study with a 
berdazimer sodium product (SB204, SB206, SB208, SB414). 
12. Have participated in any other trial of an interventional investigational drug 
or device within 14 days or concurrent participation in another 
interventional research study. 
13. History or presence of clinically significant medical, psychiatric, or 
emotional condition that, in opinion of the investigator, would compromise 
the safety of the subject or the quality of the data. 
 
Primary 
Endpoint: 
• Proportion of subjects with complete clearance of all treatable MC at Week 
12 
 
Secondary 
Endpoint: 
• Proportion of subjects with complete clearance of all treatable MC at Week 
8 
 
Exploratory 
endpoints: 
• Proportion of subjects who have a recurrence of MC after the first visit at 
which complete clearance was observed  
• Proportion of subjects developing scar(s) after clearance of lesion(s) at each 
visit (Weeks 4, 8, 12, 24) 
• Proportion of subjects with complete clearance of all treatable MC at each 
visit (Weeks 2, 4) 
• Proportion of subjects achieving at least a 75% reduction from Baseline in 
the number of all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Change from baseline of the composite score from age-matched (at baseline) 
Dermatology Life Quality Index (DLQI) assessment at Week 12 
• Subject-reported spread to household members as measured by any new 
occurrence of MC in household members of subjects at each visit (Weeks 2, 
4, 8, 12) 
• Mean change from Baseline in number of treatable MC at each visit (Weeks 
2, 4, 8, 12) 
• Mean percent change from Baseline in number of treatable MC at each visit 
(Weeks 2, 4, 8, 12) 
Page 11/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 11 of 69
 
 
• Time to complete clearance of all treatable MC 
Statistics: 
Statistical Methods 
Safety and efficacy endpoints will be displayed using descriptive statistics and 
graphical displays, where applicable. For categorical variables, frequencies, and 
percentages will be presented. The denominators for percentages will be based on 
the number of subjects appropriate for the purpose of analysis. Continuous 
variables will be summarized using descriptive statistics (number of subjects, 
mean, median, standard deviation (SD), minimum, and maximum). Where 
relevant, 95% confidence intervals will be calculated. All statistical tests of the 
primary and secondary endpoints will be conducted at the 0.05 significance level 
using 2-tailed tests. Nominal p-values will be reported for treatment comparisons 
of the exploratory endpoints.  
The study treatment period is defined from randomization through completion of 
Week 12/ET1 visit and the safety follow-up period is from the completion of Week 
12 through the completion of Week 24/ET2 visit. 
The analysis populations include the following: 
Safety Population (SAF): The Safety population will consist of all subjects who 
receive at least one application of study medication. 
Intent-To-Treat Population (ITT): The ITT population will consist of all 
subjects who are randomized. 
Per-Protocol Population (PP): The PP population will consist of all subjects in 
the ITT population who had no significant protocol deviations that impacted the 
analyses of the efficacy endpoints. 
The primary efficacy endpoint, proportion of subjects with complete clearance of 
all treatable molluscum lesions at Week 12 in the ITT, will be analyzed using a 
generalized estimating equation (GEE) for logistic regression with an 
exchangeable working correlation structure. The model will include treatment, 
investigator type (dermatologist vs other), household number of randomized 
subjects (1 subject per household vs 2 subjects per household), age and Baseline 
lesion count as factors. The odds ratio between SB206 12% and vehicle gel, 95% 
CIs for the odds ratio, and P-value for the covariate-adjusted treatment comparison 
will be presented. Only subjects who achieve complete clearance at Week 12 will 
be counted as responders for the primary analysis; all other subjects (e.g., those 
Page 12/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 12 of 69
 
 
who discontinue the study before achieving complete clearance) will be reported 
as failures. As a sensitivity analysis, the primary efficacy analysis will also be 
reported for the PP population. 
 
The familywise error rate with respect to the primary endpoint and secondary 
endpoint will be strongly controlled at the alpha=0.05 level using a fixed-sequence 
method testing strategy. If the primary endpoint is not statistically significant at 
the alpha=0.05 level, the secondary efficacy endpoint will be considered not 
significant. If the primary endpoint is statistically significant at the alpha=0.05 
level, the secondary efficacy endpoint will be analyzed. 
• Proportion of all study subjects demonstrating complete clearance of all 
treatable MC at Week 8 
If the secondary efficacy endpoint fails to reach statistical significance at the 
alpha=0.05 level, it will be considered not statistically significant.  
The dichotomous secondary efficacy endpoint will be analyzed using the GEE 
model described for the primary efficacy endpoint.  The analyses methods to be 
used for the exploratory endpoints will be detailed in the Statistical Analysis Plan 
(SAP). 
All safety and tolerability analyses will be based on the SAF population. 
All AEs that occur during the study will be recorded and coded using Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-
emergent AEs (TEAEs) are defined as AEs that occurred any time on or after the 
first in-clinic application of study drug through the last application of study 
medication. 
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 adverse events (SAEs) 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. 
Urine pregnancy tests results for females 9 years old and older will be presented 
in data listings by subject.  
Page 13/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/berdazimer sodium  
Page 13 of 69
 
 
Sample Size Estimation 
The sample size assumptions for this study were informed by the completed Phase 
2 study NI-MC201 of subjects ≥2 years of age with 3-70 MC lesions at Baseline.  
In the ITT population of the Phase 2 study, the observed rates of clearance at Week 
12 were 18% (12/66) for vehicle and 38% (18/48) for SB206 12% once daily (QD) 
and the covariate-adjusted treatment difference was 18%.  
Approximately 340 subjects, 6 months of years of age and older, with a minimum 
of 3 and a maximum of 70 lesions at Baseline will be randomized in a 2:1 
(active:vehicle) scheme.  
A sample size of 340 subjects (227 subjects in the SB206 12% QD group and 113 
subjects in the vehicle group) will provide 94% power for a 2-sided alpha test of 
size 0.05 to detect an absolute difference of 18% when the vehicle response rate is 
18%. This same sample size provides 93% power to detect a treatment difference 
of 18% when the vehicle response rate is 20% and 83% power when the treatment 
difference is 15% and the vehicle response rate is 20%.   
Page 14/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 14 of 69
 
 
 
TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM .............................................................2 
CONFIDENTIALITY AND INVESTIGATOR’S STATEMENT ................................3 
STUDY SYNOPSIS ...........................................................................................................4 
TABLE OF CONTENTS ................................................................................................14 
LIST OF TABLES ...........................................................................................................17 
LIST OF ABBREVIATIONS .........................................................................................18 
1 
INTRODUCTION AND RATIONALE .................................................................20 
1.1 
Background ..........................................................................................................20 
1.1.1 
Preclinical Pharmacology ..............................................................................21 
1.1.2 
Pharmacokinetics ...........................................................................................22 
1.1.3 
Potential for Drug-Drug Interactions ..........................................................23 
1.1.4 
Clinical Adverse Event Profile ......................................................................23 
1.1.5 
Elevations in Liver Function Tests ...............................................................24 
1.1.6 
Potential Risk of Testicular Injury ...............................................................24 
1.1.7 
Potential Risk to Fetal Development ............................................................24 
1.2 
Study Rationale ....................................................................................................24 
1.2.1 
Dosing Regimen ..............................................................................................25 
1.2.2 
Dose Selection Rationale................................................................................25 
2 
STUDY OBJECTIVE ...............................................................................................26 
3 
STUDY ENDPOINTS ..............................................................................................26 
3.1 
Primary Efficacy Endpoint .................................................................................26 
3.2 
Secondary Efficacy Endpoint..............................................................................26 
3.3 
Exploratory Endpoints ........................................................................................26 
3.4 
Safety Endpoints ..................................................................................................27 
4 
STUDY PLAN ...........................................................................................................27 
4.1 
Study Design .........................................................................................................27 
5 
POPULATION ..........................................................................................................33 
5.1 
Number of Subjects..............................................................................................33 
5.2 
Inclusion Criteria .................................................................................................33 
5.3 
Exclusion Criteria ................................................................................................33 
5.4 
Subject Screening .................................................................................................34 
5.4.1 
Screening Failures ..........................................................................................35 
5.5 
Deviation from Inclusion/Exclusion Criteria ....................................................35 
6 
STUDY CONDUCT..................................................................................................35 
6.1 
General Instructions ............................................................................................35 
6.2 
Study Procedures by Time Point ........................................................................36 
6.2.1 
Screening (Day-14 to Day 1)..........................................................................36 
6.2.2 
Visit 1/Baseline (Day 1) ..................................................................................36 
6.2.3 
Visit 2/Day 2 Telephone Contact ..................................................................37 
6.2.4 
Visit 3/Week 2 (Day 15 ±3) ............................................................................37 
6.2.5 
Visit 4/Week 4 (Day 29 ±5) ............................................................................38 
6.2.6 
Visit 5/Week 8 (Day 57 ±5) ............................................................................38 
Page 15/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 15 of 69
 
 
 
6.2.7 
Visit 6/Week 12/ET (Day 85 ±5) ...................................................................39 
6.2.8 
Visit 7/Week 16 and Visit 8/Week 20 (Day 113 +/- 7 days; Day 141 +/- 7 
days) ................................................................................................................39 
6.2.9 
Visit 9/Week 24 (Day 169 +/- 7 days) ............................................................40 
6.3 
Discontinuation ....................................................................................................40 
6.3.1 
Treatment Discontinuation ...........................................................................40 
6.3.2 
Study Discontinuation ...................................................................................41 
7 
DESCRIPTION OF STUDY PROCEDURES .......................................................42 
7.1 
Efficacy Assessments ...........................................................................................42 
7.1.1 
Molluscum Contagiosum Lesion Counts .....................................................42 
7.1.2 
Dermatology Life Quality Index (DLQI) .....................................................43 
7.2 
Safety Assessments ...............................................................................................44 
7.2.1 
Physical Exam ................................................................................................44 
7.2.2 
Pregnancy Testing ..........................................................................................44 
7.2.3 
BOTE Inflammation Score ...........................................................................44 
7.2.4 
Local Skin Reaction Score.............................................................................45 
7.2.5 
Patch Testing ..................................................................................................46 
7.2.6 
Scarring/Keloid Assessment ..........................................................................47 
7.3 
Protocol Deviations ..............................................................................................47 
8 
STUDY DRUG MANAGEMENT ...........................................................................48 
8.1 
Description ............................................................................................................48 
8.1.1 
Formulation ....................................................................................................48 
8.1.2 
Storage ............................................................................................................48 
8.2 
Packaging and Shipment .....................................................................................49 
8.3 
Method of Assigning Subjects to Treatment Groups .......................................49 
8.4 
Blinding and Unblinding Treatment Assignment .............................................49 
8.5 
Dose and Administration .....................................................................................50 
8.6 
Accountability ......................................................................................................50 
8.7 
Prohibited Concomitant Medication/Therapy ..................................................51 
8.8 
Compliance ...........................................................................................................51 
9 
ADVERSE EVENTS ................................................................................................51 
9.1 
Documenting Adverse Events .............................................................................52 
9.2 
Assessment of Severity .........................................................................................52 
9.3 
Assessment of Causality ......................................................................................52 
9.4 
Adverse Event Follow-up ....................................................................................54 
9.4.1 
Follow-Up of Non-Serious Adverse Events..................................................54 
9.4.2 
Follow-Up of Post Study Serious Adverse Events .......................................54 
9.5 
Pregnancy .............................................................................................................55 
9.6 
Overdose ...............................................................................................................56 
10 SERIOUS ADVERSE EVENT ................................................................................56 
10.1 
Definition of Serious Adverse Event ..................................................................56 
10.2 
Reporting Serious Adverse Events .....................................................................57 
11 STATISTICS .............................................................................................................58 
11.1 
General Procedures .............................................................................................58 
11.2 
Sample Size ...........................................................................................................59 
Page 16/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 16 of 69
 
 
 
11.3 
Analysis Populations ............................................................................................59 
12 Statistical Methods ....................................................................................................60 
12.1.1 
Demographic and Baseline Characteristics .................................................60 
12.1.2 
Efficacy Analysis ............................................................................................60 
12.1.3 
Analysis of Safety ...........................................................................................61 
13 ETHICS AND RESPONSIBILITIES .....................................................................61 
13.1 
Good Clinical Practice .........................................................................................61 
13.2 
Data Safety Monitoring Board (DSMB) ............................................................62 
13.3 
Institutional Review Board/Independent Ethics Committee ...........................62 
13.4 
Informed Consent ................................................................................................62 
13.5 
Records Management ..........................................................................................63 
13.6 
Source Documentation.........................................................................................63 
13.7 
Study Files and Record Retention ......................................................................63 
14 AUDITING AND MONITORING ..........................................................................64 
14.1 
Auditing ................................................................................................................64 
14.2 
Monitoring ............................................................................................................64 
15 AMENDMENTS .......................................................................................................65 
16 STUDY REPORT AND PUBLICATIONS ............................................................65 
17 STUDY DISCONTINUATION ...............................................................................66 
18 CONFIDENTIALITY ..............................................................................................66 
19 REFERENCES .........................................................................................................66 
20 APPENDICES ...........................................................................................................67 
20.1 
APPENDIX I Names of Study Personnel...........................................................67 
20.2 
APPENDIX II Procedure for Suspected Sensitization .....................................68 
 
 
 
Page 17/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 17 of 69
 
 
 
LIST OF TABLES 
Table 1: Schedule of Assessments ...................................................................................31 
Table 2: Grading System for Patch Test Reactions ......................................................69 
Table 3: Challenge Reaction Interpretation ..................................................................69 
 
 
 
Page 18/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 18 of 69
 
 
 
LIST OF ABBREVIATIONS 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
BID 
BOTE 
BSA 
CDLQI 
Twice Daily 
Beginning-of-the-end 
Body Surface Area 
Children’s Dermatology Life Quality Index 
CFR 
CIOMS 
Code of Federal Regulations 
Council for International Organizations of Medical Sciences 
CRO 
DLQI 
Clinical Research Organization 
Dermatology Life Quality Index 
DSMB 
ECG 
EGW 
Data and Safety Monitoring Board 
Electrocardiogram 
External Genital Wart 
eCRF 
ET 
Electronic Case Report Form 
Early Termination 
FDA 
Food and Drug Administration 
GEE 
Generalized Estimating Equation 
GCP 
Good Clinical Practice 
hMAP3 
Hydrolyzed N-Methylaminopropyl-trimethoxysilane 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Page 19/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 19 of 69
 
 
 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IWRS 
LLOQ 
Interactive Web Response System 
Lower Limit of Quantitation 
MC 
Molluscum Contagiosum 
MedDRA 
MMRM 
NOAEL 
Medical Dictionary of Regulatory Affairs 
Mixed-model Repeated Measures 
No Observed Adverse Effect Level 
NOVAN 
OTC 
PAW 
PK 
Novan, Inc. 
Over-the-counter 
Perianal Wart 
Pharmacokinetic 
PP 
Per-Protocol Population 
QD 
Once Daily 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
SD 
Statistical Analysis Plan 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Events 
UPT 
 
Urine Pregnancy Test 
 
Page 20/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 20 of 69
 
 
 
1 INTRODUCTION AND RATIONALE 
1.1 
Background 
Molluscum contagiosum (MC) is a common skin disorder that aﬀects mainly healthy children 
(Dohil et al, 2006). MC has the greatest incidence in individuals aged 1–14 years (Schofield et al, 
2011); prevalence in children is between 5% and 11% (Olsen et al, 2014).  
MC virus is an important human skin pathogen and can cause disﬁgurement and suffering in 
children. In adults MC is less common and often sexually transmitted. Extensive and persistent 
skin infection with the virus can indicate underlying immunodeﬁciency. MC virus is distinct from 
other poxviruses because of its host and tissue adaptations. It infects only the skin and, rarely, the 
mucous membranes. The virus has developed efficient mechanisms to grow in differentiating cells 
of the human epidermis and is well adapted to human hosts (Chen et al, 2013).  
Extensive and persistent skin infection with the virus can indicate underlying immunodeficiency. 
Patients with atopic dermatitis (AD) have an impaired skin barrier in addition to immunological 
changes which could explain the rising prevalence and high number of lesions in this population. 
Topical corticosteroids and calcineurin inhibitors (both local immunosuppressants commonly 
applied to the skin in patients with atopic dermatitis) have been implicated as contributing factors 
in some patients (Osio et al, 2011). 
MC is transmitted between human hosts by the infectious matter discharged from the lesions. 
According to a prospective community cohort study (Olsen et al, 2015), the mean time to 
resolution was 13.3 months (SD 8.2). Eighty (30%) of 269 cases had not resolved by 18 months; 
36 (13%) had not resolved by 24 months. Transmission to other children in the household occur 
in 102 (41%) of 250 cases in the literature.  
Novan has conducted Study NI-MC201, a phase 2, multi-center, double-blind, vehicle-controlled 
ascending dose, 12-week study to assess the tolerability, safety, and efficacy of SB206 in subjects 
with molluscum contagiosum. In this study, the safety and efficacy of SB206 was evaluated in 256 
subjects, males or females, 2 years of age or older, with 3 to 70 MC lesions. Different 
concentrations and dosing frequency of SB206 was tested for up to 12 weeks and the number of 
the subjects of each dose group were: 47 (4% BID), 48 (8% BID), 47 (12% BID), 48 (12% QD) 
and 66 (Vehicle).   
 
The primary endpoint for Study NI-MC201 was the proportion of subjects in the modified intent-
to-treat population who achieved complete clearance of all MC lesions at Week 12. In this analysis, 
8% BID and 12% QD groups of SB206 were statistically significantly superior to vehicle in the 
proportion of subjects with complete clearance at Week 12: 20.0% (vehicle BID/QD combined), 
41.0% (8% BID: p=0.028), and 41.9% (12% QD: p=0.024). The 4% BID (13.2%, p=0.518) and 
Page 21/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 21 of 69
 
 
 
12% BID (35.1, p=0.144) were not statistically superior. The efficacy signals appeared as early as 
2-4 weeks. In the intent-to-treat (ITT) analysis, 37.5% of subjects achieved complete clearance 
when treated with SB206 12% QD, compared to 18.2% of subjects achieving complete clearance 
with vehicle BID/QD combined (p=0.024).  The ITT results will be the basis for the sample size 
criteria used in MC301. 
Based on the clear treatment effect shown by the proportion of subjects achieving complete 
clearance of all molluscum lesions at Week 12 for SB206 12% once-daily, and favorable safety 
and tolerability profiles, Novan, Inc. (Novan) is conducting this Phase 3 multi-center, randomized, 
double-blind, vehicle-controlled, parallel group study of SB206 in subjects 6 months of age and 
older with molluscum contagiosum. SB206 is a topical gel, formed by mixing berdazimer sodium 
(NVN1000) gel with hydrogel. Berdazimer sodium gel contains berdazimer sodium, a nitric oxide-
releasing macromolecule containing covalently bound N-diazeniumdiolate nitric oxide donors; 
nitric oxide release from the macromolecule is initiated by mixing berdazimer sodium gel with 
hydrogel. 
Topical formulations of berdazimer sodium at concentrations ranging from 1-16% have been 
studied.  Over 1600 healthy volunteers or subjects with MC, acne, genital warts or tinea pedis have 
been exposed to Vehicle and over 2700 exposed to berdazimer sodium as of December 31, 2018. 
In clinical studies completed to date, topical application of berdazimer sodium has generally been 
well-tolerated with no safety concerns identified. 
1.1.1 
Preclinical Pharmacology 
During the development of SB204 (berdazimer sodium gel co-administered with hydrogel) for 
acne, SB206 (berdazimer sodium gel co-administered with hydrogel) for the treatment of external 
genital warts and perianal warts, SB208 (berdazimer sodium gel co-administered with hydrogel) 
for tinea pedis and SB414 (berdazimer sodium ointment co-administered with hydrogel), Novan 
has conducted over 90 nonclinical studies. In addition, specifically for SB206, Novan completed 
a 4-week daily dosing with 2-week recovery GLP dermal bridging study in miniature swine. Under 
the conditions of this study, the No Observed Adverse Effect Level (NOAEL) was considered to 
be greater than the nominal dose level evaluated (~48 mg/kg/day berdazimer sodium which 
equates to approximately 1.7 mg/cm2/day), administered as BID 8% SB206 Gel or QD 12% SB206 
Gel. There were no meaningful effects on mortality/moribundity, clinical observations, physical 
examination findings, food consumption, weekly body weight or weekly body weight change, 
clinical pathology parameters, ophthalmologic or electrocardiographic examinations, or organ 
weight findings. Microscopic changes, limited to the superficial dermis and epidermis, were 
minimal to mild but had not completely resolved following the 2-week recovery period. The 
induced changes included hyperkeratosis, epidermal hyperplasia and mononuclear dermal 
inflammation (mononuclear cell infiltration and dermal edema). Due to an insufficient number of 
plasma samples with quantifiable hydrolyzed n-methylaminopropyl-trimethoxysilane (hMAP3) 
Page 22/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 22 of 69
 
 
 
concentrations (values above the LOQ of 5 ng/mL), it was not possible to perform a 
noncompartmental TK analysis. There was no evidence of systemic nitric oxide exposure at any 
of the dose levels tested. This study with SB206 in miniature swine was successful in bridging the 
safety of topical administration of berdazimer sodium in the SB204 formulation with the SB206 
formulation. 
For additional information refer to the Investigator’s Brochure (IB). 
1.1.2 
Pharmacokinetics 
The systemic bioavailability of berdazimer sodium after dermal administration has been 
investigated in two maximal use studies in adults and adolescent subjects with moderate to severe 
acne vulgaris, and no quantifiable systemic exposure was observed. In adult subjects with 
moderate to severe acne vulgaris (NI-AC101) administration of SB204 8% (berdazimer sodium 
gel 16% co-administered with hydrogel) or Vehicle Gel daily for 5 days to the face, chest, back, 
upper shoulders twice daily (BID) (17% body surface area [BSA]) showed no detectable systemic 
exposure on Day 1 or Day 5 to hydrolyzed N-methylaminopropyl-trimethoxysilane (hMAP3), a 
silicon containing component of the parent compound. There was no noticeable difference in 
systemic nitrate levels on Day 1 or Day 5 in subjects treated with SB204 or Vehicle Gel and no 
evidence of accumulation. Likewise, in an open-label pharmacokinetic (PK), study (NI-AC103) 
in adolescents (ages 9-16 years) with moderate to severe acne vulgaris topical administration of 
SB204 4% was applied once daily (QD) for 21 days to 17% BSA and again no detectable systemic 
exposure to hMAP3 and no plasma nitrate concentrations outside of normal variability and 
negligible accumulation of nitrate after 21 days of dosing.  
Additionally, 
in 
a 
4-way, 
randomized, 
double-blind, 
cross-over 
study 
examining 
electrocardiogram (ECG) effects following SB204 application (NI-AC104), there was no 
quantifiable systemic exposure to hMAP3 and no difference in plasma nitrate levels in 48 subjects 
with moderate to severe acne treated with SB204 (berdazimer sodium) 4%, SB204 (berdazimer 
sodium) 12% or Vehicle Gel applied to 17% BSA. No changes in ECG were observed with 
therapeutic or supratherapeutic doses of SB204. 
In a 2-week atopic dermatitis (AD) study (NI-AD101), and a 4-week psoriasis (NI-PS101) study, 
a limited number of subjects who received SB414 6% (berdazimer sodium ointment 12% co-
administered with buffered hydrogel) demonstrated quantifiable systemic exposure to the study 
treatment at limited time points. Although both SB206 and SB414 have the same active 
pharmaceutical ingredient, the formulations are different: SB206 is a gel and SB414 is a cream. 
The cream formulation of SB414 resulted in low and not quantifiable systemic exposure to hMAP3 
observed in the NI-AD101 and NI-PS101 studies for all but 2 subjects at 12 hours post-dose. Note 
that SB414 formulation is cream while SB204 formulation is gel, similar to SB206.   
Page 23/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 23 of 69
 
 
 
In the NI-MC201 study, plasma hMAPs concentrations in all PK blood samples at Week 12 or end 
or treatment were below the lower limit of quantitation (LLOQ). 
1.1.3 
Potential for Drug-Drug Interactions 
Since no quantifiable exposure has been observed to date with SB204 and SB206 clinically, the 
risk of drug-drug interactions is low. 
1.1.4 
Clinical Adverse Event Profile 
As of December 31, 2018, topical formulations of berdazimer sodium at concentrations ranging 
from 1% to 16% have been studied in 21 completed studies. Almost 1600 healthy volunteers or 
subjects with acne, genital warts, tinea pedis, psoriasis and atopic dermatitis have been exposed to 
Vehicle and over 2700 exposed to berdazimer sodium. 
Novan completed a Phase 2 ascending dose study of SB206 in 256 subjects with MC. No deaths 
or serious adverse events (SAEs) occurred during this study. Seven subjects were discontinued 
from treatment with the study drug due to an AE, all in active treatment groups (3 subjects in the 
4% BID group; 2 in the 8% BID group; and 2 in the 12% BID group). Treatment discontinuation 
was due to application site reactions in 6 of these subjects and to worsening MC in the other. The 
active study drug (SB206) given at doses ranging from 4% BID to 12% QD was well tolerated. 
Most AEs were mild to moderate. The only AEs that appeared to be clearly associated with SB206 
were those involving administration site reactions. 
Novan completed a Phase 2 ascending dose study assessing the tolerability, safety, and efficacy of 
SB206 in subjects with external genital warts (EGW) and perianal warts (PAW). In this study, 
there were no safety concerns with single daily dose application; BID application of SB206 to the 
genitalia was associated with local application site reactions in some subjects which led to 
treatment discontinuation. The results of this study are supportive of the continued clinical 
development of SB206. 
SB204 is in development for the treatment of acne vulgaris. The acne clinical program for SB204 
includes 9 completed Phase 1 studies in healthy volunteers or subjects with acne vulgaris, 3 
completed Phase 2 studies, and the completed Phase 3 program (two 12-week placebo-controlled 
studies and one 40-week open label long-term safety study in subjects ages 9 years old and older). 
Based on the clinical data acquired to date, topical application of berdazimer sodium to healthy 
volunteers or subjects with acne vulgaris has generally been well-tolerated with no safety concerns 
identified. 
Novan has also completed a study in subjects with tinea pedis using SB208. There were no safety 
concerns identified with QD dosing to one or both feet; there were no application site AEs reported. 
Page 24/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 24 of 69
 
 
 
Novan has completed two studies in subjects with atopic dermatitis and psoriasis using SB414. In 
both studies, SB414 was generally well tolerated and the incidence of treatment-related treatment-
emergent adverse events (TEAEs) was low. Administration site reactions were the most common 
treatment-related adverse events and tolerability (change in itch and burning/stinging) was similar 
across treatment groups. There was no evidence of meaningful trends in safety parameters. In 
completed studies, no clinically significant changes have been observed in laboratory assessments 
in subjects treated with topical berdazimer sodium. There have been no clinically significant 
changes in physical examination, including vital signs, in subjects treated with topical berdazimer 
sodium. 
1.1.5 
Elevations in Liver Function Tests 
No clinically significant changes have been observed in laboratory assessments. 
1.1.6 
Potential Risk of Testicular Injury 
In a nonclinical GLP study of fertility and early embryonic development in rats after daily oral 
administration of berdazimer sodium there was no adverse findings in male fertility parameters or 
reproductive parameters in either sex. 
Additionally, since no quantifiable exposure has been observed to date after dermal administration 
of SB204 and SB206 clinically, the risk of testicular injury is low. 
1.1.7 
Potential Risk to Fetal Development 
Oral administration of berdazimer sodium drug substance in GLP embryo-fetal developmental 
toxicity studies in rats and rabbits showed minor effects on fetal development only at the highest 
doses. 
Additionally, due to the lack of systemic exposure after dermal administration of SB204 clinically 
and SB206 clinically observed to date, the risk to fetal development is low. 
In prior studies using berdazimer sodium in different diseases, there have been 6 reported 
pregnancies; of those, two were completed to term with healthy babies. One woman had an elective 
termination of her pregnancy and one woman had a miscarriage. The outcome of the other two 
pregnancies is unknown.  
1.2 
Study Rationale 
MC is benign and generally self-limiting. The average duration of a single lesion is about 2 months; 
however, since the lesions spread easily by autoinoculation from scratching or trauma, the mean 
duration of infection is often more than a year. 
Page 25/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 25 of 69
 
 
 
Nitric oxide, an endogenous small molecule, provides localized immunity against foreign 
organisms by acting both as a short-lived immune modulator and a direct broad-spectrum 
antimicrobial agent. Topical exogenous nitric oxide has been investigated as an antimicrobial agent 
due to its broad-spectrum activity, ability to inhibit viral replication, and the ability to readily 
diffuse through cell membranes. 
There is a significant unmet medical need to treat MC, considering most patients with MC are 
healthy young children. Ablative treatment often causes fear to the children and interferes in 
physician-patient relationships. Repeated ablative treatments are difficult. Using anesthesia 
involves safety risk and costs. Not treating increases the potential of further dissemination of the 
disease. Prevention of further dissemination of the disease is also important from a public health 
perspective. Topical application of SB206 may accelerate resolution of MC without causing pain 
and/or scarring, decrease the frequency of ablative treatment, and provide an effective, convenient 
treatment option for patients with MC.  
1.2.1 
Dosing Regimen 
Subjects will apply treatment once daily to all lesions identified at Baseline and new lesions that 
arise during treatment for a minimum of 4 weeks and up to 12 weeks. Each dose of SB206 will 
consist of hydrogel thoroughly mixed with berdazimer sodium gel. Each dose of vehicle will 
consist of hydrogel thoroughly mixed with vehicle gel. Subjects will be instructed on the correct 
use of study drug and the amount to apply during Baseline/Day 1 according to the corresponding 
subject instructions for use that will be provided to the subject. In addition, study personnel will 
ensure that the subjects or caregivers can identify the treatment area(s) and know where and how 
to apply the study drug. Dosing should be applied at home, except on the day of study visits when 
the dose should be applied in the clinic. The subject, caregiver, or study personnel will apply to 
the lesions and approximately 1 cm surrounding each lesion. Periocular lesions will be treated if 
the lesions are at least 2 cm from the edge of the eye.  
If the investigator determines all lesions are cleared at a clinic visit, the treatment may stop. At 
Weeks 2, 4, and 8, the investigator will determine if new lesions have occurred since the last visit, 
and the subject or caregiver will be instructed by the investigator to re-initiate treatment. If 
treatment is stopped due to clearance, subjects will continue regularly scheduled visits through 
Week 24/ET2. Subjects will be followed for recurrence/new lesions until Week 24. For the purpose 
of this study, a recurrence of MC will be documented as an AE. 
1.2.2 
Dose Selection Rationale 
Novan completed a Phase 2 ascending dose study of SB206 in 256 subjects with MC. The primary 
endpoint for Study NI-MC201 was the proportion of subjects in the modified intent-to-treat 
population who achieved complete clearance of all MC lesions at Week 12. In this analysis, 8% 
Page 26/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 26 of 69
 
 
 
BID and 12% QD groups of SB206 were statistically significantly superior to vehicle in the 
proportion of subjects with complete clearance at Week 12: 20.0% (vehicle BID/QD combined), 
41.0% (8% BID: p=0.028), and 41.9% (12% QD: p=0.024). The difference in proportion (95% 
CI) from vehicle was statistically significant for 8% BID (0.206 [0.022, 0.389], P = 0.028) and 
12% QD (0.204 [0.027, 0.381], P = 0.024). A sensitivity analysis of the primary efficacy endpoint 
in the ITT population produced results consistent with the primary analysis results. Secondary and 
exploratory efficacy endpoints also support selection of 12% QD. In the Phase 2 study, 7 subjects 
were discontinued from treatment with the study drug due to an AE, all in active treatment groups 
(3 subjects in the 4% BID group; 2 in the 8% BID group; and 2 in the 12% BID group). Treatment 
discontinuation was due to application site reactions in 6 of these subjects and to worsening MC 
in the other. No subject discontinued treatment due to AEs in the 12% QD group. 
Based on totality of the data, SB206 12% QD was selected for this Phase 3 study. 
2 STUDY OBJECTIVE 
This study is being conducted to evaluate the efficacy and safety of SB206 12% QD for the 
treatment of MC.   
3 STUDY ENDPOINTS  
The following endpoints will be assessed during the study. 
3.1 
Primary Efficacy Endpoint 
• Proportion of subjects with complete clearance of all treatable MC at Week 12 
3.2 
Secondary Efficacy Endpoint 
• Proportion of subjects with complete clearance of all treatable MC at Week 8 
3.3 
Exploratory Endpoints 
• Proportion of subjects who have a recurrence of MC after the first visit at which complete 
clearance was observed 
• Proportion of subjects developing scar(s) after clearance of lesion(s) at each visit (Weeks 
4, 8, 12, 24) 
• Proportion of subjects with complete clearance of all treatable MC at each visit (Weeks 2, 
4) 
Page 27/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 27 of 69
 
 
 
• Proportion of subjects achieving at least a 75% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Change from baseline of the composite score from age-matched (at baseline) Dermatology 
Life Quality Index (DLQI) assessment at Week 12  at Week 12 
• Subject-reported spread to household members as measured by any new occurrence of MC 
in household members of subjects at each visit (Weeks 2, 4, 8, 12) 
• Mean change from Baseline in number of treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Mean percent change from Baseline in number treatable MC at each visit (Weeks 2, 4, 8, 
12) 
• Time to complete clearance of all treatable MC  
3.4 
Safety Endpoints 
Safety assessments will be performed at scheduled timepoints throughout the study and include 
physical examination, urine pregnancy test, Beginning of the End (BOTE) Inflammation Score, 
Local Skin Reaction Scores (LSRs), concomitant medications, and adverse events (including 
scarring/keloid scarring). 
4 STUDY PLAN 
4.1 
Study Design 
This is a Phase 3 multi-center, randomized, double-blind, vehicle-controlled, parallel group study 
to be conducted in approximately 340 subjects with MC. After obtaining informed consent/assent, 
subjects who satisfy entry criteria will be randomized 2:1 (active:vehicle). Subjects receiving 
current treatment for MC at the time of the Screening Visit will enter a wash out period of up to 
14 days prior to randomization. In the event no wash out period is required. Screening and Baseline 
visit activities may be combined into a single visit. At randomization, subjects will be stratified 
into four strata corresponding to the cross-classification of household number of randomized 
subjects (1 subject per household vs 2 subjects per household) and investigator type (dermatologist 
vs other).  Households randomizing 2 subjects will receive the same treatment assignment for both 
subjects. Up to two subjects from the same household may be randomized on the same day, if both 
individually meet all inclusion/exclusion criteria. For subjects in the same household, Screening 
can occur on different days; however, the Baseline visit must occur on the same day.   
Page 28/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 28 of 69
 
 
 
Subjects or their caregivers will apply SB206 12% or Vehicle Gel once daily for a minimum of 4 
weeks and up to 12 weeks to all lesions identified at Baseline and new treatable lesions that arise 
during the course of the study. Subjects or their caregivers will continue to treat the area until the 
next scheduled visit even if the lesion(s) clear. If the investigator determines all lesions are cleared 
at a clinic visit, the treatment may stop. At Weeks 2, 4, and 8, the investigator will count and record 
the number of active (raised, treatable) molluscum lesions per body area. The investigator will also 
determine if new lesions have occurred since the last visit, and the subject or caregiver will be 
instructed by the investigator to re-initiate treatment. If treatment is stopped due to clearance, 
subjects will continue regularly scheduled visits through Week 24. 
Subjects will visit the clinic at Screening/Baseline, Week 2, Week 4, Week 8, Week 12, and Week 
24. Subjects will be contacted via phone on Day 2 to collect subject information on early dose 
reactions. At Weeks 16 and 20, subjects will be contacted via phone to capture information 
regarding MC recurrence and AEs; at Week 24, the subject will be seen at the site for a final study 
visit. Subjects who discontinue the study prior to the Week 12 visit due to adverse events or other 
reasons will be asked to complete the Week 12 visit assessments; this will be recorded as an Early 
Termination (ET1) visit. No study drug treatment will be provided after the Week 12 visit. Subjects 
who discontinue from the study after Week 12 but prior to Week 24 will be asked to come to the 
site to complete Week 24 assessments; this visit will be recorded as an ET2 visit. 
Safety assessments include BOTE Inflammation Scores, Local Skin Reaction Scores (LSRs), 
adverse event collection, including scarring/keloid and urine pregnancy tests (UPTs). Safety 
assessments will be completed at specified site visits through Week 12. After Week 12, safety 
information for ongoing AEs and new AEs will be collected, along with information regarding 
MC recurrence. For the purpose of this study, a recurrence of MC will be documented as an AE. 
Inflammatory reactions around the MC has been associated with imminent resolution of MC 
(sometimes referred to as “beginning-of-the-end” [“BOTE”] sign). The investigator (or designated 
evaluator) will assess the presence and overall degree of inflammatory reactions at MC lesions at 
Baseline (pre-dose) and Weeks 2-12. In most cases, clinical features can differentiate between 
BOTE and LSR. BOTE may be associated with itch, but not pain. BOTE is usually asymptomatic, 
self-limited, localized to individual MC lesions, and does not require discontinuation of study 
treatment or additional treatment. LSR is generally more diffuse, associated with significant itch 
or tenderness, may necessitate discontinuation of study treatment and may need treatment for 
symptomatic relief (e.g. a topical corticosteroid or topical anesthetic). For very severe LSR, 
systemic corticosteroids may be considered. Investigators will assess the treatment area at each 
scheduled visit and use their medical judgement to differentiate between BOTE and LSRs. BOTE 
Inflammation Score and LSR score will be recorded at each visit. BOTE should not be considered 
an AE. When LSRs are clinically significant at the application site, the Investigator should report 
the condition as AE(s). 
Page 29/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 29 of 69
 
 
 
At Baseline (30 min. post-dose) and Weeks 2 through Week 12 the evaluators will rate LSRs on 
individual 
features 
including 
erythema, 
flaking/scaling, 
crusting, 
swelling, 
vesiculation/pustulation, and erosion/ulceration using the BOTE Inflammation Score (Section 
7.2.3).  
Local Skin Reaction (LSR) Scores 
Clinically significant LSRs reported as AEs and/or subject reported intolerability (i.e. itching, 
pain) may result in an investigator-directed temporary treatment hold (drug holiday), and topical 
corticosteroids may be used to treat LSRs for up to 2 weeks. If a drug holiday is prescribed, 
Investigational product (IP) will still be dispensed at the clinic visit to ensure the subject may 
resume dosing prior to the next clinic visit. The subject may reinitiate study drug treatment prior 
to the next scheduled visit. Upon re-initiation of study drug treatment, if a subject develops 
worsening LSRs, allergic contact dermatitis may be suspected. The investigator may take 
photographs of the suspected allergic contact dermatitis and discuss possible confirmation of 
allergic contact dermatitis with the CRO medical monitor. The investigator should also discuss 
necessity of patch testing with the subject/caregiver. The investigator will then discontinue the 
subject from study drug treatment and treat the area(s) with corticosteroids for up to 2 weeks. If 
the subject provides consent/assent, the investigator will consult the clinical research organization 
(CRO) medical monitor to implement the process for patch testing.  
Adverse events will be assessed and collected after the initiation of study drug treatment through 
the end of the subject’s last visit. Treatment-related adverse events will be followed up until 
resolution or up to one year after last treatment, whichever occurs earlier.  
Scar formation will be assessed starting at the Week 4 visit through Week 12 and again at Week 
24. The investigator will map locations of the molluscum lesions at Baseline. Additional lesions 
identified through Week 12 will be added to the map. Using the map as a guidance, the investigator 
will assess the treated areas for scar/keloid formation. MC lesions may resolve with pitted scars 
(indentation), and the small scars that maintain original MC size (<5 mm) and less than 1 mm in 
depth will heal over time. Any pitted scars <5 mm in diameter and <1 mm in depth will not be 
considered AEs since these are considered part of the normal healing process. . If a scar is larger 
than 5 mm in diameter or greater than 1 mm in depth, this will be considered an adverse event for 
the purposes of this study. In addition, keloid/hypertrophic scars will also be recorded as adverse 
events.   
If a subject’s treatment is discontinued by the investigator or the subject because of an AE, that 
AE should be indicated as the reason for treatment discontinuation. All subjects will be encouraged 
to remain in the study throughout the 24-week study duration. 
Page 30/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 30 of 69
 
 
 
In the event of suspected allergic contact dermatitis, photographs may be taken of the affected 
area(s) and transmitted to the CRO medical monitor for review prior to initiating patch testing.  
When approximately 200 subjects (cumulative across studies NI-MC302 and NI-MC302) have 
completed 4 weeks of treatment, a Data Safety Monitoring Board (DSMB) will review all available 
unblinded safety data (including completed patch testing results).  
Page 31/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Safety and Efficacy Study  
Confidential
SB206/berdazimer sodium gel 
Page 31 of 69
 
 
 
Table 1: Schedule of Assessments 
 
Screening 
Treatment  
 
Screening1 
(Day -14 
to Day 1) 
Visit 11 
Baseline 
(Day 1) 
 
V2 
Telephone 
Contact 
(Day 2) 
Visit 32 
Week 2 
(Day 15 ±3) 
Visit 42 
Week 4 
(Day 29 ±5) 
Visit 52 
Week 8 
(Day 57 ±5) 
Visit 62 
Week 12/ 
ET1 
(Day 85 ±5) 
Informed Consent (Assent) 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical and Medication History 
X 
 
 
 
 
 
 
Lesion Count or Recurrence 
X 
X 
 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
X 
Urine Pregnancy Test3 
X 
X 
 
 
X 
X 
X 
BOTE Inflammation Score4 
 
X 
(pre-dose) 
 
X 
X 
X 
X 
Local Skin Reactions (LSR) (post-dose)4 
 
X 
 
X 
X 
X 
X 
Scarring/Keloid Assessment  
 
 
 
 
X 
X 
X 
DLQI/CDLQI5 
 
X 
 
 
 
 
X 
Review of Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Drug Dispensed 
 
X 
 
 
X 
X 
 
Dispense Subject Diary 
 
X 
 
X 
X 
X 
 
Review Subject Application Instructions 
 
X 
 
X 
X 
X 
 
In Clinic Study Drug Application6 
 
X 
 
X 
X 
X 
X 
Review Study Drug Compliance 
 
 
 
X 
X 
X 
X 
Collect Study Drug 
 
 
 
 
X 
X 
X 
Collect Subject Diary 
 
 
 
X 
X 
X 
X 
Record Adverse Event (AE) and 
Concomitant Medication (CM) Changes7 
 
X 
X 
X 
X 
X 
X 
 
Page 32/70


16.1.1 Protocol NI-MC302 
Novan: A Phase 3 Molluscum Contagiosum Safety and Efficacy Study  
Confidential
SB206/berdazimer sodium gel 
Page 32 of 69
 
 
 
 
Safety Follow-up 
 
Visit 72 
Week 16 
Telephone Contact 
(Day 113±5) 
Visit 82 
Week 20 
Telephone Contact 
(Day 141±5) 
Visit 92 
Week 24/ ET2 
(Day 169±5) 
Scarring/Keloid Assessment  
 
 
X 
Record Adverse Event (AE) and Concomitant Medication (CM) 
Changes7 
X 
X 
X 
1Screening and Baseline may occur on the same day. If this occurs, lesion count and review of inclusion/exclusion criteria will only occur once. If two members of the same 
household qualify for study participation, they must be randomized on the same day.  
2All visit dates are in reference to Baseline, e.g. Week 2 occurs 14 days after Baseline Visit. 
3Females 9 years of age and older.  
4BOTE Inflammation Score will be assessed pre-dose at Baseline, and post-dose from Visit 3 through Visit 6. LSRs will be performed post-dose at each applicable visit. 
5DLQI will be administered for subjects age 16 and older. The CDLQI will be administered for subjects ages 4 to age 16. If a subject turns 16 during the course of the study, the 
CDLQI will continue to be administered for consistency.  
6Study drug application will occur in clinic at each study visit, from Baseline through Visit 5. Subjects will not apply the study drug at home on days where a study visit will 
occur. 
7At Screening, subjects should be asked if any household members currently have MC. In addition to recording AE and CM changes, subjects should be asked if there are any 
new occurrences of MC in household members of subjects at each visit, except Screening and Day 2.  
NOTE:  Unscheduled visits are permitted as needed for medical reasons. 
 
Page 33/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 33 of 69
 
 
 
5 POPULATION 
5.1 
Number of Subjects 
Approximately 340 males and females, 6 months of age and older, with a minimum of 3 and a 
maximum of 70 lesions of MC at baseline will be randomized in a 2:1 (active:vehicle) scheme.  
5.2 
Inclusion Criteria 
1. Be 6 months of age or older, and in good general health; 
2. Have a written informed consent form signed by subject or a parent or legal guardian 
and an assent form as required;  
3. Have between 3 and 70 treatable MC at Baseline; 
4. Female subjects age 9 and above must have a negative UPT at Baseline; 
5. Female subjects age 9 and above must agree to practice a medically acceptable form of 
birth control during the study and for 30 days after their final study visit; 
6. Be willing and able to follow study instructions and likely to complete all study 
requirements. 
5.3      Exclusion Criteria 
1. Have strongly suggested sexually transmitted MC and do not agree to refrain from 
sexual activities throughout the study period. 
2. Are immunosuppressed, have immunodeficiency disorder, or are on 
immunosuppressive treatment; 
3. Have significant injury on and/or surrounding MC that may impact ability to treat and 
count lesions; 
4. Have received treatment with topical calcineurin inhibitors or steroids on MC or 
within 2 cm of MC lesions within 14 days prior to Baseline; 
5. Have received treatment for MC during the 14 days prior to Baseline with 
podophyllotoxin, imiquimod, cantharidin, sinecatechins, topical retinoids, oral or 
topical zinc, or other homeopathic or over the counter (OTC) products including, but 
Page 34/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 34 of 69
 
 
 
not limited to, ZymaDerm and tea tree oil, cimetidine and other histamine H2 
receptor antagonists (including Zantac);  
6. Have received surgical procedures related to MC (cryotherapy, curettage, other) 
within 14 days prior to Baseline; 
7. Have MC only in periocular area; 
8. Female subjects who are pregnant, planning a pregnancy or breastfeeding; 
9. Have known hypersensitivity to any ingredients of SB206 or Vehicle Gel including 
excipients; 
10. Have participated in a previous study with a berdazimer sodium product (SB204, 
SB206, SB208, SB414); 
11. Have more than 1 family member currently participating in a study with a berdazimer 
sodium product (SB204, SB206, SB208, SB414) 
12. Have participated in any other trial of an interventional investigational drug or device 
within 14 days or concurrent participation in another interventional research study. 
13. History or presence of clinically significant medical, psychiatric, or emotional 
condition that, in opinion of the investigator, would compromise the safety of the 
subject or the quality of the data. 
5.4 
Subject Screening 
Written informed consent (assent form where required) will be obtained before any study-related 
procedures are performed. The investigator may discuss the study and the possibility for entry with 
a potential subject without first obtaining consent. A subject 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 forms (ICF)/assent forms must be forwarded to the contract 
research organization (CRO) for approval prior to submission to an Institutional Review Board 
(IRB) and/or Independent Ethics Committee (IEC) as appropriate. Each subject will sign the ICF 
that has been approved by the same IRB responsible for protocol approval. Each ICF/assent form 
Page 35/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 35 of 69
 
 
 
must adhere to the ethical principles stated in the Declaration of Helsinki and will include the 
elements required by Food and Drug Administration (FDA) regulations in 21 CFR as well as the 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and 
applicable federal and local regulatory requirements. The ICF/assent form(s) must also include a 
statement that Novan and the CRO (or their designees) and auditing regulatory agencies will have 
direct access to the subject’s records and medical history.  
Once the appropriate essential information has been provided to the subject/caregiver and fully 
explained by the investigator (or a qualified designee) and it is felt that the subject/caregiver 
understands the implications and risks of participating in the study, the IRB approved ICF/assent 
document shall be signed and dated by both the subject/caregiver and the person obtaining consent 
(investigator or designee), and by any other parties required by the IRB or other regulatory 
authorities. The subject/caregiver will be given a copy of the signed ICF/assent 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. 
5.4.1 
Screening Failures 
A subject is considered screened once they have a signed ICF/assent and completed one screening 
assessment. A screen failure subject will be any screened subject who does not get randomized to 
a treatment arm. Subjects will be allowed to rescreen once. 
5.5 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the Inclusion/Exclusion Criteria is not allowed. Any deviation identified during 
the study should be discussed with the CRO and/or Novan. 
6 STUDY CONDUCT 
6.1 
General Instructions 
Prospective subjects as defined by the eligibility criteria (Inclusion/Exclusion Criteria) will be 
considered for entry into this study. Subjects’ ICF/assent must be obtained prior to conducting any 
procedures. Some Baseline procedures (i.e., review of inclusion/exclusion criteria, brief physical 
exam, adverse event assessment, concomitant medication review, and UPT) must be completed 
prior to randomization. Subjects who meet all eligibility criteria who do not require washout from 
any current treatment may be screened and randomized on the same day. 
After the required procedures are completed and study eligibility is confirmed, the subject will be 
randomized to treatment utilizing an Interactive Web Response System (IWRS) which will 
identify the study drug to be dispensed to the subject. The subject/caregiver will be trained on the 
Page 36/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 36 of 69
 
 
 
mixing, application, and storage of the study drug. The first application should be done at the 
clinic, and application should also be done in clinic at Week 2, Week 4, Week 8, and Week 12.  
6.2 
Study Procedures by Time Point 
6.2.1 
Screening (Day-14 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 SB206 with the subject/caregiver and obtain written ICF/assent. 
2. Obtain demographic information. 
3. Obtain subject’s medical history (including start date of the subject’s current episode of 
molluscum (i.e., when molluscum was first noticed by the subject/caregiver)), household 
MC status, medication history, and concomitant medication information. 
4. Perform lesion mapping and lesion count. 
5. If applicable, obtain UPT and evaluate results. If pregnancy test is positive, the subject may 
not participate in the study. 
6. Review inclusion/exclusion to confirm whether subject qualifies to participate in the study. 
6.2.2 
Visit 1/Baseline (Day 1) 
The following procedures must be performed and recorded at the Baseline visit. If Screening and 
Baseline visits occur the same day, procedures with an asterisk (*) should only be performed once 
and will be recorded as Baseline values.  
1. Complete age-matched Dermatology Life Quality Index (DLQI) assessment, as applicable. 
2. Perform a brief physical examination. 
3. Perform lesion mapping and lesion count.* 
4. Perform BOTE Inflammation Score (pre-dose). 
5. Obtain urine pregnancy test, as applicable. If pregnancy test is positive, the subject may 
not participate in the study.  
6. Update concomitant medication information. 
Page 37/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 37 of 69
 
 
 
7. Confirm eligibility and randomize subject. 
8. Dispense subject diary and study drug.  
9. Weigh and record study product tubes.  
10. Instruct subject on dispensing, mixing, and application of study product and diary 
completion. 
11. Have subject/caregiver apply first dose in clinic from kit assigned at randomization. 
12. Complete Local Skin Reaction assessment approximately 30 minutes post dose. 
13. Collect and record AE information for any AEs reported. 
6.2.3 
Visit 2/Day 2 Telephone Contact 
The following procedure must be performed and recorded at the Day 2 telephone contact. 
1. Contact subject to confirm how the subject is feeling. 
6.2.4 
Visit 3/Week 2 (Day 15 ±3) 
The following procedures must be performed and recorded at the Week 2 visit. 
1. Perform lesion mapping and update lesion map with location for any new lesions. 
2. Assess for subject recurrence of MC. 
3. Review study compliance.  
4. Dispense subject diary.  
5. Review dosing instructions and have subject/caregiver apply daily dose in clinic using the 
kit assigned at randomization. 
6. Perform BOTE Inflammation Score (post-dose). 
7. Complete Local Skin Reaction Assessment (post-dose). 
8. Collect and record AE information for AEs reported. 
9. Update concomitant medication information and confirm if any new occurrences of MC 
were reported in the subject’s household. 
Page 38/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 38 of 69
 
 
 
6.2.5 
Visit 4/Week 4 (Day 29 ±5) 
The following procedures must be performed and recorded at the Week 4 visit. 
1. Obtain pregnancy test and evaluate results, as applicable. If pregnancy test is positive, the 
subject may continue in the study; however, study drug should be discontinued. 
2. Perform lesion counts and update lesion map with location for any new lesions. 
3. Assess for subject recurrence of MC. 
4. Perform scarring/keloid assessment. 
5. Weigh returned study drug and review study compliance. 
6. Weigh, record, and dispense new supply of study product and dispense subject diary. 
7. Review dosing instructions and have subject/caregiver apply daily dose in clinic using the 
newly dispensed kit. 
8. Perform BOTE Inflammation Score (post-dose). 
9. Perform Local Skin Reaction Assessment (post-dose). 
10. Collect and record AE information for AEs reported. 
11. Update concomitant medication information and confirm if any new occurrences of MC 
were reported in the subject’s household. 
6.2.6 
Visit 5/Week 8 (Day 57 ±5) 
The following procedures must be performed and recorded at the Week 8 visit. 
1. Obtain pregnancy test and evaluate results, as applicable. If pregnancy test is positive, the 
subject may continue in the study; however, study drug should be discontinued. 
2. Perform lesion mapping and update lesion map with location for any new lesions. 
3. Perform scarring/keloid assessment. 
4. Weigh returned study drug and review study compliance. 
5. Weigh, record, and dispense new supply of study product and dispense subject diary. 
Page 39/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 39 of 69
 
 
 
6. Review dosing instructions and have subject/caregiver apply daily dose in clinic using the 
newly dispensed kit. 
7. Perform BOTE Inflammation Score (post-dose). 
8. Perform Local Skin Reaction Assessment (post-dose). 
9. Collect and record AE information for AEs reported. 
10. Update concomitant medication information and confirm if any new occurrences of MC 
were reported in the subject’s household. 
6.2.7 
Visit 6/Week 12/ET (Day 85 ±5) 
The following procedures must be performed and recorded at the Week 12/ET1 visit. 
1. Complete age-matched Dermatology Life Quality Index (DLQI) assessment, as applicable. 
2. Obtain pregnancy test and evaluate results, as applicable.  
3. Perform lesion mapping and update lesion map with location for any new lesions. 
4. Perform scarring/keloid assessment 
5. Perform a brief physical examination. 
6. Subject/caregiver administer final dose of study drug from previously dispensed kit. 
7. Perform BOTE Inflammation Score (post-dose). 
8. Perform Local Skin Reaction Assessment (post-dose). 
9. Weigh returned study drug and review study compliance. 
10. Collect and record AE information for AEs reported. 
11. Update concomitant medication information and confirm if any new occurrences of MC 
were reported in the subject’s household. 
6.2.8 
Visit 7/Week 16 and Visit 8/Week 20 (Day 113 +/- 7 days; Day 141 +/- 7 
days) 
The following procedures must be performed and recorded at the Week 16 and Week 20 visits. It 
is expected that these visits should be done by telephone. 
Page 40/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 40 of 69
 
 
 
1. Collect and record information for new and ongoing AEs, including recurrence of MC. 
2. Update concomitant medication information. 
6.2.9 
Visit 9/Week 24 (Day 169 +/- 7 days) 
The following procedures must be performed and recorded at the Week 24 visit. 
1. Perform scarring/keloid assessment. 
2. Collect and record information for new and ongoing AEs, including subject recurrence of 
MC. 
3. Update concomitant medication information. 
6.3 
Discontinuation 
6.3.1 
Treatment Discontinuation 
If at any time during the study the investigator determines that it is not in the best interest of the 
subject to continue treatment, the subject’s treatment will be discontinued. The investigator can 
discontinue the treatment for a subject at any time if medically necessary. If a subject’s treatment 
is permanently discontinued by the investigator because of an AE, that AE should be indicated as 
the reason for treatment discontinuation. In this case, the subject is discontinued from the 
treatment, but still participates in the study and the subject is encouraged to follow the visit 
schedule and complete all assessments.  
In addition, the investigator may instruct the subject to temporarily halt treatment of a specified 
region (i.e., due to an adverse event). This treatment modification and the reason for the temporary 
drug interruption should be documented in the subject’s source documents and eCRF. The lesions 
in the impacted area should continue to be counted in the lesion count during the period of 
treatment modification.  
The investigator may discontinue a subject’s treatment if the subject/caregiver 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 treatment discontinuation must be 
completed. 
Reasons for an investigator’s withdrawal of a subject from the treatment may include, but are 
not limited to, the following: 
• Safety (e.g., severe adverse reactions, pregnancy) 
Page 41/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 41 of 69
 
 
 
• 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 the 
CRO whether the subject is to be withdrawn. 
Reason(s) for discontinuation from the treatment as listed in the study record will be entered into 
the study database as follows: 
• Completed (complete clearance prior to Week 12) 
• Adverse Event (including LSRs deemed to be significant by investigator) 
• Withdrawal by Subject/Caregiver 
• Physician Decision 
• Protocol Violation 
• Lost to Follow-Up 
• Pregnancy 
• Lack of Efficacy 
• Worsening of Molluscum Contagiosum 
• Other 
6.3.2 
Study Discontinuation 
A subject/caregiver may voluntarily withdraw from study participation at any time. If the 
subject/caregiver 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. In the event of discontinuation from the study, (i.e., prior to Week 
12/ET1) every effort should be made to have the subject return to the study center to complete the 
Week 12 evaluations (ET1 visit). Subjects who withdraw from the study will not be replaced. 
Subjects who discontinue from the study after Week 12 but prior to Week 24 will be asked to 
return to the study center to complete the Week 24 evaluations (ET2 visit). 
All subjects who fail to return to the study center 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/caregiver 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 
Page 42/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 42 of 69
 
 
 
subject contacts the investigator. 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. 
An investigator may withdraw a subject from the study when a subject is lost to follow-up.   
All premature discontinuations and their causes must be carefully documented in the subject’s 
study record and in the study database. 
All Week 12 or Week 24 evaluations should be performed at the time of premature discontinuation 
as applicable. All data gathered on the subject prior to termination will be made available to the 
CRO. The investigative site should make all reasonable efforts to ensure the subject returns to 
complete the appropriate termination visit, even if the subject is not able to attend other study 
visits.  
Study completion or reason(s) for discontinuation from the study as listed in the study record will 
be entered into the study database as follows: 
• Completed Treatment Per Investigator’s Instructions and Completed All Study Visits 
• Withdrawal by Subject/Caregiver 
• Lost to Follow-Up 
Novan has the right to terminate or stop the study at any time. Should this be necessary, the 
investigator will ensure that proper study discontinuation procedures are completed. 
7 DESCRIPTION OF STUDY PROCEDURES 
Study procedures and their timings are summarized in the Schedule of Assessments (refer to Table 
1). 
7.1 
Efficacy Assessments 
7.1.1 
Molluscum Contagiosum Lesion Counts 
Molluscum contagiosum is a viral infection characterized by small, discrete, waxy, skin-colored, 
dome-shaped papules, an average of 3–5 mm in diameter. The papules may be umbilicated and 
contain a caseous plug. When the lesions are squeezed or traumatized, a creamy, grey-white 
material can be extruded. If the investigator cannot clearly differentiate the lesions as is the case 
for agminated (clustered lesions)) this should be counted as one lesion. If the investigator can 
differentiate and count the umbilical tops separately, each lesion should be counted separately. The 
Page 43/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 43 of 69
 
 
 
investigator should be consistent with the method of recording agminated lesions throughout the 
study. 
For the purpose of this clinical trial, only active MC lesions are counted. Treatable lesions are any 
active (raised, palpable) MC lesions that are dome-shaped, pearly and shiny white top centered 
papules that are at least 2 cm away from the ocular region.  
All study personnel who will perform lesion counts must pass the study training including lesion 
count training. Training on how to accurately count the number of MC lesions will be provided.  
Mapping of lesions: At every visit from Baseline through Week 12, all lesions should be recorded 
on the body map and will clearly note the location of each lesion or agminated lesion. The lesion 
map is intended to assist study personnel in performing lesion counting and scar/keloid assessment. 
Definition of Clearance: For the purpose of this study, “clear” means resolution of the active 
(raised, palpable) treatable molluscum lesion(s). After resolution, the residual surface changes 
such as pitted scar (indentation) < 1 mm in depth at the molluscum lesion area (<5 mm in diameter), 
hyper or hypopigmentation may remain. As these are considered part of the normal healing, they 
will not be captured as adverse events. Refer to the lesion count training for details. 
The same evaluator should perform lesion counts at Screening, Baseline, and Weeks 2, 4, 8 and 
12/ET1. In the event that this is not possible due to unforeseen circumstances, a different evaluator 
may evaluate the subject. The evaluator must pass the study training including lesion count 
training. It is particularly important to ensure the same evaluator performs the Baseline and Week 
12/ET1 for lesion count for a subject and also Baseline and Week 24/ET2 assessment for 
scarring/keloid scarring. 
7.1.2 
Dermatology Life Quality Index (DLQI) 
The Dermatology Life Quality Index (DLQI) questionnaire is designed for use in adults (i.e., 
subjects aged 16 years and above). The questions are designed to be completed with a one week 
recall period. It is self-explanatory and can be simply handed to the subject who is asked to fill it 
in without the need for detailed explanation. It is usually completed in one to two minutes. The 
Children’s Dermatology Life Quality Index (CDLQI) questionnaire is the DLQI that is adapted 
for use in children (i.e., subjects from age 4 up to age 16). 
Both the DLQI and the CDLQI are calculated by summing the score of each question resulting in 
a maximum score of 30 and a minimum score of 0.  
Page 44/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 44 of 69
 
 
 
7.2 
Safety Assessments 
7.2.1 
Physical Exam 
A brief physical examination will be performed to evaluate objective anatomic findings. This 
physical examination will be performed at Baseline and at Week 12/ET1. Any clinically significant 
changes in the physical exam from baseline will be recorded as AEs. 
7.2.2 
Pregnancy Testing 
Urine pregnancy testing for females 9 years of age and older will be collected at Screening, 
Baseline, Week 4, Week 8 and Week 12/ET1. In addition to having a negative UPT at Baseline, 
before the first application of study drug, females 9 years of age and older must be willing to use 
an acceptable form of birth control during the study. The following are considered acceptable 
methods of birth control for this study: abstinence with a documented acceptable method of birth 
control if the subject becomes sexually active, oral contraceptives, contraceptive patches, 
contraceptive implant, vaginal contraceptive, double-barrier methods (e.g., condom and 
spermicide), contraceptive injection, Intrauterine Device (IUD), hormonal IUD, permanent 
contraception, same sex partner or partner who has had a vasectomy. Tubal ligation is not 
considered to be surgical sterilization; women with tubal ligations will be required to complete 
UPTs at the required timepoints. 
7.2.3 
BOTE Inflammation Score 
Inflammatory reactions around the MC has been associated with imminent resolution of MC 
(sometimes referred to as “beginning-of-the-end” [“BOTE”] signs). In most cases, clinical features 
can differentiate between BOTE and LSR. BOTE may be associated with itching, but not pain. 
BOTE is usually asymptomatic, self-limited, localized to individual MC lesions, and does not 
require discontinuation of study treatment or additional treatment.  
Investigators will assess the treatment area at each scheduled visit and use their medical judgement 
to differentiate between BOTE and LSRs. The BOTE Inflammation Score will be recorded at each 
visit. BOTE should not be considered an AE since this is part of normal disease progression.  
 
 
Page 45/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 45 of 69
 
 
 
BOTE Inflammation Score 
Score 
Global 
Assessment 
Description 
0 
No inflammation 
No evidence of local inflammation 
1 
Mild 
Minimal erythema and/or edema 
2 
Moderate 
Definite erythema and/or edema with or 
without hemorrhagic crusting 
3 
Severe 
Erythema and edema with definite 
hemorrhagic crusting 
4 
Very Severe 
Strong reaction spreading beyond the 
treated area, bullous reaction, erosions 
7.2.4 
Local Skin Reaction Score 
The investigator (or designated evaluator) will assess localized skin reactions (LSRs) at Baseline 
(at least 30 minutes post-dose), and at Weeks 2, 4, 8 and 12. The individual components of LSRs 
are scored separately on a scale of 0-4, with higher numbers indicating more severe reactions. The 
individual 
components 
include 
erythema, 
flaking/scaling, 
crusting, 
swelling, 
vesiculation/pustulation, and erosion/ulceration. 
 
Compared to BOTE, LSR is generally more diffuse, associated with significant itch or tenderness, 
may necessitate discontinuation of study treatment and may need treatment for symptomatic relief 
(e.g. a topical corticosteroid or topical anesthetic). For very severe LSR, systemic corticosteroids 
may be considered. 
Investigators will assess the treatment area at each scheduled visit and use their medical judgement 
to differentiate between BOTE and LSRs. When LSRs are clinically significant in the opinion of 
the investigator, s/he should report the condition as an AE(s) (e.g. application site erythema, 
application site edema). 
In the event of an LSR, the investigator may choose to initiate a drug holiday for the study drug 
for up to 2 weeks; treatment with corticosteroids may be ordered during the drug holiday at the 
investigator’s discretion. For very severe LSR, systemic corticosteroids may be considered. The 
subject should be instructed how many days to hold study drug and site staff should phone the 
Page 46/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 46 of 69
 
 
 
subject on the planned day of resuming study drug to ensure that the LSR has resolved. If the LSR 
has not resolved, the drug holiday may be extended as long as the total period of withholding study 
drug does not exceed 2 weeks. If the LSR has resolved, the subject may resume treatment. If the 
LSR flares again after re-introduction of study drug, allergic contact dermatitis may be suspected. 
The subject may again be treated with up to 2 weeks of corticosteroids.  
If allergic contact dermatitis is suspected, study drug should be discontinued permanently and an 
AE of allergic contact dermatitis should be recorded as the reason for discontinuation. Week 
12/ET1 assessments should be completed at the time of discontinuation, but the subject should 
continue in the study and complete study-related visits through Week 24.  
Patch testing (see Section 7.2.5 and Section 20.2) should be offered to the subject. 
LSR Score 
 
Erythema 
Flaking/ 
Scaling 
Crusting 
Swelling 
Vesiculation/ 
Pustulation 
Erosion/ 
Ulceration 
0 
Not present 
Not present 
Not present Not present 
Not present 
Not present 
1 
Slightly 
pink 
Mild, 
limited 
Isolated 
crusting 
Minimal, 
limited 
Fine vesicles 
Superficial 
erosion 
2 
Pink or light 
red 
Moderate 
Crusting     
< 50% 
Mild, 
palpable 
Scant 
transudate or 
exudate 
Moderate 
erosion 
3 
Red, 
restricted to 
treatment 
area 
Coarse 
Crusting     
> 50% 
Moderate 
Moderate 
transudate or 
exudate 
Marked, 
extensive 
4 
Red 
extending 
outside 
treatment 
area 
Scaling 
extending 
outside 
treatment 
area 
Crusting 
extending 
outside 
treatment 
area 
Marked 
swelling 
extending 
outside 
treatment 
area 
Marked 
transudate or 
exudate 
Black eschar 
or ulceration 
7.2.5 
Patch Testing  
In the event that a subject has an LSR that is felt to be suggestive of allergic contact dermatitis, 
patch testing may be initiated to confirm. This should be offered to the subject/caregiver. If the 
subject/caregiver consents to patch testing and once the LSR has been completely resolved for a 
period of 2 weeks and up to 2 months, patch testing will commence. Novan will provide the patch 
testing instruction once requested from the CRO medical monitor. Additional drug product for 
Page 47/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 47 of 69
 
 
 
patch testing may be supplied through IWRS if the currently assigned subject’s investigational 
product has been assignment was > than 60 days of the patch testing date(s). 
If allergic contact dermatitis is suspected, study drug should be discontinued permanently and an 
AE of allergic contact dermatitis should be recorded as the reason for discontinuation. Week 
12/ET1 assessments should be completed at the time of discontinuation, but the subject should 
continue to participate in the study and complete study related visits through Week 24.  
In the event of suspected allergic contact dermatitis, photographs may be taken of the affected 
area(s) and transmitted to the CRO medical monitor for review prior to initiating patch testing.  
See Section 20.2 for further information. 
7.2.6 
Scarring/Keloid Assessment 
Scar formation will be assessed starting at the Week 4 visit through Week 12, and again at Week 
24. For the purposes of this study, scar is defined as follows: pitted scars with ≥ 5 mm in diameter 
or ≥ 1 mm in depth, and hypertrophic/keloid scars originated from MC lesion.  Pitted scars < 5 
mm in diameter and < 1 mm in depth originated from MC lesion are considered part of normal 
healing process and will not be captured as AEs.   
7.3 
Protocol Deviations 
This study will be conducted as described in this protocol, except for in emergency situations 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 the CRO at the earliest possible 
time by telephone. This will allow an early joint decision regarding the subject’s continuation in 
the study. This decision will be documented by the investigator and the CRO. 
 
 
Page 48/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 48 of 69
 
 
 
8 STUDY DRUG MANAGEMENT 
8.1 
Description 
8.1.1 
Formulation  
Investigational Drug: SB206 12% 
Comparator Drug: Vehicle Gel 
Dosing:  
Up to approximately 2mL of SB206 QD 
Dosing:  
Up to approximately 2mL of Vehicle Gel QD 
8.1.2 
Storage 
Upon receipt from Novan, or Novan’s designee, a study staff member will place all study supplies 
in a refrigerated temperature-controlled and monitored area. The SB206/Vehicle study product 
should be refrigerated (2-8°C/36-46°F) until dispensed. 
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 or there is a temperature 
excursion during shipment), the CRO must be contacted immediately. In such an event, study 
supplies should be quarantined and not be administered to any subject until Novan or Novan’s 
designee provides further direction. 
It is expected that the site staff will maintain refrigerator temperature logs in the refrigerated study 
drug storage area, recording the temperature at least once each working day. Excursions in 
temperature during storage should be discussed with the CRO immediately and study supplies 
should be quarantined and not administered until Novan provides approval for use. Other supplies 
will be stored at room temperature. 
The study drug will be dispensed at the discretion of and by the direction of the designated study 
personnel in accordance with the conditions specified in this protocol. It is the investigator’s 
responsibility to ensure that accurate records of study drug dispensing and return are maintained. 
Page 49/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 49 of 69
 
 
 
8.2 
Packaging and Shipment 
Novan, or designee, will provide all study drug to the sites. Sites are required to maintain all 
records of shipment and receipt in the Investigator Site File. 
8.3 
Method of Assigning Subjects to Treatment Groups 
In this randomized, double-blind, vehicle-controlled study, subjects who meet study entry criteria 
will be randomly assigned in a 2:1 ratio (active: vehicle). The randomization schedule will be 
computer generated using a permuted block algorithm and will randomly allocate IP to 
randomization numbers. The randomization numbers will be assigned sequentially through a 
central IWRS as subjects are entered into the study. At randomization, subjects will be stratified 
into four strata corresponding to the cross-classification of household number of randomized 
subjects (1 subject per household vs 2 subjects per household) and investigator type (dermatologist 
vs other).  Households randomizing 2 subjects would receive the same treatment assignment for 
both subjects. Approximately 340 subjects, 6 months of years of age and older, with a minimum 
of 3 and a maximum of 70 lesions at Baseline will be randomized.  
8.4 
Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the study will be blinded 
to treatment assignment, with the exception of a specified unblinded statistician who will generate 
and have access to the randomization code. The unblinded study personnel will not otherwise 
participate in study procedures or data analysis prior to unblinding of the study data to all study 
related personnel.  
When approximately 200 subjects (cumulative across studies NI-MC302 and NI-MC302) have 
completed 4 weeks of treatment, a DSMB will review all available unblinded safety data 
(including patch testing). Personnel who are not otherwise involved in the study will prepare the 
unblinded data and summary tables for this analysis.  
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in the 
conduct of the study. Individual treatment unblinding is discouraged since knowledge of the 
treatment assignment will not materially change the planned management of a medical emergency. 
Unblinding should be discussed in advance with the medical monitor if possible. Study personnel 
will utilize the IWRS for emergency unblinding. If the investigator is not able to discuss treatment 
unblinding in advance, then he or she must notify the CRO medical monitor as soon as possible 
about the unblinding incident without revealing the subject’s treatment assignment. The 
investigator or designee must record the date and reason for study discontinuation on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the subject’s treatment assignment.  
Page 50/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 50 of 69
 
 
 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he or she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
8.5 
Dose and Administration 
Subjects will apply treatment once daily for up to 12 weeks to all active lesions identified at 
baseline and new lesions that arise during treatment If the investigator determines all lesions are 
cleared at a clinic visit, the treatment may stop. If treatment is stopped due to clearance, subjects 
will continue regularly scheduled visits through Week 24/ET2. 
An increase in the number of MC lesions (with or without inflammatory reaction) during the early 
treatment phase is often observed. It is important to instruct the subject/caregiver to treat the new 
lesions as well as the existing lesions. 
Each dose will consist of berdazimer gel or vehicle gel with hydrogel thoroughly mixed together 
by the subject or caregiver and applied to the lesions and approximately 1 cm surrounding each 
lesion. Periocular lesions will be treated if the lesions are at least 2 cm from the edge of the eye. If 
a subject has more than 20 MC, a second dose of berdazimer gel or vehicle gel with hydrogel can 
be prepared to ensure appropriate coverage of all lesions.   
At the investigator’s discretion, the subject may be placed on a drug holiday for up to 2 weeks at 
a time in the event of a significant local skin reaction (LSR). This will be captured in the electronic 
data capture (EDC) system and the subject’s diary. The investigator should instruct the subject 
how long to hold study drug and the planned date to re-start treatment. Site staff should contact 
the subject on the day of the planned re-start and assess whether the LSR has resolved enough to 
resume treatment. If it has not resolved sufficiently, the drug holiday may be extended as long as 
the entire extension has not exceeded 2 weeks. If the LSR flares after re-introduction of study drug, 
the study drug should be permanently discontinued and the EDC system updated appropriately. 
Please see Section 7.2.4 for additional information. 
8.6 
Accountability 
The dispensing and return of all study drug will be recorded on a dispensing log. The subject 
number/initials, and the initials and date of the person dispensing and receiving the returned 
medication will be documented on this form. All study product will be weighed at the time it is 
dispensed and when it is returned. The tube weights will be recorded in the electronic case report 
form (eCRF). 
Page 51/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 51 of 69
 
 
 
Inventory records must be readily available for inspection by the trial monitor and/or auditor, and 
open to government inspection at any time. 
Study drug returned by subjects at will be held on site until accountability has been completed. 
The site will be instructed on return or destruction of used and unused clinical supplies. 
8.7 
Prohibited Concomitant Medication/Therapy 
Any medication/therapy used by the subject following first application of study product will be 
considered a concomitant medication (e.g., aspirin, acetaminophen, birth control pills, vitamins, 
etc.). Every attempt should be made to keep concomitant medication/therapy dosing constant 
during the study. Any change to concomitant medications/therapies should be noted on the 
subject’s study record and in the study database. When applicable, an AE should be completed for 
any subject starting a concomitant medication/therapy after enrollment into the study. 
Immunosuppressive treatment is prohibited during the study. Use of topical calcineurin inhibitors 
or steroids on MC or within 2 cm of MC lesions is prohibited within 14 days of baseline and during 
the study. Use of the following concomitant medications to treat MC 14 days prior to baseline and 
during the study is prohibited: podophyllotoxin, imiquimod, cantharidin, sinecatechins, topical 
retinoids, oral or topical zinc, other homeopathic or over-the-counter products including, but not 
limited to, ZymaDerm and tea tree oil, cimetidine and other histamine H2 receptor antagonists. 
Surgical procedures to treat MC (cryotherapy, curettage, other) are prohibited during the study. 
8.8 
Compliance 
Subjects will be provided a diary to record doses. Review of subject compliance will be conducted 
at each visit and missed doses recorded on the subject diary will be recorded on the eCRF.   
No reconciliation will be performed on the diary compliance against the tube weights. Subject 
compliance will be based on calculation from the missed doses recorded from the subject diary 
only. 
9 ADVERSE EVENTS 
Adverse events will be assessed and collected after the initiation of study drug treatment through 
the end of the subject’s last visit. In order to avoid bias in eliciting AEs, subjects/caregivers should 
be asked the following non-leading question: “How have you felt since your last visit?” Adverse 
events will be assessed and reported after the subject is dosed, beginning from Baseline through 
the end of the subject’s last visit. SAEs will be collected from the time of consent through the end 
of the subject’s last visit. Adverse events that occur from time of consent up to the time of treatment 
administration should be recorded as medical history for all participants. Treatment-related 
Page 52/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 52 of 69
 
 
 
adverse events will be followed up until resolution or up to one year after last treatment, whichever 
occurs earlier. 
9.1 
Documenting Adverse Events 
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 no later than 5 days of the site’s first knowledge. The 
site must report related SAEs to the Sponsor within 24 hours after first knowledge of the event by 
the study site. The date of onset, date ended, accurate event term, seriousness, severity, outcome, 
relationship to study drug, therapy required, and action taken regarding study drug and study 
participation will be reported for each AE. 
Significant LSRs (as judged by the investigator) and scarring (pitted scars ≥ 1mm in depth), scars 
that are larger than the original MC and/or extend outside the treatment area, and 
hypertrophic/keloid scars will be captured as adverse events. 
9.2 
Assessment of Severity 
The investigator is responsible for evaluating all AEs and determining the severity of the event.  
Severity will be categorized according to the following definitions: 
• Mild:  Event may be noticeable to subject; does not influence daily activities; usually does 
not require intervention 
• Moderate:  Event may be of sufficient severity to make subject uncomfortable; 
performance of daily activities may be influenced; intervention may be needed 
• Severe:  Event may cause severe discomfort; usually interferes with daily activities; subject 
may not be able to continue in the study; treatment or other intervention usually needed  
The investigator will follow all subjects who experience AEs as described in Section 9.4. 
9.3 
Assessment of Causality 
Relationship of each AE to study drug must be assessed.  
Several factors should be considered when assessing the relationship (causality) of an event to the 
study drug or administration of the study drug. 
• Alternative etiology – Is the event due to an underlying disease/condition being treated or 
to another known, underlying disease/condition of the participant? 
Page 53/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 53 of 69
 
 
 
• Known relationship – Has the event been observed before in participants treated with this 
product or similar products? 
• Temporal relationship – Is there a reasonable temporal relationship between the time of 
onset for the event and the administration of the study drug? 
• Concomitant medication – Is the event a known side effect of a concomitant medication? 
Per the Council for International Organizations of Medical Sciences (CIOMS) VI working group, 
the use of “cannot-be-ruled-out” to imply drug relatedness will lead to excessive over-reporting 
and excess noise in the system. It is virtually impossible to completely rule out the role of a drug 
in causing an adverse event in single-case reporting. Differentiating from the procedural causes 
may also be difficult. Hence, the review of aggregated controlled data is an important component 
for the determination of the safety profile of any investigation product. Aggregate review is 
completed by the Sponsor. 
Therefore, given the above, the Investigator should assess the relatedness to the study drug using 
a standard of a reasonable possibility of a causal relationship between the study drug and the AE, 
as per the examples in the table below: 
 
Assessment of Causality 
Reasonable possibility: classification 
includes definitely, probably (likely), 
possibly related events 
• Reasonable temporal sequence to drug 
administration 
• Event 
can 
be 
fully 
attributable 
to 
administration of the study drug 
• Known pharmacological action of the study 
drug 
• Specific tests available (positive allergy test, 
antibodies, metabolites) 
• As adverse drug reaction in the product 
information (Investigator’s Brochure) 
• Reported in the literature as a possible side 
effect 
• Dechallenge (event abates on discontinuation 
of the study drug/without treatment) 
• Rechallenge positive (event reappears on re-
exposure to study drug) 
Page 54/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 54 of 69
 
 
 
• Not explained otherwise by the subject’s 
clinical state or medical history or by other 
concomitant agents/therapies, etc.  
No 
reasonable 
possibility: 
classification includes definitely not, 
probably not, unlikely related events 
• No reasonable temporal sequence to study 
drug administration 
• Event is explained by a number of other factors 
such as a subject’s clinical state, medical 
history or other concomitant agents/therapies 
• Etiology has been clarified and is in no way 
related to the study drug 
• No reason for suspecting a causal relationship 
to the study drug and 
• Investigators have established this beyond 
reasonable doubt 
The causal relationship will be recorded on a binary scale by answering yes or no the following 
questions: is there a reasonable possibility of a causal relationship between the study drug and the 
AE? The phrase “reasonable causal relationship” means to convey, in general, that there are facts, 
evidence or argument that support a causal relationship to the study drug.   
9.4 
Adverse Event Follow-up 
9.4.1 
Follow-Up of Non-Serious Adverse Events 
Non-serious AEs that are not resolved at the time of the last scheduled study visit (Week 24/ET2) 
must be recorded in the study database as ongoing/not recovered/not resolved. No further follow-
up will occur for any AEs that are not related to the study drug unless this is required by a health 
authority or the Medical Monitor.   
Treatment related adverse events, including LSRs, pitted scars ≥  5 mm in diameter or ≥ 1mm in 
depth originated from MC lesion and hypertrophic scars/keloid, will be followed up until 
resolution or up to 1 year after last treatment, whichever is sooner.  
9.4.2 
Follow-Up of Post Study Serious Adverse Events 
Serious adverse events that are identified on the last scheduled contact (Week 24/ET2) must be 
recorded in the study database and reported to the CRO according to the reporting procedures 
outlined in Section 10. 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-
Page 55/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 55 of 69
 
 
 
up. The investigator should continue to report any significant follow-up information to the Sponsor 
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. 
9.5 
Pregnancy 
Females 9 years of age and older must use an effective method of birth control during the course 
of the study and for 30 days following their final study visit. The following are considered 
acceptable methods of birth control for this study: abstinence with a documented acceptable 
method of birth control if the subject becomes sexually active, oral contraceptives, contraceptive 
patches, contraceptive implant, vaginal contraceptive, double-barrier methods (e.g., condom and 
spermicide), contraceptive injection, Intrauterine Device (IUD), hormonal IUD, permanent 
contraception, same sex partner or partner who has had a vasectomy. Tubal ligation is not 
considered to be surgical sterilization; women with tubal ligations will be required to complete 
UPTs at the required timepoints. 
A female is considered to be of childbearing potential unless she is post-menopausal (no menses 
for 24 consecutive months), surgically sterilized (documented hysterectomy, documented bilateral 
salpingectomy, documented bilateral oophorectomy) or under 9 years of age. Tubal ligation does 
not meet the definition of surgically sterile. 
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. 
Page 56/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 56 of 69
 
 
 
During the study, females 9 years of age and older should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual cycle). Study 
drug shall be held immediately if a subject is suspected to be pregnant and study drug must be 
permanently discontinued if pregnancy is confirmed. The Investigator must immediately notify 
the medical monitor/CRO of any female subject who becomes pregnant any time during study 
participation, record the information on the pregnancy notification form and email the form to the 
CRO. Subjects found to be pregnant prior to Week 12 will stop study drug treatment, continue 
with study visits through Week 24 and follow up with pregnancy outcome. Beyond Week 24, the 
site should follow-up with the subject periodically during the pregnancy for ongoing health and 
safety information through the end of the pregnancy, as applicable. The investigator is responsible 
for following the pregnancy through the end of the pregnancy and for providing the assessment of 
the healthy live birth or for reporting any abnormal  outcome such as stillbirth, miscarriage, or 
deformity to the CRO/Sponsor (Note: Congenital anomaly/birth defect/ etc. are considered SAEs 
and require separate reporting per Section 10.) 
9.6 
Overdose 
There is no specific antidote for SB206.  In the event of an overdose, best supportive care should 
be utilized. Methylene blue may be used to treat subjects exhibiting methemoglobinemia. The 
Medical Monitor/CRO/Sponsor must be notified of any subject exhibiting signs of 
methemoglobinemia. 
10 SERIOUS ADVERSE EVENT 
10.1 Definition of Serious Adverse Event 
A SAE is any event that meets any of the following criteria: 
• Death 
 
• Life-threatening event (i.e., the subject was at immediate risk of death from the event as it 
occurred. It does not include a reaction that if it had occurred in a more serious form might 
have caused death. For example, drug induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life threatening even though drug induced hepatitis 
can be fatal.) 
• Inpatient hospitalization or prolongation of existing hospitalization (AEs requiring 
hospitalization should be considered SAEs. Hospitalization for elective surgery or routine 
clinical procedures that are not the result of AE (e.g., elective surgery for a pre-existing 
condition that has not worsened) need not be considered AEs or SAEs. If anything, 
Page 57/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 57 of 69
 
 
 
untoward is reported during the procedure, that occurrence must be reported as an AE, 
either 'serious' or 'non-serious' according to the usual criteria. In general, hospitalization 
signifies that the subject has been detained (usually involving at least an overnight stay) at 
the hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician's office or outpatient setting. When in doubt as to whether 
'hospitalization' occurred or was necessary, the AE should be considered serious.) 
• Persistent or significant disability/incapacity (if the experience results in a substantial 
and/or permanent disruption of the subject's ability to carry out normal life functions) 
• Congenital anomaly/birth defect in the offspring of a subject who received SB206 or 
Vehicle Gel 
• Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are: 
− Intensive treatment in an emergency room or at home for allergic bronchospasm 
− Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
− Development of drug dependency or drug abuse 
10.2 Reporting Serious Adverse Events 
Any SAE, whether deemed drug-related or not, must be reported to the CRO as soon as possible 
after the investigator or coordinator has become aware of its occurrence. The 
investigator/coordinator must notify the CRO within 24 hours of notification of the event. When 
appropriate, Novan will notify the appropriate regulatory body of drug related SAEs.  
If a subject experiences an SAE or pregnancy, the investigator must: 
1. Report the SAE or pregnancy immediately (within 24 hours) after the Investigator becomes 
aware of the event. 
2. Complete an SAE or pregnancy notification form and send the appropriate reporting form 
to the safety office 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. 
Page 58/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 58 of 69
 
 
 
4. Provide a more detailed report to both the CRO 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 study drug. 
5. The Investigator will notify the IRB of the SAE or pregnancy according to specific IRB 
requirements. 
6. The Investigator will collect information on SAEs until the subject’s health has returned to 
baseline status, until all parameters have returned to normal, or remaining health issues 
have otherwise been explained. 
7. The Investigator is responsible for following pregnancies through the end of the pregnancy 
and for providing the assessment of the healthy live birth or for reporting any abnormal 
pregnancy outcome such as stillbirth, miscarriage, or deformity to the CRO/Sponsor. 
 
For clarity on how to record an adverse event that progresses into a serious adverse event, there 
should be two events recorded: the first event would be the beginning adverse event, and the 
second event would be the serious adverse event (i.e. only the time the AE qualified as serious). 
Resolution of the SAE should be recorded in the same manner, two end dates for SAE and AE, 
where the SAE and AE may or may share the same end date.   
11 STATISTICS 
11.1 General Procedures 
The study treatment period is defined from randomization through completion of Week 12/ET1 
visit and the safety follow-up period is from the completion of Week 12 through the completion 
of Week 24/ET2 visit. 
After all subjects have completed their Week 12/ET1 visit, thus completing the Treatment Period 
of the study, the database through Week 12/ET1 will be frozen and unblinded for purposes of the 
primary analysis of efficacy and safety.  While this analysis is being prepared, the subjects will 
continue through Week 24/ET2. After all subjects have completed their Week 24/ET2 visit, the 
database will be locked and the follow-up data will be analyzed. Prior to unblinding and the 
primary analysis of efficacy and safety, a detailed, finalized SAP will be completed and placed on 
file. The Statistical Analysis Plan will contain a more comprehensive explanation than that 
provided here of the methodology used in the statistical analyses, as well as the rules and data 
handling conventions used to perform the analyses and the procedure used to account for missing 
data. 
Page 59/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 59 of 69
 
 
 
Safety and efficacy endpoints will be displayed using descriptive statistics and graphical displays, 
where applicable. For categorical variables, frequencies, and percentages will be presented. The 
denominator for percentage will be based on the number of subjects appropriate for the purpose of 
analysis. Continuous variables will be summarized using descriptive statistics (number of subjects, 
mean, median, standard deviation [SD], minimum, and maximum). Where relevant, 95% 
confidence intervals will be calculated. Any statistical tests will be conducted at the 0.05 
significance level using 2-tailed tests, and nominal p-values will be reported.  
11.2 Sample Size 
Approximately 340 subjects, 6 months of years of age and older, with a minimum of 3 and a 
maximum of 70 lesions at Baseline will be randomized in a 2:1 (active:vehicle) scheme. The 
sample size assumptions for this study were informed by the completed Phase 2 study NI-MC201 of 
subjects ≥2 years of age with 3-70 MC lesions at Baseline.  In the ITT population of the Phase 2 
study, the observed rates of clearance at Week 12 were 18% (12/66) for vehicle and 38% (18/48) 
for SB206 12% once daily (QD) and the covariate-adjusted treatment difference was 18%.  
A sample size of 340 subjects (227 subjects in the SB206 12% QD group and 113 subjects in the 
vehicle group) will provide 94% power for a 2-sided alpha test of size 0.05 to detect an absolute 
difference of 18% when the vehicle response rate is 18%. This same sample size provides 93% 
power to detect a treatment difference of 18% when the vehicle response rate is 20% and 83% 
power when the treatment difference is 15% and the vehicle response rate is 20%.  
11.3 Analysis Populations 
The analysis populations include the following: 
Safety Population: The Safety population will consist of all subjects who receive at least one 
application of study medication. 
Intent-To-Treat Population (ITT): The ITT population will consist of all subjects who are 
randomized. 
Per-Protocol Population (PP): The PP population will consist of all subjects in the ITT 
population. who had no significant protocol deviations that impacted the analyses of the efficacy 
endpoints. 
Page 60/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 60 of 69
 
 
 
12 STATISTICAL METHODS 
12.1.1 
Demographic and Baseline Characteristics 
Subject demographic and Baseline characteristics will be summarized by treatment group for the 
SAF, ITT, and PP populations. Relevant medical history, current medical conditions, and any other 
relevant information will be listed by subject. 
12.1.2 
Efficacy Analysis 
The primary efficacy endpoint, proportion of subjects with complete clearance of all treatable 
molluscum lesions at Week 12 in the ITT, will be analyzed using a generalized estimating equation 
(GEE) for logistic regression with an exchangeable working correlation structure. The model will 
include treatment, investigator type (dermatologist vs other), household number of randomized 
subjects (1 subject per household vs 2 subjects per household), age and Baseline lesion count as 
factors. The odds ratio between SB206 12% and vehicle gel, 95% CIs for the odds ratio, and P-
value for the covariate-adjusted treatment comparison will be presented. Only subjects who 
achieve complete clearance at Week 12 will be counted as responders for the primary analysis; all 
other subjects (e.g., those who discontinue the study before achieving complete clearance) will be 
reported as failures. As a sensitivity analysis, the primary efficacy analysis will also be reported 
for the PP population. 
 
The familywise error rate with respect to the primary endpoint and secondary endpoint will be 
strongly controlled at the alpha=0.05 level using a fixed-sequence method testing strategy. If the 
primary endpoint is not statistically significant at the alpha=0.05 level, the secondary efficacy 
endpoint will be considered not significant. If the primary endpoint is statistically significant at 
the alpha=0.05 level, the secondary efficacy endpoint will be analyzed. 
• Proportion of all study subjects demonstrating complete clearance of all treatable MC at 
Week 8 
If the secondary efficacy endpoint fails to reach statistical significance at the alpha=0.05 level, it 
will be considered not statistically significant.  
The dichotomous secondary efficacy endpoint will be analyzed using the GEE model described 
for the primary efficacy endpoint. Other sensitivity analyses may be performed and will be 
specified in the SAP. 
The analyses methods to be used for the exploratory endpoints will be detailed in the SAP, 
including any additional exploratory analyses that may be conducted. The SAP will be finalized 
before unblinding and database lock. 
Page 61/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 61 of 69
 
 
 
12.1.3 
Analysis of Safety 
12.1.3.1 
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 that occurred any time on or after the first in-clinic application of study drug 
through the last application of study medication. Medical history noted prior to the first study drug 
administration that worsen after Baseline will also be reported as AEs and included in the 
summaries.  
Treatment-emergent AEs will be summarized by treatment group, the number of subjects reporting 
a TEAE, System Organ Class (SOC), preferred term, severity, relationship to study drug 
(causality), and seriousness.  When summarizing AEs by severity and relationship, each subject 
will be counted only once within a system organ class or a preferred term by using the event with 
the highest severity and greatest relationship within each classification. 
Serious AEs will be summarized by treatment group, severity, and relationship to study drug, and 
individual SAEs will be listed by subject. In addition, a list of subjects who prematurely 
discontinue from the study due to an AE will be provided. 
12.1.3.2 
Physical Examination 
Changes in physical examination from baseline to end of treatment will be summarized.  Any 
clinically significant changes from Baseline will be documented as an AE. 
12.1.3.3 
Urine Pregnancy Tests 
Urine pregnancy tests results for females 9 years of age and older will be presented in data listings 
by subject.   
13 ETHICS AND RESPONSIBILITIES 
13.1 Good Clinical Practice 
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 
the CRO 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. 
Page 62/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 62 of 69
 
 
 
13.2 Data Safety Monitoring Board (DSMB) 
When approximately 200 subjects (cumulative across studies MC301 and MC302) have completed 
4 weeks of treatment, a Data Safety Monitoring Board (DSMB) will review all available unblinded 
safety data (including patch testing). All responsibilities of the DSMB and details of data to be 
reviewed will be detailed in the DSMB charter. 
13.3 Institutional Review Board/Independent Ethics Committee 
The protocol, informed consent/ assent form(s), recruitment materials, and all participant materials 
will be submitted to the Institutional Review Board (IRB) for review and approval. Approval of 
both the protocol and the consent/assent form must be obtained before any subject is screened. 
Any amendment to the protocol will require review and approval by the IRB before the changes 
are implemented to the study.  In addition, all changes to the consent/assent form will be IRB-
approved; a determination will be made regarding whether a new consent needs to be obtained 
from subjects who provided consent, using a previously approved consent form. 
13.4 Informed Consent 
Informed consent is a process that is initiated prior to the subject agreeing to participate in the 
study and continues throughout the subject’s study participation. Consent/assent forms will be IRB 
-approved and the subject will be asked to read and review the document. The investigator will 
explain the research study to the subject and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the subject’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research subjects. Subjects will 
have the opportunity to carefully review the written consent/assent form and ask questions prior 
to signing. The subjects should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The informed consent/assent document 
should be signed prior to any procedures being done specifically for the study. Subjects must be 
informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent/assent document will be given to the subjects 
for their records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the subject undergoes any study-
specific procedures. The rights and welfare of the subjects will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
Page 63/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 63 of 69
 
 
 
13.5 Records Management 
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. 
13.6 Source Documentation 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Data recorded on the eCRF derived from source documents should be 
consistent with the data recorded on the source documents. 
Clinical data will be entered into a 21 CFR Part 11-compliant data capture system provided by the 
CRO. The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will 
be entered directly from the source documents. 
13.7 Study Files and Record Retention 
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. 
Page 64/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 64 of 69
 
 
 
14 AUDITING AND MONITORING 
14.1 Auditing 
In addition to the routine monitoring procedures, audits of clinical research activities in accordance 
with standard operating procedures (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 the CRO immediately that this request has been made. 
Study conduct may be assessed during the course of the study by a Quality Assurance 
representative(s) to ensure that the study is conducted in compliance with the protocol and GCP.  
He/she will be permitted to inspect the study documents (study protocol, study records, 
investigational product, original, study-relevant medical records). All subject data will be treated 
confidentially. 
14.2 Monitoring 
All aspects of the study will be monitored by the CRO or Novan according to 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 the CRO and Novan at any time for review and audit to 
ensure the integrity of the data. The investigator must notify the CRO immediately if the 
responsible IRB has been disqualified or if proceedings leading to disqualification have begun. 
The investigator must conduct the protocol in accordance with applicable GCP regulations and 
guidelines, applicable informed consent regulations (21 C.F.R. § 50.20, 1999), and in compliance 
with the principles in the Declaration of Helsinki. Every attempt must be made to follow the 
protocol and to obtain and record all data requested for each subject at the specified times. If data 
is not recorded per protocol, the reason(s) must be clearly documented on the study records. 
Before study initiation, at a site initiation visit or at a meeting with the investigator(s), a CRO 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. 
Page 65/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 65 of 69
 
 
 
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 
AEs/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 the CRO and the responsible IRB with a study summary shortly 
after study completion. 
15 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Novan. A protocol change intended to eliminate an apparent immediate hazard to 
subjects may be implemented immediately, provided the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes. Novan will submit protocol amendments to the appropriate regulatory 
authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Novan, the amendment to the protocol 
substantially changes the study design and/or increases the potential risk to the subject and/or has 
an impact on the subject's involvement as a study participant, the currently approved written 
informed consent form will require similar modification. In such cases, informed consent will be 
renewed for subjects enrolled in the study before continued participation. 
16 STUDY REPORT AND PUBLICATIONS 
Novan is responsible for preparing and providing the appropriate regulatory authorities with 
clinical study reports according to the applicable regulatory requirements. 
The publication policy of Novan is discussed in the investigator's Clinical Research Agreement. 
Page 66/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 66 of 69
 
 
 
17 STUDY DISCONTINUATION  
Both Novan and the principal investigator reserve the right to terminate the study at the 
investigator’s site at any time. Should this be necessary, Novan or a specified designee will inform 
the appropriate regulatory authorities of the termination of the study and the reasons for its 
termination, and the principal investigator will inform the IRB/IEC of the same. In terminating the 
study, Novan and the principal investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 
18 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be disclosed 
to any person or entity not directly involved with the study unless prior written consent is gained 
from Novan. However, authorized regulatory officials, IRB/IEC personnel, Novan and its 
authorized representatives are allowed full access to the records. 
Subject’s will only be identified at a minimum by unique subject numbers in the study database. 
If required, the subject's full name may be made known to an authorized regulatory agency or other 
authorized official. 
19 REFERENCES 
 
1. 
Chen X, Anstey AV, Bugert JJ. Molluscum contagiosum virus infection. Lancet Infect Dis 
2013; 13: 877–88. 
2. 
Dohil M, Lin P, Lee J, Lucky AW, Paller AS, Eichenfield LF. The epidemiology of 
molluscum contagiosum in children. J Am Acad Dermatol 2006; 54: 47-54. 
3. 
Olsen, JR, Gallacher, J, Piguet, V, and Francis, NA. Epidemiology of molluscum 
contagiosum in children: a systematic review. Fam Pract. 2014; 31: 130–136. 
4. 
Olsen JR, Gallacher J, Finlay AY, Piguet V, Francis NA. Time to resolution and effect on 
quality of life of molluscum contagiosum in children in the UK: a prospective community 
cohort study. Lancet Infect Dis 2015; 15: 190–95.  
5. 
Osio A, Deslandes E, Saada V, Morel P, Guibal F. Clinical characteristics of molluscum 
contagiosum in children in a private dermatology practice in the greater Paris area, France: 
a prospective study in 661 patients. Dermatology 2011; 222: 314–20.  
6. 
Schofield JK, Fleming D, Grindlay D, Williams H. Skin conditions are the commonest new 
reason people present to general practitioners in England and Wales. Br J Dermatol 2011; 
165: 1044–50. 
 
Page 67/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 67 of 69
 
 
 
20 APPENDICES 
20.1 APPENDIX I Names of Study Personnel 
Sponsor: 
Novan, Inc. 
4105 Hopson Road 
Morrisville, NC 27560 
Clinical Research 
Organizations: 
Synteract 
5909 Sea Otter Place 
Carlsbad, CA 92010 
Safety Number or 
Contact Email: 
Tel: (760) 268-8080 
Fax: (760) 268-6500 
Email: SafetyFax@Synteract.com 
 
 
 
 
Page 68/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 68 of 69
 
 
 
20.2 APPENDIX II Procedure for Suspected Sensitization 
In the event that a subject has a local skin reaction (LSR) severe enough that is felt to be 
suggestive of allergic contact dermatitis, patch testing may be initiated for confirmation after 
consultation with the CRO Medical Monitor and with the consent of the subject/caregiver. Once 
the LSR has been completely resolved for a period of 2 weeks and up to 2 months, patch testing 
may commence. Novan will provide more detailed patch testing instructions once requested from 
the CRO Medical Monitor. The site will use a study drug kit already assigned to the subject in 
order to complete the testing. 
 
For patch testing: 
• Discontinue study treatment (see Section 7.2.4 regarding LSRs) 
• Document the event as an AE and consult with the CRO Medical Monitor. Detailed 
instructions for the patch testing will be provided after discussion with the Medical 
Monitor. 
• When applicable, challenge patch testing should be performed after all signs and 
symptoms of the LSR have been resolved for approximately 2 weeks to 2 months. 
• The randomized study treatment will be applied to a naïve area on the participant’s back 
or arm. Use the subject’s most recently assigned study drug kit to obtain material for 
testing. 
• The participant will return to the site approximately 48 hours after the application of the 
patches. Approximately 30 minutes, 24 hours and 48 hours after patch removal, the patch 
site(s) will be evaluated using the scale below (Table 2). If the 48-hour reading is 
equivocal, it is recommended to evaluate the site at 72 to 96 hours after removal. Take 
photographs if the reaction interpretation is positive or equivocal and transmit them to the 
Medical Monitor. Further instructions will be given after review of the photos. 
• At the last reading, the investigator will make the final interpretation of any challenge 
reactions. See Table 3 below.  
 
 
Last 
application 
of study 
treatment 
Patch 
application:  
≥ 2 weeks - 
< 2 months 
after AE 
resolution 
48 hours 
after 
application: 
Remove 
patch 
30 minutes 
after 
removal:  
1st reading 
(Table 2) 
24 hours 
after 
removal:  
2nd reading 
(Table 2) 
48 hours after 
removal:  
3rd reading 
(Table 2) and 
Interpretation 
(Table 3) 
Page 69/70


16.1.1 Protocol NI-MC302  
Novan: A Phase 3 Molluscum Contagiosum Efficacy and Safety Study  
Confidential
SB206/Berdazimer Sodium Gel 
Page 69 of 69
 
 
 
Table 2: Grading System for Patch Test Reactions 
Score 
Description 
+/- 
Doubtful reaction, faint macular erythema 
+ 
Weak, non-vesicular reaction with erythema, infiltration and papules 
++ 
Strong vesicular reaction with erythema, infiltration and papules 
+++ 
Spreading bullous reaction 
- 
Negative reaction 
IR 
Irritant reaction 
Table 3: Challenge Reaction Interpretation 
Score 
Description 
Negative 
Might include an irritative reaction 
Equivocal 
Unable to determine 
Positive 
Reaction definitely due to sensitization 
 
 
 
 
 
 
 
 
 
 
 
Page 70/70


 
 
 
 
NI-MC302 Clinical Study Report 
 
16.1.9 Documentation of Statistical Methods 
Page 1/1 
Confidential 
 
 
16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 
 
This appendix includes 
 
Document 
Version, Date 
Statistical Analysis Plan 
Version 1.0, 10 September 2019 
Statistical Analysis Plan 
Version 2.0, 18 November 2019 
Statistical Analysis Plan 
Version 3.0, 12 December 2019 
 
 
 
 
 
 
 


 
TMP-SOP-0202-001-03_SAP Template 
Page 1/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
 
 
 
Statistical Analysis Plan 
 
Novan, Inc.  
NI-MC302 
 
A Phase 3 Multi-Center, Randomized, Double-Blind, Vehicle-Controlled, Parallel Group 
Study Comparing the Efficacy and Safety of SB206 and Vehicle Gel Once Daily in the 
Treatment of Molluscum Contagiosum 
Protocol Version: 26Mar2019 
 
 
 
Sponsor:  
 
Novan, Inc.  
4105 Hopson Road 
Morrisville, NC 27560 
 
 
Prepared by:  
Christopher Tait 
5909 Sea Otter Place, Suite 100 
Carlsbad, CA 92010 
 
 
Version 
Date 
Version 1 
10 Sep 2019 
 
 
 
 
 
Page 2/120


11SEP2019
Page 3/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 3/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................................. 6 
2. 
STUDY DOCUMENTS ......................................................................................................... 6 
3. 
STUDY OBJECTIVES .......................................................................................................... 6 
4. 
STUDY DESIGN AND PLAN .............................................................................................. 6 
5. 
DETERMINATION OF SAMPLE SIZE ............................................................................ 9 
6. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................. 10 
7. 
NOTATION OF TREATMENT GROUPS AND VISITS ............................................... 11 
8. 
ANALYSIS POPULATIONS .............................................................................................. 11 
9. 
STUDY POPULATION....................................................................................................... 12 
9.1 
SUBJECT DISPOSITION .................................................................................................. 12 
9.2 
ELIGIBILITY.................................................................................................................. 12 
9.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 12 
9.4 
EXTENT OF EXPOSURE ................................................................................................. 13 
9.5 
PROTOCOL DEVIATIONS .............................................................................................. 13 
9.6 
MEDICAL HISTORY ...................................................................................................... 14 
9.7 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................. 14 
10. EFFICACY ANALYSES ..................................................................................................... 15 
10.1 EFFICACY ENDPOINTS .................................................................................................. 15 
10.2 BASELINE VALUES ....................................................................................................... 16 
10.3 ADJUSTMENTS FOR COVARIATES ................................................................................ 16 
10.4 HANDLING OF DROPOUTS OR MISSING DATA ............................................................. 16 
10.5 INTERIM ANALYSIS AND DATA MONITORING ............................................................. 16 
10.6 EXAMINATION OF SUBGROUPS .................................................................................... 16 
10.7 MULTIPLE COMPARISON/MULTIPLICITY ..................................................................... 17 
10.8 MULTICENTER STUDIES ............................................................................................... 17 
11. METHODS OF EFFICACY ANALYSIS .......................................................................... 17 
11.1 PRIMARY EFFICACY ANALYSIS ................................................................................... 17 
11.2 SECONDARY EFFICACY ANALYSES ............................................................................. 18 
11.3 EXPLORATORY ANALYSES .......................................................................................... 18 
12. OTHER ANALYSES ........................................................................................................... 19 
13. SAFETY ANALYSES .......................................................................................................... 20 
13.1 ADVERSE EVENTS ........................................................................................................ 20 
13.2 LOCAL SKIN REACTION ............................................................................................... 21 
13.3 EVENTS OF SPECIAL INTEREST .................................................................................... 21 
13.4 URINE PREGNANCY TEST ............................................................................................ 21 
13.5 PHYSICAL EXAMINATION ............................................................................................ 21 
13.6 PATCH TESTING ........................................................................................................... 21 
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................ 22 
15. REFERENCES ..................................................................................................................... 23 
16. APPENDICES ...................................................................................................................... 24 
Page 4/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 4/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
APPENDIX A: DERMATOLOGY LIFE QUALITY INDEX (DLQI) AND CHILDREN’S 
DERMATOLOGY LIFE QUALITY INDEX (CDLQI) SCORING ............................. 24 
APPENDIX B: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS .................... 28 
APPENDIX C: SAS PROGRAMMING QC REQUIREMENTS ....................................................... 32 
APPENDIX D:  LIST OF TABLES, FIGURES, AND LISTINGS ...................................................... 33 
Page 5/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 5/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Full Notation 
AE 
adverse event 
ATC 
anatomical/therapeutic/chemical 
BOTE 
beginning of the end 
CDLQI 
Children’s Dermatology Life Quality Index 
CRO 
contract research organization 
DLQI 
Dermatology Life Quality Index 
DSMB 
data safety monitoring board 
eCRF 
electronic case report form 
ICH 
International Council for Harmonisation 
ITT 
Intent-to-Treat 
LSR 
local skin reaction 
MC 
molluscum contagiosum 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per-Protocol 
QC 
quality control 
QD 
once daily 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
 
  
 
Page 6/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 6/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Novan, Inc. protocol version 1.0 [A Phase 3 Multi-Center, 
Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Study Comparing the Efficacy 
and Safety of SB206 and Vehicle Gel Once Daily in the Treatment of Molluscum Contagiosum]. 
The purpose of this plan is to provide specific guidelines from which the statistical analyses will 
proceed. Any deviations from this plan will be documented in the clinical study report. 
2. STUDY DOCUMENTS 
The following study documents are used for the preparation of the statistical analysis plan (SAP): 
x Protocol version 1.0, 26Mar2019 
x Annotated electronic case report form (eCRF) version 2.0, 30Jul2019 
x Data management plan version 1.0, 15Apr2019 
3. STUDY OBJECTIVES 
The objective of the study is to evaluate the efficacy and safety of SB206 12% once daily (QD) 
for the treatment of molluscum contagiosum (MC). 
4. STUDY DESIGN AND PLAN 
This is a Phase 3 multi-center, randomized, double-blind, vehicle-controlled, parallel group study 
to be conducted in approximately 340 subjects ≥6 months of age with MC. After obtaining 
informed consent/assent, subjects who satisfy entry criteria will be randomized to a 2:1 
(active:vehicle) scheme. Subjects receiving current treatment for MC at the time of the Screening 
Visit will enter a washout period of up to 14 days prior to randomization. In the event no 
washout period is required, Screening and Baseline visit activities may be combined into a single 
visit. At randomization, subjects will be stratified into 4 strata corresponding to the cross-
classification of household number of randomly assigned subjects (1 subject per household vs 2 
subjects per household) and investigator type (dermatologist vs other). Households randomizing 
2 subjects will receive the same treatment assignment for both subjects. Up to 2 subjects from 
the same household may be randomly assigned on the same day, if both individually meet all 
inclusion and exclusion criteria. For subjects in the same household, Screening can occur on 
different days; however, the baseline visit must occur on the same day. 
Subjects or their caregivers will apply SB206 12% or Vehicle Gel QD for a minimum of 4 weeks 
and up to 12 weeks to all lesions identified at Baseline and new treatable lesions that arise during 
the course of the study. Subjects or their caregivers will continue to treat the area until the next 
scheduled visit even if the lesion(s) clear. If the investigator determines all lesions are cleared at 
a clinic visit, the treatment may stop. At Weeks 2, 4, 8 and 12, the investigator will count and 
record the number of active (raised, treatable) molluscum lesions per body area. At Weeks 2, 4, 
Page 7/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 7/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
and 8, the investigator will determine if new lesions have occurred since the last visit, and the 
subject or caregiver will be instructed by the investigator to re-initiate treatment. If treatment is 
stopped due to clearance, subjects will continue regularly scheduled visits through Week 24. 
Subjects will visit the clinic at Screening/Baseline, Week 2, Week 4, Week 8, Week 12, and 
Week 24. Subjects will be contacted via phone on Day 2 to collect subject information on early 
dose reactions. At Weeks 16 and 20, subjects will be contacted via phone to capture information 
regarding MC recurrence and adverse events (AEs); at Week 24, the subject will be seen at the 
site for a final study visit to assess scarring, keloid, and MC recurrence. Subjects who 
discontinue the study prior to the Week 12 visit due to AEs or other reasons will be asked to 
complete the Week 12 visit assessments: this will be recorded as an Early Termination (ET1) 
visit. No study drug treatment will be provided after the Week 12 visit. Subjects who discontinue 
from the study after Week 12 but prior to Week 24 will be asked to come to the site to complete 
Week 24 assessments; this will be recorded as an ET2 visit. 
Safety assessments include local skin reactions (LSRs), AE collection, including scarring/keloid, 
and urine pregnancy tests. Safety assessments will be completed at specified site visits through 
Week 12. After Week 12, safety information for ongoing AEs and new AEs will be collected, 
along with information regarding household MC occurrence. 
Inflammatory reactions around the MC has been associated with imminent resolution of MC 
(sometimes referred to as “beginning-of-the-end” [“BOTE”] sign). The investigator (or 
designated evaluator) will assess the presence and overall degree of inflammatory reactions at 
MC lesions at Baseline (before dosing) and Weeks 2 through 12. In most cases, clinical features 
can differentiate between BOTE and LSR. BOTE may be associated with itch, but not pain. 
BOTE is usually asymptomatic, self-limited, and localized to individual MC lesions and does not 
require discontinuation of study treatment or additional treatment. LSR is generally more diffuse, 
associated with significant itch or tenderness, may necessitate discontinuation of study treatment, 
and may need treatment for symptomatic relief (e.g., a topical corticosteroid or topical 
anesthetic). For very severe LSR, systemic corticosteroids may be considered. Investigators will 
assess the treatment area at each scheduled visit and use their medical judgement to differentiate 
between BOTE and LSRs. BOTE Inflammation Score and LSR score will be recorded at each 
visit. BOTE should not be considered an AE. When LSRs are clinically significant at the 
application site, the investigator should report the condition as an AE(s). 
At Baseline (at least 30 minutes after dosing) and Weeks 2 through 12, the investigators will rate 
LSRs on individual features including erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration. At Baseline (pre-dose) and Weeks 2 through 12, 
the investigators will rate BOTE signs using the BOTE Inflammation Score.  
The following tables describe the scoring parameters for the BOTE Inflammation Score and LSR 
score. 
Page 8/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 8/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
BOTE Inflammation Score 
Score 
Global Assessment 
Description 
0 
No inflammation 
No evidence of local inflammation 
1 
Mild 
Minimal erythema and/or edema 
2 
Moderate 
Definite erythema and/or edema with or 
without hemorrhagic crusting 
3 
Severe 
Erythema and edema with definite 
hemorrhagic crusting 
4 
Very severe 
Strong reaction spreading beyond the 
treated area, bullous reaction, erosions 
 
LSR Score 
Score 
Erythema 
Flaking/ 
Scaling 
Crusting 
Swelling 
Vesiculation/ 
Pustulation 
Erosion/ 
Ulceration 
0 
Not present 
Not 
present 
Not 
present 
Not 
present 
Not present 
Not 
present 
1 
Slightly 
pink 
Mild, 
limited 
Isolated 
crusting 
Minimal, 
limited 
Fine vesicles 
Superficial 
erosion 
2 
Pink or 
light red 
Moderate 
Crusting   
< 50% 
Mild, 
palpable 
Scant 
transudate or 
exudate 
Moderate 
erosion 
3 
Red, 
restricted to 
treatment 
area 
Coarse 
Crusting   
> 50% 
Moderate 
Moderate 
transudate or 
exudate 
Marked, 
extensive 
4 
Red 
extending 
outside 
treatment 
area 
Scaling 
extending 
outside 
treatment 
area 
Crusting 
extending 
outside 
treatment 
area 
Marked 
swelling 
extending 
outside 
treatment 
area 
Marked 
transudate or 
exudate 
Black 
eschar or 
ulceration 
Clinically significant LSRs that are reported as AEs and/or subject-reported intolerability (i.e., 
itching, pain) may result in an investigator-directed temporary treatment hold (drug holiday), and 
topical corticosteroids may be used to treat LSRs for up to 2 weeks. The subject may re-initiate 
study drug treatment prior to the next scheduled visit. Upon re-initiation of study drug treatment, 
if a subject develops worsening LSRs, allergic contact dermatitis may be suspected. The 
investigator may take photographs of the suspected allergic contact dermatitis and discuss 
possible confirmation of allergic contact dermatitis with the contract research organization’s 
Page 9/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 9/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
(CRO) medical monitor. The investigator should also discuss the necessity of patch testing with 
the subject/caregiver. The investigator will then discontinue the subject from study drug 
treatment and treat the area(s) with corticosteroids for up to 2 weeks. If the subject provides 
consent/assent, the investigator will consult with the CRO’s medical monitor to implement the 
process for patch testing.  
Adverse events will be assessed and collected after the initiation of study drug treatment through 
the end of the subject’s last visit. Treatment-related AEs will be followed up until resolution or 
up to 1 year after last treatment, whichever is sooner.  
Scar formation will be assessed starting at the Week 4 visit through Week 12 and again at 
Week 24. The investigator will map locations of the molluscum lesions at Baseline. Additional 
lesions identified through Week 12 will be added to the map. Using the map as a guidance, the 
investigator will assess the treated areas for scar/keloid formation. The investigator will count 
and record the number of active (raised, treatable) molluscum lesions per body area. If a new 
scar is noted after the subject treated with study drug, this will be considered an AE for the 
purposes of this study. In addition, keloid/hypertrophic scars will also be recorded as AEs.  
If a subject’s treatment is discontinued by the investigator or the subject because of an AE, that 
AE should be indicated as the reason for treatment discontinuation. All subjects will be 
encouraged to remain in the study throughout the 24-week study duration. 
When approximately 200 subjects (cumulative across studies MC301 and MC302) have 
completed 4 weeks of treatment, a data safety monitoring board (DSMB) will review all 
available unblinded safety data (including patch testing).  
5. DETERMINATION OF SAMPLE SIZE 
Approximately 340 subjects, 6 months of age and older, with a minimum of 3 and a maximum of 
70 MC lesions at Baseline will be randomized in a 2:1 (active:vehicle) scheme. The sample size 
assumptions for this study were informed by the completed Phase 2 study NI-MC201 of subjects 
2 years of age and older with between 3 and 70 MC lesions at Baseline. In the Intent-to-Treat 
(ITT) Population of the Phase 2 study, the observed rates of complete clearance at Week 12 were 
18% (12/66) for vehicle and 38% (18/48) for SB206 12% QD and the covariate-adjusted 
treatment difference was 18%.  
A sample size of 340 subjects (227 subjects in the SB206 12% QD group and 113 subjects in the 
vehicle group) will provide 94% power for a 2-sided alpha test of size 0.05 to detect an absolute 
difference of 18% when the vehicle response rate is 18%. This same sample size provides 93% 
power to detect a treatment difference of 18% when the vehicle response rate is 20% and 83% 
power when the treatment difference is 15% and the vehicle response rate is 20%.  
Since the intra-cluster correlation is estimated to be small (<10%) and the average size of 
households is expected to be capped at roughly 1.3, the sample size is still sufficient when 
considering the fact that the subjects within the household may not be independent. 
Page 10/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 10/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
6. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs. 
Unless otherwise noted, all statistical testing will be 2-sided and will be performed at the 0.05 
significance level. Tests will be declared statistically significant if the calculated P-value is 
≤0.05.  
Continuous variable summaries will include the number of subjects (n) with non-missing values, 
mean, standard deviation (SD), median, minimum, and maximum. Other statistics such as 
quartiles, confidence intervals (CIs), and number of missing values may be added as appropriate.  
Categorical variable summaries will include the frequency and percentage of subjects who are in 
the category or each possible value. In general, the denominator for the percentage calculation 
will be based upon the total number of subjects in the study population within each treatment 
group, unless otherwise specified. The denominator for by-visit displays will be the number of 
subjects in the relevant study population with non-missing data at each visit.  
All summary tables will be presented by treatment group. Baseline summaries will also include 
an overall summary column.  
Individual subject data obtained from the eCRFs and any derived data will generally be 
presented by subject in data listings. 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
breaking the blind.  
Any analyses performed subsequent to breaking the blind will be considered post hoc and 
exploratory. Post hoc analyses will be labeled as such on the output and identified in the clinical 
study report. 
All analyses and tabulations will be performed using SAS£ software Version 9.4 or higher. 
Tables, listings, and figures will be presented in RTF format.  
The process for SAS program validation and quality control (QC) for programs and outputs is 
documented in the Synteract working instruction “SAS programming quality control.” 
Study-specific QC requirements can be found in Appendix C: SAS Programming QC 
Requirements. 
 
The study treatment period is defined from randomization through completion of Week 12/ET1 
visit and the safety follow-up period is from the completion of Week 12 through the completion 
of Week 24/ET2 visit. 
 
After all subjects have completed their Week 12/ET1 visit, thus completing the Treatment Period 
of the study, the database through Week 12/ET1 will be frozen and unblinded for purposes of the 
Page 11/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 11/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
primary analysis of efficacy and safety.  While this analysis is being prepared, the subjects will 
continue through Week 24/ET2. After all subjects have completed their Week 24/ET2 visit, the 
database will be locked and the follow-up data will be analyzed. 
7. NOTATION OF TREATMENT GROUPS AND VISITS 
Analysis visits 
 
Baseline is defined as the last nonmissing value recorded prior to the first application of study 
drug. If time is not recorded and the assessment was on the same day as the first application of 
study drug, then it will be assumed the assessment occurred prior to the application of study drug. 
The baseline record will have an analysis visit of “Baseline”. 
 
For all evaluations of all parameters, assessments will be analyzed according to the visit at which 
they occurred (i.e., per the eCRF visit label). In order to account for the fact that the Week 12 and 
Early Termination visits are collected on the same eCRF in the database, a check against the Study 
Exit form will be made to determine if the visit is a Week 12 or an Early Termination Visit. If the 
visit is an Early Termination visit, then the visit will be mapped according to the table below. If 
there is no corresponding Study Exit form on the same date, then it will be considered a Week 12 
visit. If there is no assessment in a given visit, then the following visit windows will be applied to 
determine if an unscheduled visit may be used: 
 
Visit 
Analysis Visit 
Target Study 
Day 
Study Day Analysis 
Window 
 
 
 
 
Week 2 (±3 days) 
Week 2 
15 
Day 12 to 22 
Week 4 (±5 days) 
Week 4 
29 
Day 23 to 43 
Week 8 (±5 days) 
Week 8 
57 
Day 44 to 71 
Week 12 (±5 days) 
Week 12 
85 
Day 72 to 98 
 
Days are measured from the date of randomization. Study days corresponding to measurements 
are calculated as: 
x Assessment date – date of randomization + 1, if assessment date is on or after the date of 
randomization. 
x Assessment date – date of randomization, if measurement date is before the date of 
randomization. 
In the event of multiple unscheduled records falling in the same analysis window, the assessment 
which is closest to the target study day will be chosen for analysis.  
8. ANALYSIS POPULATIONS 
The following subject population will be used for disposition analyses:  
Page 12/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 12/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
x The Enrolled Population will consist of all subjects who sign informed consent. If a 
subject is randomly assigned to a treatment, then treatment assignment will be based on 
randomized treatment; otherwise, they will be deemed a screen failure and will only 
appear in the overall summary columns of output. 
The following subject population will be used for safety analyses:  
x The Safety Population will consist of all subjects who receive at least 1 application of 
study medication. Treatment assignment will be based on the treatment actually received. 
If a subject receives any amount of SB206, then they will be summarized in the SB206 
12% QD arm.  
The following subject populations will be used for efficacy analyses:  
x The ITT Population will consist of all subjects who are randomized. Treatment 
assignment will be based on the randomized treatment.  
x The Per-Protocol (PP) Population will consist of all subjects in the ITT Population who 
had no significant protocol deviations that impacted the analyses of efficacy endpoints. 
Final determination of subject inclusion in the PP Population will be made prior to 
unblinding. Treatment assignment will be based on the randomized treatment. 
9. STUDY POPULATION 
9.1 Subject Disposition 
Subject disposition information will be summarized for all subjects by treatment group. 
Summaries will include: the number of subjects screened, the number of subjects in each 
analysis population, the number of subjects where study treatment stopped, primary reason for 
study treatment stopped, the number of subjects completing 12 weeks of the study (defined as 
having an end of treatment reason of “Completed Treatment Per Protocol” or a reason of 
“Complete Clearance Prior to Week 12” and does not have a Study Exit date prior to the 
subject’s), the number of subjects completed the study, and the primary reason for 
discontinuation. 
 
A summary of the number of subjects in each center and each population will be presented.  
9.2 Eligibility 
A listing of subjects not fulfilling any eligibility criteria will be created. 
9.3 Demographic and Baseline Characteristics 
Demographic variables include age, sex, ethnicity, and race. Age will be calculated in years 
relative to the informed consent date.  
Page 13/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 13/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Other baseline characteristics include lesion counts at baseline, site type (dermatologist vs other), 
number of sites and a breakdown of site type, number of randomly assigned subjects in 
household (1 subject vs 2 subjects), number of households and breakdown of household size, age 
at diagnosis of the current molluscum episode and time since diagnosis. Descriptive statistics 
will be presented for ages and other continuous variables. Frequency counts and percentages will 
be presented for sex, ethnicity, race and other categorical variables. Demographic and baseline 
characteristics will be summarized for the Safety, ITT, and PP Populations.  
9.4 Extent of Exposure 
Study drug exposure will be summarized for each treatment using the total number of 
applications, the duration of treatment, and the number of subjects requiring a treatment 
interruption and modification. Duration of treatment is defined as the last application date minus 
the first application date plus 1. 
Study drug compliance will be summarized and calculated as follows: 
Compliance [%] = (Actual applications applied)/(Planned applications) ×100, where 
x Actual applications applied = Planned applications – the number of applications missed 
x Planned applications = Number of applications (days) planned up to the point of 
treatment discontinuation.  
This implies that if a subject treatment discontinues treatment prior to Week 12 due to complete 
clearance, then the number of applications takes this information into account and the subject is 
not penalized for having complete clearance.  
Compliance will be further summarized into 2 groups:  
1. Subjects who did not have any interruptions or modifications using the same formula as 
above, and 
2. Subjects with modifications or interruptions. For these subjects, an adjusted compliance 
will be calculated in the following manner: the actual applications applied will be the 
same as above but the planned applications will exclude the time where the subject has 
dosing interrupted.  
9.5 Protocol Deviations 
Significant protocol deviations that could potentially affect the efficacy or safety conclusions of 
the study will be identified prior to database lock and unblinding of individual subject treatment 
information. Significant protocol deviations may include, but are not limited to: 
x Randomly assigned subjects who did not satisfy selected inclusion and exclusion criteria 
x Randomly assigned subjects who developed withdrawal criteria during the study but were 
not withdrawn 
Page 14/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 14/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
x Subjects who were randomized incorrectly including subjects of the same household who 
are randomized to different treatments  
x Subjects who received the wrong treatment 
x Subjects where the subject/site staff were unproperly unblinded 
x Week 12 Lesion Count not performed 
x Subjects who received an excluded concomitant treatment. 
The decision whether a subject is excluded from the PP Population will be made during the data 
review meeting prior to unblinding and database lock. Reasons for exclusion of a subject from 
the analysis and protocol deviations will be listed. 
A listing of all protocol deviations including the deviation designation (major or minor and 
significant or not), category, and indication of whether the deviation led to an exclusion of a 
subject from the PP Population will be presented in a data listing.   
Major and significant protocol deviations will be summarized by deviation category and 
treatment group.  
9.6 Medical History 
Medical history verbatim terms in the eCRFs will be mapped to system organ classes and 
preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0. 
Subject incidence of unique medical history terms by MedDRA system organ class and preferred 
term will be presented. The summary will be ordered by descending order of incidence of system 
organ class and preferred term within each system organ class. 
9.7 Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms in the eCRFs will be mapped to 
anatomical/therapeutic/chemical (ATC) class and preferred names using the WHODrug Global 
B3 (version March 2019). Prior medications are those medications started prior to the first 
application of study drug. Concomitant medications are those medications started on or after the 
date of first application of study drug or medications started prior to initial application of study 
drug and continued during the study. A medication can be classified as both prior and 
concomitant. If it cannot be determined whether the medication was a prior (or concomitant) 
medication due to a partial start or stop date, then it will be counted as both prior and 
concomitant; see Appendix B for the imputation of missing dates algorithm. 
Prior and concomitant medications will be summarized for each treatment by WHODrug Global 
ATC class Level 3 and preferred name. These summaries will present the number and percentage 
of subjects using each medication. Subjects may have more than 1 medication per ATC class and 
preferred name. At each level of subject summarization, a subject is counted once if he/she 
Page 15/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 15/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
reported 1 or more medications at that level. Each summary will be ordered by descending order 
of incidence of ATC class and preferred name within each ATC class. 
10. EFFICACY ANALYSES 
The primary efficacy analysis will be based on the ITT Population. Additional supportive 
efficacy analyses will be performed using the PP Population. 
10.1 Efficacy Endpoints 
The primary efficacy endpoint is the proportion of subjects with complete clearance of all 
treatable MC at Week 12.  
The secondary efficacy endpoint is the proportion of subjects with complete clearance of all 
treatable MC at Week 8.  
Complete clearance is defined as having a total number of lesions count of 0.  
The exploratory endpoints are the following: 
x Proportion of subjects with complete clearance of all treatable MC at Week 2 and Week 4 
visits 
x Proportion of subjects achieving at least a 75% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
x Percent change from Baseline in number of treatable MC at each visit (Weeks 2, 4, 8, 12) 
x Change from Baseline in number of treatable MC at each visit (Weeks 2, 4, 8, 12) 
x Proportion of subjects who have a recurrence of MC after the first visit at which complete 
clearance was observed, defined as the total lesion count being greater than 0 at any point 
after achieving a count of 0 
x Time to complete clearance of all treatable MC, defined as the days between the date of 
first dose and the first date of clearance. Subjects who do not achieve complete clearance 
will be censored at the date of the last lesion count assessment.  
x Proportion of subjects with scarring, defined as an answer of Yes to either question on the 
Scarring/Keloid Assessment eCRF page: “Was the presence of a scar > 1 mm deep and/or 
5 mm wide noted?” or “Was the presence of a scar noted?”, after clearance of lesion(s) at 
each visit (Weeks 4, 8, 12, 24) 
x Proportion of subjects with keloid or hypertrophic scar, defined as an answer of Yes to 
the Scarring/Keloid Assessment eCRF page question “Was the presence of a keloid or 
hypertrophic scar noted?”, after clearance of lesion(s) at each visit (Weeks 4, 8, 12, 24) 
Page 16/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 16/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
x Change from Baseline of the composite score from age-matched (at Baseline) 
Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index 
(CLDQI) assessment at Week 12 
x Subject-reported spread to household members as measured by any new occurrence of 
MC in household members of subjects at each visit (Weeks 2, 4, 8, 12, 16, 20, 24) 
10.2 Baseline Values 
Unless otherwise noted, baseline is defined as the last nonmissing value recorded prior to the 
first application of study drug. If time is not recorded and the assessment was on the same day as 
the first application of study drug, then it will be assumed the assessment occurred prior to the 
application of study drug. If a subject was randomized but not treated, then baseline is defined as 
the last nonmissing value on or before the date of randomization. 
10.3 Adjustments for Covariates 
The model for the primary efficacy will include adjustments for the following covariates: 
investigator type (dermatologist vs other), household number of randomized subjects (1 subject 
per household vs 2 subjects per household), age, and baseline lesion count. 
10.4 Handling of Dropouts or Missing Data 
In analyses based on response, a missing response will be considered a nonresponder.  
For a sensitivity analysis, subjects with missing lesion count at Week 12 but who demonstrated 
complete clearance at the last collected lesion assessment will be counted as responders.  
10.5 Interim Analysis and Data Monitoring 
When approximately 200 subjects (cumulative across studies NI-MC301 and NI-MC302) have 
completed 4 weeks of treatment, a DSMB will review all available unblinded safety data 
(including patch testing). All responsibilities of the DSMB and details of the analysis and data to 
be reviewed is detailed in the DSMB charter. 
10.6 Examination of Subgroups 
Subgroup analyses of complete clearance at Week 12 for investigator type (dermatologist vs 
other) and household number of randomized subjects (1 subject per household vs 2 subjects per 
household), and will be presented in a forest plot for the ITT Population. An additional subgroup 
analysis of complete clearance at Week 12 for age (≤1 year old, >1 to ≤2 years old, >2 to ≤6 
years old, >6 to ≤12 years old, >12 to ≤18 years old, >18 years old) and MC disease duration 
prior to baseline (≤6 months vs >6 months) will be summarized descriptively for the ITT 
Population. 
Page 17/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 17/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
10.7 Multiple Comparison/Multiplicity 
The familywise error rate with respect to the primary endpoint and secondary endpoint will be 
strongly controlled at the alpha=0.05 level using a fixed-sequence method testing strategy. If the 
primary endpoint is not statistically significant at the alpha=0.05 level, the secondary efficacy 
endpoint will be considered not significant. If the primary endpoint is statistically significant at 
the alpha=0.05 level, then the secondary efficacy endpoint will be analyzed. If the secondary 
efficacy endpoint fails to reach statistical significance at the alpha=0.05 level, it will be 
considered not statistically significant. 
10.8 Multicenter Studies 
This is a multicenter study, having approximately 35 centers participating in the study. The 
center effects will be investigated in the primary statistical analysis model. 
11. METHODS OF EFFICACY ANALYSIS 
11.1 Primary Efficacy Analysis 
The primary efficacy comparison will test the following hypotheses: 
H0: The proportion of subjects with complete clearance is equal between SB206 12% QD and 
Vehicle; 
H1: The proportion of subjects with complete clearance is different between SB206 12% QD 
and Vehicle.  
 
The primary efficacy model will be the following for ߨு೔ as the probability of complete 
clearance for the ith subject in household H: 
 
ߨு೔ൌ
݁ሺఉబାఉభכ௑ಹ೔భାఉమכ௑ಹ೔మାఉయכ௑ಹ೔యାఉరכ௑ಹ೔రାఉఱכ௑ಹ೔ఱሻ
ͳ ൅݁ሺఉబାఉభכ௑ಹ೔భାఉమכ௑ಹ೔మାఉయכ௑ಹ೔యାఉరכ௑ಹ೔రାఉఱכ௑ಹ೔ఱሻ
 
 
where H = Household, i = subject within the household, ߚ଴ is the intercept,  
ܺு೔భൌ൜ͳǡ ݂݅ݐݎ݁ܽݐ݉݁݊ݐ݅ݏܵܤʹͲ͸
Ͳǡ ݂݅ݐݎ݁ܽݐ݉݁݊ݐ݅ݏܸ݄݈݁ܿ݅݁ 
 
ܺு೔మൌ൜ͳǡ ݂݅ݏݑܾ݆݁ܿݐ݅ݏ݂ݎ݋݉ܽʹݏݑܾ݆݁ܿݐ݄݋ݑݏ݄݁݋݈݀
Ͳǡ ݂݅ݏݑܾ݆݁ܿݐ݅ݏ݂ݎ݋݉ܽͳݏݑܾ݆݁ܿݐ݄݋ݑݏ݄݁݋݈݀ 
 
ܺு೔యൌ൜ͳǡ ݂݅ݏݑܾ݆݁ܿݐ݅ݏ݂ݎ݋݉ܽܦ݁ݎ݉ܽݐ݋݈݋݃ݕݏ݅ݐ݁
Ͳǡ ݂݅ݏݑܾ݆݁ܿݐ݅ݏ݂ݎ݋݉ܽ݊ܱݐ݄݁ݎݏ݅ݐ݁ 
 
ܺு೔రis the subject’s baseline lesion count, and ܺு೔రis the subject’s age at baseline; treatment will 
be included in the class statement with PARAM=REF and REF=Vehicle. The working 
Page 18/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 18/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
correlation will have an exchangeable structure. The model will include a repeated statement for 
subject household with household ID in the class statement. Also, the data structure will be 
ordered according to household ID and subject ID in household. 
 
Treatment groups will be compared using a generalized estimating equation for logistic 
regression with an exchangeable working correlation structure. The model will include 
treatment, investigator type (dermatologist vs other), household number of randomly assigned 
subjects (1 subject per household vs 2 subjects per household), age, and baseline lesion count as 
factors. The odds ratio between SB206 12% and vehicle gel, 95% confidence intervals for the 
odds ratio, and P-value for the covariate-adjusted treatment comparison will be presented; 
together with predicted proportions along with their associated 95% confidence interval. 
As a sensitivity analysis, the above primary analysis model will be applied to the PP Population. 
An additional sensitivity analysis counting subjects who discontinued prior to Week 12 or have a 
missing lesion count assessment but who demonstrated complete clearance at the last collected 
lesion assessment as responders will be presented. The impact of mis-stratifications may be 
explored via a sensitivity analysis.   
An analysis where the complete clearance response probability for any dropouts prior to Week 
12 will be varied across the following scenarios (Vehicle response probability, SB206 response 
probability): 
(0.1, 0.1) 
(0.1, 0.0) 
 
 
 
(0.2, 0.2) 
(0.2, 0.1) 
(0.2, 0.0) 
 
 
(0.3, 0.3) 
(0.3, 0.2) 
(0.3, 0.1) 
(0.3, 0.0) 
 
(0.4, 0.4) 
(0.4, 0.3) 
(0.4, 0.2) 
(0.4, 0.1) 
(0.4, 0.0) 
An additional sensitivity analysis will be performed in a subset of the ITT population where only 
1 subject from each household is chosen based on the subject with the highest number of 
baseline treatable MC and the oldest to break ties, if needed, to contribute to the model. A 
logistic regression model including treatment, investigator type, age, and baseline lesion counts 
will be utilized. 
11.2 Secondary Efficacy Analyses 
The secondary endpoint of the proportion of subjects with complete clearance of all treatable MC 
at Week 8 will be analyzed in the same manner as the primary endpoint. A sensitivity analysis 
using the PP Population will be provided.  
11.3 Exploratory Analyses 
The exploratory endpoints based on the proportion of subjects achieving complete clearance or 
75% reduction will be analyzed in the same manner as the primary endpoint.  
Page 19/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 19/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Since the within-household correlation is expected to be small and the change and percent 
change from Baseline in the number of treatable MC are exploratory, they will be analyzed using 
a repeated measures mixed model for the respective visits with the same covariates as the 
primary model together with visits and treatment by visit; an unstructured covariance matrix will 
be utilized. If the calculation of the percent change from baseline is influenced by outliers with 
calculated values >100%, then the influence of outliers will be avoided for analysis by censoring 
them so that all values were in the range of -100% to 100%. 
Since the within-household correlation is expected to be small and time to first complete 
clearance of all MC is exploratory, it will be analyzed using Kaplan-Meier methods. The number 
and percentage of subjects achieving complete clearance, number and percentage of censored 
subjects, and Kaplan-Meier estimates of first quartile, median, and third quartile will be 
summarized by treatment group. Differences in Kaplan-Meier curves between the treatments will 
be tested for significance using a stratified log-rank test. 
The proportion of subjects with scarring and the proportion of subjects with keloid or 
hypertrophic scarring will be summarized descriptively at each visit. 
The change from Baseline of the composite score from age-matched (at Baseline) DLQI/CDLQI 
will be summarized descriptively and separately for each questionnaire. The scoring algorithms 
are detailed in Appendix A. Additionally, the changes from Baseline in the following subscales: 
Symptoms and Feelings, Daily Activities, Leisure, Work and School, Personal Relationships, 
and Treatment, for DLQI, and Symptoms and Feelings, Leisure, School or Holidays, Personal 
Relationships, Sleep, and Treatment, for CDLQI, and each question will be summarized 
descriptively. 
The subject-reported spread of MC to household members not in the study will be summarized 
descriptively including a breakdown of whether or not there was any spread and then a 
breakdown of the amount of spread within the household at each visit at the household level.  
12. OTHER ANALYSES 
The following analyses of BOTE vs lesion count/complete clearance will be presented: 
x Percent change from Baseline at Week 12 in relation to the highest BOTE score during 
treatment. 
x Complete clearance at Week 12 in relation to the highest BOTE score during treatment. 
x Percent change from Baseline at each visit in relation to BOTE score at Week 2. 
x Complete clearance at each visit in relation to BOTE score at Week 2. 
In these analyses, the BOTE scores will be analyzed in the ITT Population as follows: 
1. Dichotomized: 
a. Score of 0 or 1: No to Mild 
Page 20/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 20/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
b. Score of 2, 3, or 4: Moderate to Very Severe 
A shift table comparing the baseline BOTE score to each scheduled postbaseline assessment will 
be presented for the Safety Population.  
13. SAFETY ANALYSES 
All safety analyses will be based on the Safety Population. 
 
A listing of all deaths will be presented. 
13.1 Adverse Events 
All AE summaries will be restricted to treatment-emergent AEs (TEAEs), which are defined as 
those AEs that occurred any time on or after the first in-clinical application of study drug through 
the last application of study medication and those existing AEs that worsened during this same 
period. If it cannot be determined whether the AE is treatment emergent due to a partial onset 
date, then it will be counted as such; see Appendix B for the imputation of missing dates 
algorithm. Verbatim terms in the eCRFs will be mapped to preferred terms and system organ 
classes using the MedDRA Version 22.0.  
Each AE summary will be displayed by treatment group. Summaries that are displayed by 
system organ classes and preferred terms will be ordered by descending order of incidence of 
system organ class and preferred term within each system organ class. Summaries of the 
following types will be presented: 
x Overall summary of TEAEs that contain an overview of each item below. 
x Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system 
organ class and preferred term.  
x Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
maximum severity. At each level of subject summarization, a subject is classified 
according to the maximum severity if the subject reported 1 or more events. Adverse 
events with missing severity will be considered severe for this summary. 
x Subject incidence of TEAEs by MedDRA system organ class, preferred term, and closest 
relationship to study drug (Related/Not Related). Related AEs are those reported as 
“Definite,” “Probable,” or “Possible,” and unrelated AEs are those reported as “Unlikely” 
or “Unrelated.” At each level of subject summarization, a subject is classified according 
to the closest relationship if the subject reported 1 or more events. Adverse events with a 
missing relationship will be considered related for this summary. 
x Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA system organ class and preferred term.  
Page 21/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 21/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
x Subject incidence of TEAEs leading to study drug discontinuation by MedDRA system 
organ class and preferred term. 
x Subject incidence of TEAEs leading to death as an outcome by MedDRA system organ 
class and preferred term. 
Separate listings of all AEs, all SAEs and all AEs leading to study drug discontinuation will be 
provided.  
13.2 Local Skin Reaction 
The LSR composite score will be calculated by summing up all the numerical responses (0-4) to 
each individual parameter for a composite score that ranges between 0 and 24. The change from 
Baseline of the LSR composite score will be summarized descriptively. A table summarizing 
each LSR parameter (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and 
erosion/ulceration) score at each scheduled postbaseline assessment will be presented. 
Additionally, a shift table comparing the baseline score for each LSR parameter to each 
scheduled postbaseline assessment will be presented for the Safety Population. 
13.3 Events of Special Interest 
Events of Special Interest will include subjects with any TEAE where the preferred term contains 
“application site”, subjects with at least 1 post-baseline occurrence of moderate BOTE 
inflammation score, or subjects with at least 1 post-baseline LSR component score ≥ 1. A 
summary including the number and percentage of subjects with at least 1 event of special 
interest, AEs of interest by MedDRA system organ class and preferred term, at least 1 moderate 
BOTE inflammation score, and any LSR component score ≥ 1 will be provided for the Safety 
Population. The analysis will also be repeated with the LSR criteria revised to include any post-
baseline LSR component (excluding erythema) score ≥ 1 and erythema score ≥ 2. 
13.4 Urine Pregnancy Test 
Urine pregnancy test results will be included in a data listing only.  
13.5 Physical Examination 
A shift table summarizing the shift from Baseline to end of treatment in normal/abnormal will be 
presented.  
13.6 Patch Testing 
A table summarizing any patch testing results by time point will be presented.  
Page 22/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 22/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The following modifications and/or clarifications to the methodology specified in the protocol 
will be: 
x The DLQI and CDLQI will be summarized separately 
x The order of the exploratory endpoints was updated 
x The Mean percent change in baseline endpoint was updated to be more generic in order 
to analyze the median in the case of skewness 
 
 
Page 23/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 23/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
15. REFERENCES 
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for industry ICH E9: Statistical principles 
for clinical trials. September 1998 [cited 2019 May 20]. Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
073137.pdf 
 
Cardiff University. Dermatology Life Quality Index. April 1992 [cited 2019 May 20]. Available 
from: https://www.cardiff.ac.uk/medicine/resources/quality-of-life-questionnaires/dermatology-
life-quality-index 
 
Cardiff University. Children’s Dermatology Life Quality Index. April 1992 [cited 2019 May 20]. 
Available from: https://www.cardiff.ac.uk/medicine/resources/quality-of-life-
questionnaires/childrens-dermatology-life-quality-index 
Page 24/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 24/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
16. APPENDICES 
Appendix A: Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) Scoring 
DLQI: 
Question 
Scoring 
Subscale 
1. Over the last week, how itchy, sore, 
painful or stinging has you skin been? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all = 0 
Symptoms and 
Feelings 
2. Over the last week, how embarrassed 
or self conscious have you been because 
of your skin? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all = 0 
Symptoms and 
Feelings 
3. Over the last week, how has your skin 
interfered with you going shopping or 
looking after your home or garden? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Daily Activities 
4. Over the last week, how much has 
your skin influenced the clothes you 
wear? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Daily Activities 
5. Over the last week, how much has 
your skin affected any social or leisure 
activities? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Leisure 
6. Over the last week, how much has 
your skin made it difficult for you to do 
any sport? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Leisure 
7. Over the last week, has your skin 
prevented you from working or 
studying? 
 
If “No”, over the last week how much 
has your skin been a problem at work or 
studying? 
Yes = 3 
No 
Not Relevant = 0 
 
A lot = 2 
A little = 1 
Not at all = 0 
Work and School 
8. Over the last week, how much has 
your skin created problems with your 
partner or any of your close friends or 
relatives? 
Very much = 3 
A lot = 2 
A little = 1
Not at all/Not Relevant = 0 
Personal 
Relationships 
 
Page 25/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 25/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Question 
Scoring 
Subscale 
9. Over the last week, how much has 
your skin caused any sexual difficulties? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Personal 
Relationships 
10. Over the last week, how much of a 
problem has the treatment for your skin 
been, for example by making your home 
messy, or by taking up time? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Treatment 
Note: DLQI is administered in subjects ≥ 16 years old. 
 
 
The DLQI composite score is then the sum of the scores to all 10 questions and will range from 0 
to 30. If 1 question is unanswered, this is allocated a score of 0 and the DLQI score is then 
summed. If 2 or more questions are unanswered, the questionnaire is not scored.  
The subscales will be expressed as percentages of the maximum score: 
 
Subscale 
Maximum Score 
Symptoms and Feelings 
6 
Daily Activities 
6 
Leisure 
6 
Work and School 
3 
Personal Relationships 
6 
Treatment 
3 
 
 
 
Page 26/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 26/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
CDLQI: 
Question 
Scoring 
Subscale 
1. Over the last week, how itchy, 
“scratchy”, sore, or painful has your skin 
been? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Symptoms and 
Feelings 
2. Over the last week, how embarrassed or 
self conscious, upset or sad have you been 
because of your skin? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Symptoms and 
Feelings 
3. Over the last week, how has your skin 
affected your friendships? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Personal 
Relationships 
4. Over the last week, how much have you 
changed or worn different or special 
clothes/shoes because of your skin? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
5. Over the last week, how much has your 
skin trouble affected going out, playing, or 
doing hobbies? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
6. Over the last week, how much have you 
avoided swimming or other sports because 
of your skin trouble? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
7. Last week, was it school time? If school 
time: Over the last week, how much did 
your skin problem affect your school work? 
 
Was it holiday time? If holiday time: Over 
the last week, has your skin problem 
interfered with your enjoyment of the 
holiday? 
Prevented school = 3 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
School or 
Holidays 
8. Over the last week, how much trouble 
have you had because of your skin with 
other people calling you names, teasing, 
bullying, asking questions or avoiding 
you? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Personal 
Relationships 
 
 
 
Page 27/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 27/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
 
Question 
Scoring 
Subscale 
9. Over the last week, how much has 
your sleep been affected by your skin 
problem? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Sleep 
10. Over the last week, how much of a 
problem has the treatment for your skin 
been? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Treatment 
Note: CDLQI is administered in subjects 4 years old up to 16 years old. 
 
The CDLQI composite score is then the sum of the scores to all 10 questions and will range from 
0 to 30. If a question is unanswered, this is allocated a score of 0 and the CDLQI score is then 
summed.  
The subscales will be expressed as percentages of the maximum score: 
 
Subscale 
Maximum Score 
Symptoms and Feelings 
6 
Leisure 
9 
School or Holidays 
3 
Personal Relationships 
6 
Sleep 
3 
Treatment 
3 
 
 
 
Page 28/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 28/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Appendix B: Presentation of Data and Programming Specifications 
General  
x Specialized text styles, such as bold, italics, borders, and shading will not be used in 
tables, figures, and data listings unless they add significant value to the table, figure, or 
data listing. 
x Only standard keyboard characters are to be used in tables and data listings. 
x Special characters, such as nonprintable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
x Hexadecimal character representations are allowed (e.g., μ, D, ß). 
x All footnotes will be left justified and at the bottom of a page. Footnotes must be used 
sparingly and must add value to the table, figure, or data listing. 
 
Tables 
x Formal organization of tabulations may be changed during programming, if appropriate, 
e.g., tables for the different variables may be combined into a single table, or tables with 
more than 1 variable may be split into several tables. 
x Means and medians will be presented to 1 more decimal place than the raw data. 
Standard deviations will be presented to 2 more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
x Percentages will be presented to the tenths place. 
x For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the subjects discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0. 
Categories with zero counts will not have zero percentages displayed. 
x Lower and upper confidence interval values must be presented to 1 decimal place more 
than the raw/derived data (i.e., to the same number of decimal places as the mean). 
x Percentiles (e.g., 25%, 75%) must be presented to 1 decimal place more than the 
raw/derived data. 
x For all inferential analyses, P values will be rounded to 4 decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P values less than 0.0001 will be 
presented as “<0.0001.” 
x The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source table number(s) if applicable (in case aggregated 
results like mean or median are plotted) or the source listing(s) (in case individual responses are 
plotted) and/or source dataset(s) (e.g., AdaM).  
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
Page 29/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 29/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Figures 
x Legends will be used for all figures with more than 1 variable or item displayed. 
Treatment group sizes (n=xx) will be included, as appropriate. 
x Figures will be in black and white but can be in color to add value to the clarity and 
readability of a figure. Lines must be wide enough to see the line after being copied. 
x For box plots, the horizontal line will represent the median, + represents the group mean, 
the length of the box represents the interquartile range (25th-75th percentiles), and the 
whiskers will represent the minimum and maximum. 
x The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source listing number(s) and/or source dataset(s) (e.g., AdaM).  
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
 
Listings 
x Formal organization of the listing may be changed during programming, if appropriate, 
e.g., additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints. 
x If not otherwise specified, all data listings will be sorted by sequence/treatment, center, 
subject number, visit, and date/time, as appropriate.  
x All date values will be presented in a SAS date (e.g., 29AUG2001) format.  
x All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26). Seconds will only be reported if they were measured as part of 
the study. 
x The last footnote will be 
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
 
 
 
Page 30/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 30/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Missing or incomplete dates (i.e., AEs, concomitant medications, and start dates of current 
molluscum episode and initial diagnosis) 
The most conservative approach will be systematically considered. If the AE onset date is 
missing/incomplete, it is assumed to have occurred during the study treatment phase (i.e., 
considered a TEAE) except if the partial onset date or other data, such as the stop date, indicates 
differently. Similarly, a medication with partial start and stop dates could be considered as both a 
prior and concomitant treatment. 
 
The following algorithms will be applied to missing and incomplete start and stop dates: 
 
Start Dates 
x If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first application of study drug, provided the start month and year are 
the same as the first application of study drug and the stop date is either after the first 
application of study drug or completely missing. Otherwise, the missing day portion will 
be estimated as “01.” 
x If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first application of study drug, provided the start year 
is the same as the first application of study drug and the stop date is either after the first 
application of study drug or completely missing. Otherwise, the event will be assumed to 
start on the first day of the given year (e.g., ??-???-2013 is estimated as 01-JAN-2013) or 
the subject’s date of birth, whichever is latest. 
x If the start date is completely missing and the stop date is either after the application of 
study drug or completely missing, the start date will be estimated to be the first day of 
study drug application. Otherwise, the start date will be estimated to be the first day of 
the same year as the stop date or the subject’s date of birth, whichever is latest. All other 
non-AE and non-concomitant medication day calculations where only partial dates are 
available will be handled as follows: the first day of the month will be used in the 
calculations if the day part of a start date is missing while January 1 will be employed if 
both the month and day parts of a start date are missing. 
 
Stop Dates 
x If only the day of resolution is unknown, the day will be assumed to be the last day of the 
month (e.g., ??-JAN-2013 will be treated as 31-JAN-2013).  
x If both the day and month of resolution are unknown, the event will be assumed to have 
ceased on the last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013).  
x If the stop date is completely missing and the event is not continuing, the event will be 
assumed to be after first application of study drug and will be imputed using the last 
known date on the study. 
 
For the start dates of current molluscum episode and initial diagnosis, the day will be estimated 
as “01” if only day is missing. If both month and day are missing, then it will be estimated as 
“01-JUN-YYYY” or the subject’s date of birth, whichever is latest. 
Page 31/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 31/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
If the start date of current molluscum episode is partial, then the following imputation will be 
made: 
x If only the day is unknown, the day will be assumed to be the first day of the month or 
the date of birth, whichever is later. 
x If the day and month are missing, then the start date will be estimated to be June 1st or the 
date of birth, whichever is later. 
 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
x Days – A duration expressed in days between 1 date (date1) and another later date (date2) is 
calculated using the formulas noted below: 
Duration in days = date2 – date1 + 1. 
x Months – A duration expressed in months will be calculated as (later date – earlier date + 
1)/(30.4167). 
x Years – A duration expressed in years will be calculated as (later date – earlier date + 
1)/(365). 
x Change from Baseline – Change from Baseline will be calculated as follows: 
Change from Baseline = postbaseline value – baseline value. 
x Percent change from Baseline – Change from Baseline will be calculated as follows: 
Percent change from Baseline = (postbaseline value – baseline value)/baseline value  
× 100. 
 
 
Page 32/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
10Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 32/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Appendix C: SAS Programming QC Requirements  
Derived datasets are independently programmed by two programmers. The separate datasets 
produced by the 2 programmers must match 100%. Detailed specifications for the derived 
datasets are documented in the study analysis dataset specifications provided to the client at 
study conclusion. 
Tables are independently reprogrammed by a second programmer for numeric results.  
Listings are checked for consistency against corresponding tables, figures, and derived datasets. 
Figures are checked for consistency against corresponding tables and listings, or independently 
reprogrammed if there are no corresponding tables or listings. 
The entire set of TLFs is checked for completeness and consistency prior to its delivery to the 
client by the lead biostatistician and a senior level, or above, reviewer.
Page 33/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                      10Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 33/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Appendix D:  List of Tables, Figures, and Listings 
The following proposal for section 14 and 16.2 is completed according to ICH E3 guidelines. The ICH heading numbers and description are in bold. 
Minor changes from this planned index do not need to be amended in the SAP.  
Formal organization of tabulations may be changed during programming, if appropriate, e.g., tables for the different variables may be combined into 
a single table, or tables with more than 1 variable may be split into several tables. 
The shells for the outputs below are contained in the file titled “Novan NI-MC302 SAP TLFs Version 1.0”. 
TABLES, FIGURES, AND GRAPHS  
Table 
Number 
 
Table Title 
Analysis Population 
14 
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE 
TEXT 
 
14.1 
DEMOGRAPHIC DATA 
 
14.1.1.1 
Subject Disposition 
Enrolled 
14.1.1.2 
Enrollment by Site 
ITT 
14.1.2.1 
Demographic and Baseline Characteristics  
Safety 
14.1.2.2 
Demographic and Baseline Characteristics 
ITT 
14.1.2.3 
Demographic and Baseline Characteristics 
PP 
14.1.3.1 
Study Drug Exposure 
Safety 
14.1.3.2 
Study Drug Compliance 
Safety 
14.1.4.1 
Significant and Major Protocol Deviations 
ITT 
14.1.5 
Medical History 
ITT 
14.1.6.1 
Prior Medications 
ITT 
14.1.6.2 
Concomitant Medications 
ITT 
14.2 
Efficacy data 
 
14.2.1.1 
Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.2 
Complete Clearance Lesion Count Response at Week 12 
PP 
Page 34/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                      10Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 34/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Table 
Number 
 
Table Title 
Analysis Population 
14.2.1.3 
Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.4 
Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
PP 
14.2.1.6 
Proportion of Subjects with Complete Clearance at Week 12 by Subgroup 
ITT 
14.2.1.7 
Dropout Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.8 
One Subject Per Household Sensitivity Analysis: Complete Clearance Lesion Count Response at 
Week 12 
ITT 
14.2.2.1 
Complete Clearance Lesion Count Response at Week 8 
ITT 
14.2.2.2 
Complete Clearance Lesion Count Response at Week 8 
PP 
14.2.3.1 
Complete Clearance Lesion Count Response at Weeks 2 and 4 
ITT 
14.2.3.2 
Summary of a 75% Reduction in Lesion Counts from Baseline Response by Visit 
ITT 
14.2.3.3.1 
Percent Change from Baseline in Lesion Count by Visit 
ITT 
14.2.3.4.1 
Change from Baseline in Lesion Count by Visit 
ITT 
14.2.3.5 
Summary of Recurrence after Complete Clearance 
ITT 
14.2.3.6.1 
Kaplan-Meier Estimates of Time to Complete Clearance (Days) from Start of Dosing 
ITT 
14.2.3.7 
Summary of Scarring and Keloid by Visit 
ITT 
14.2.3.8.1 
Summary of the Dermatology Life Quality Index (DLQI) and Subscales by Visit 
ITT 
14.2.3.8.2 
Summary of the Dermatology Life Quality Index (DLQI) Individual Questions by Visit 
ITT 
14.2.3.8.3 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT 
14.2.3.8.4 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) Individual Questions by 
Visit 
ITT 
14.2.3.9 
Summary of Increase in Subject-Reported Spread to Household Members by Visit 
ITT 
14.2.3.10.1 
Summary of Lesion Counts by Highest Dichotomized BOTE Score 
ITT 
14.2.3.10.3 
Percent Change from Baseline in Lesion Count over Time by Dichotomized Week 2 BOTE 
Score 
ITT 
14.2.3.10.4 
Summary of Complete Clearance by Visit and Dichotomized Week 2 BOTE Score 
ITT 
14.2.3.10.5 
Summary of the Beginning of the End (BOTE) Inflammation Score Results by Visit 
Safety 
14.3 
Safety data 
 
14.3.1 
Displays of Adverse Events 
 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
Page 35/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                      10Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 35/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Table 
Number 
 
Table Title 
Analysis Population 
14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety 
14.3.1.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.4 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug 
Safety 
14.3.1.5 
Summary of Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
Safety 
14.3.1.6 
Summary of Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
Safety 
14.3.1.7 
Summary of Treatment-Emergent Adverse Events Leading to Death by System Organ Class and 
Preferred Term 
Safety 
14.3.2 
Listings of deaths, other serious and significant adverse events 
 
14.3.2.1 
Listing of Serious Adverse Events 
Safety 
14.3.2.2 
Listing of Adverse Events Leading to Study Drug Discontinuation 
Safety 
14.3.2.3 
Listing of Deaths 
Safety 
14.3.6 
Other safety data 
 
14.3.6.1.1 
Summary of Local Skin Reaction (LSR) Composite Score by Visit 
Safety 
14.3.6.1.2 
Summary of Local Skin Reaction (LSR) Score Results by Visit 
Safety 
14.3.6.1.3 
Shift Summary of Local Skin Reaction (LSR) Score Results by Visit 
Safety 
14.3.6.2 
Summary of Events of Special Interest 
Safety 
14.3.6.3 
Summary of Physical Examination Findings 
Safety 
14.3.6.4 
Summary of Patch Testing Results 
Safety 
 
Page 36/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                      10Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 36/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Figure 
Number 
 
Figure Title 
Analysis Population 
14.2.1.5 
Forest Plot: Odds Ratio (95% CI) of the Proportion of Subjects with Complete Clearance at 
Week 12 
ITT 
14.2.3.3.2 
Percent Change from Baseline in Lesion Count over Time by Treatment Group 
ITT 
14.2.3.4.2 
Mean Change from Baseline in Lesion Count over Time by Treatment Group 
ITT 
14.2.3.6.2 
Kaplan-Meier Plot of Time to Complete Clearance (Days) from Start of Dosing 
ITT 
14.2.3.10.2 
Plot of Complete Clearance at Week 12 by Highest Dichotomized Categorized BOTE Score 
ITT 
 
Page 37/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                      10Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 37/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
Section 16.2: List of Data Listings 
ICH Listing 
Number 
 
Listing Title 
Analysis 
Population
16.1.7 
Subject Randomization 
 
16.2 
SUBJECT DATA LISTINGS 
 
16.2.1 
Discontinued subjects 
 
16.2.1.1 
Subject disposition 
Enrolled 
16.2.2 
Protocol deviations 
 
16.2.2.1 
Protocol Deviations  
ITT 
16.2.2.2 
Inclusion/Exclusion Criteria 
Enrolled 
16.2.3 
Subjects excluded from the efficacy analysis 
 
16.2.3.1 
Analysis Populations 
Enrolled 
16.2.4 
Demographic data 
 
16.2.4.1 
Demographic and Baseline Characteristics 
ITT 
16.2.4.2 
Patch Testing Consent/Assent 
 
16.2.4.3 
Medical History 
ITT 
16.2.4.4 
Prior and Concomitant Medications 
ITT 
16.2.5 
Compliance and/or drug concentration data  
 
16.2.5.1 
Study Drug Administration 
Safety 
16.2.5.2 
Study Drug Accountability 
Safety 
16.2.5.3 
Treatment Adjustment 
Safety 
16.2.6 
Individual efficacy response data 
 
16.2.6.1 
Lesion Counts 
ITT 
16.2.6.2 
Lesion Count Derived Efficacy Variables and Time to Complete Clearance 
ITT 
16.2.6.3 
Scarring/Keloid Assessment 
ITT 
16.2.6.4 
Dermatology Life Quality Index (DLQI) and Subscales 
ITT 
16.2.6.5 
Children’s Dermatology Life Quality Index (CDLQI) and Subscales 
ITT 
16.2.6.6 
Household Transmission 
ITT 
16.2.7 
Adverse events listings 
 
16.2.7.1 
All Adverse Events 
Safety 
Page 38/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                      10Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 38/38 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 1.0 
ICH Listing 
Number 
 
Listing Title 
Analysis 
Population
16.2.8  
Listing of individual laboratory measurements by subject, when required by regulatory authorities 
 
16.2.8.1 
Urine Pregnancy Test 
Safety 
16.2.9 
Other data 
 
16.2.9.1 
Beginning-of-the-End (BOTE) Inflammation Score 
Safety 
16.2.9.2 
Local Skin Reactions (LSR) 
Safety 
16.2.9.3 
Physical Examination 
Safety 
16.2.9.4 
Patch Testing 
Safety 
16.2.9.5 
Telephone Contact 
ITT 
 
Page 39/120


 
TMP-SOP-0202-001-03_SAP Template 
Page 1/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
 
 
 
Statistical Analysis Plan 
 
Novan, Inc.  
NI-MC302 
 
A Phase 3 Multi-Center, Randomized, Double-Blind, Vehicle-Controlled, Parallel Group 
Study Comparing the Efficacy and Safety of SB206 and Vehicle Gel Once Daily in the 
Treatment of Molluscum Contagiosum 
Protocol Version: 26Mar2019 
 
 
 
Sponsor:  
 
Novan, Inc.  
4105 Hopson Road 
Morrisville, NC 27560 
 
 
Prepared by:  
Christopher Tait 
5909 Sea Otter Place, Suite 100 
Carlsbad, CA 92010 
 
 
Version 
Date 
Version 1 
10 Sep 2019 
Version 2 
18 Nov 2019 
 
 
 
 
 
Page 40/120


Novan.Jnc. 
Nl-MC302 
rr· 
s y n t e r  c t  
Approval 
Statistical Analysis Plan 
18Nov20)9 
• 
Upon review of this document, including the table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are acceptable. 
Si nature 
Christopher Ta· , PhD 
Senior Biostatistician 
S 
teract 
David Hebert, PhD 
Senior Director, Head of Biometrics 
Novan, Inc. 
TMP-SOP-0202-001-03_SAP Template 
CONFIDENTIAL 
Novan N1-MC302 SAP Version 2.0 
Date 
Page 2/40 
Page 41/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 3/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................................. 6 
2. 
STUDY DOCUMENTS ......................................................................................................... 6 
3. 
STUDY OBJECTIVES .......................................................................................................... 6 
4. 
STUDY DESIGN AND PLAN .............................................................................................. 6 
5. 
DETERMINATION OF SAMPLE SIZE ............................................................................ 9 
6. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................. 10 
7. 
NOTATION OF TREATMENT GROUPS AND VISITS ............................................... 11 
8. 
ANALYSIS POPULATIONS .............................................................................................. 12 
9. 
STUDY POPULATION....................................................................................................... 12 
9.1 
SUBJECT DISPOSITION .................................................................................................. 12 
9.2 
ELIGIBILITY.................................................................................................................. 12 
9.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 13 
9.4 
EXTENT OF EXPOSURE ................................................................................................. 13 
9.5 
PROTOCOL DEVIATIONS .............................................................................................. 14 
9.6 
MEDICAL HISTORY ...................................................................................................... 14 
9.7 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................. 14 
10. EFFICACY ANALYSES ..................................................................................................... 15 
10.1 EFFICACY ENDPOINTS .................................................................................................. 15 
10.2 BASELINE VALUES ....................................................................................................... 16 
10.3 ADJUSTMENTS FOR COVARIATES ................................................................................ 16 
10.4 HANDLING OF DROPOUTS OR MISSING DATA ............................................................. 16 
10.5 INTERIM ANALYSIS AND DATA MONITORING ............................................................. 17 
10.6 EXAMINATION OF SUBGROUPS .................................................................................... 17 
10.7 MULTIPLE COMPARISON/MULTIPLICITY ..................................................................... 17 
10.8 MULTICENTER STUDIES ............................................................................................... 17 
11. METHODS OF EFFICACY ANALYSIS .......................................................................... 18 
11.1 PRIMARY EFFICACY ANALYSIS ................................................................................... 18 
11.2 SECONDARY EFFICACY ANALYSES ............................................................................. 19 
11.3 EXPLORATORY ANALYSES .......................................................................................... 20 
12. OTHER ANALYSES ........................................................................................................... 20 
13. SAFETY ANALYSES .......................................................................................................... 21 
13.1 ADVERSE EVENTS ........................................................................................................ 21 
13.2 LOCAL SKIN REACTION ............................................................................................... 22 
13.3 EVENTS OF SPECIAL INTEREST .................................................................................... 22 
13.4 URINE PREGNANCY TEST ............................................................................................ 22 
13.5 PHYSICAL EXAMINATION ............................................................................................ 23 
13.6 PATCH TESTING ........................................................................................................... 23 
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................ 23 
15. REFERENCES ..................................................................................................................... 24 
16. APPENDICES ...................................................................................................................... 25 
Page 42/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 4/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
APPENDIX A: DERMATOLOGY LIFE QUALITY INDEX (DLQI) AND CHILDREN’S 
DERMATOLOGY LIFE QUALITY INDEX (CDLQI) SCORING ............................. 25 
APPENDIX B: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS .................... 29 
APPENDIX C: SAS PROGRAMMING QC REQUIREMENTS ....................................................... 33 
APPENDIX D:  LIST OF TABLES, FIGURES, AND LISTINGS ...................................................... 34 
Page 43/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 5/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Full Notation 
AE 
adverse event 
ATC 
anatomical/therapeutic/chemical 
BOTE 
beginning of the end 
CDLQI 
Children’s Dermatology Life Quality Index 
CRO 
contract research organization 
DLQI 
Dermatology Life Quality Index 
DSMB 
data safety monitoring board 
eCRF 
electronic case report form 
ICH 
International Council for Harmonisation 
ITT 
Intent-to-Treat 
LSR 
local skin reaction 
MC 
molluscum contagiosum 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per-Protocol 
QC 
quality control 
QD 
once daily 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
 
  
 
Page 44/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 6/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Novan, Inc. protocol version 1.0 [A Phase 3 Multi-Center, 
Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Study Comparing the Efficacy 
and Safety of SB206 and Vehicle Gel Once Daily in the Treatment of Molluscum Contagiosum]. 
The purpose of this plan is to provide specific guidelines from which the statistical analyses will 
proceed. Any deviations from this plan will be documented in the clinical study report. 
2. STUDY DOCUMENTS 
The following study documents are used for the preparation of the statistical analysis plan (SAP): 
• Protocol version 1.0, 26Mar2019 
• Annotated electronic case report form (eCRF) version 2.0, 30Jul2019 
• Data management plan version 2.0, 23Aug2019 
3. STUDY OBJECTIVES 
The objective of the study is to evaluate the efficacy and safety of SB206 12% once daily (QD) 
for the treatment of molluscum contagiosum (MC). 
4. STUDY DESIGN AND PLAN 
This is a Phase 3 multi-center, randomized, double-blind, vehicle-controlled, parallel group study 
to be conducted in approximately 340 subjects ≥6 months of age with MC. After obtaining 
informed consent/assent, subjects who satisfy entry criteria will be randomized to a 2:1 
(active:vehicle) scheme. Subjects receiving current treatment for MC at the time of the Screening 
Visit will enter a washout period of up to 14 days prior to randomization. In the event no 
washout period is required, Screening and Baseline visit activities may be combined into a single 
visit. At randomization, subjects will be stratified into 4 strata corresponding to the cross-
classification of household number of randomly assigned subjects (1 subject per household vs 2 
subjects per household) and investigator type (dermatologist vs other). Households randomizing 
2 subjects will receive the same treatment assignment for both subjects. Up to 2 subjects from 
the same household may be randomly assigned on the same day, if both individually meet all 
inclusion and exclusion criteria. For subjects in the same household, Screening can occur on 
different days; however, the baseline visit must occur on the same day. 
Subjects or their caregivers will apply SB206 12% or Vehicle Gel QD for a minimum of 4 weeks 
and up to 12 weeks to all lesions identified at Baseline and new treatable lesions that arise during 
the course of the study. Subjects or their caregivers will continue to treat the area until the next 
scheduled visit even if the lesion(s) clear. If the investigator determines all lesions are cleared at 
a clinic visit, the treatment may stop. At Weeks 2, 4, 8 and 12, the investigator will count and 
record the number of active (raised, treatable) molluscum lesions per body area. At Weeks 2, 4, 
Page 45/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 7/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
and 8, the investigator will determine if new lesions have occurred since the last visit, and the 
subject or caregiver will be instructed by the investigator to re-initiate treatment. If treatment is 
stopped due to clearance, subjects will continue regularly scheduled visits through Week 24. 
Subjects will visit the clinic at Screening/Baseline, Week 2, Week 4, Week 8, Week 12, and 
Week 24. Subjects will be contacted via phone on Day 2 to collect subject information on early 
dose reactions. At Weeks 16 and 20, subjects will be contacted via phone to capture information 
regarding MC recurrence and adverse events (AEs); at Week 24, the subject will be seen at the 
site for a final study visit to assess scarring, keloid, and MC recurrence. Subjects who 
discontinue the study prior to the Week 12 visit due to AEs or other reasons will be asked to 
complete the Week 12 visit assessments: this will be recorded as an Early Termination (ET1) 
visit. No study drug treatment will be provided after the Week 12 visit. Subjects who discontinue 
from the study after Week 12 but prior to Week 24 will be asked to come to the site to complete 
Week 24 assessments; this will be recorded as an ET2 visit. 
Safety assessments include local skin reactions (LSRs), AE collection, including scarring/keloid, 
and urine pregnancy tests. Safety assessments will be completed at specified site visits through 
Week 12. After Week 12, safety information for ongoing AEs and new AEs will be collected, 
along with information regarding household MC occurrence. 
Inflammatory reactions around the MC has been associated with imminent resolution of MC 
(sometimes referred to as “beginning-of-the-end” [“BOTE”] sign). The investigator (or 
designated evaluator) will assess the presence and overall degree of inflammatory reactions at 
MC lesions at Baseline (before dosing) and Weeks 2 through 12. In most cases, clinical features 
can differentiate between BOTE and LSR. BOTE may be associated with itch, but not pain. 
BOTE is usually asymptomatic, self-limited, and localized to individual MC lesions and does not 
require discontinuation of study treatment or additional treatment. LSR is generally more diffuse, 
associated with significant itch or tenderness, may necessitate discontinuation of study treatment, 
and may need treatment for symptomatic relief (e.g., a topical corticosteroid or topical 
anesthetic). For very severe LSR, systemic corticosteroids may be considered. Investigators will 
assess the treatment area at each scheduled visit and use their medical judgement to differentiate 
between BOTE and LSRs. BOTE Inflammation Score and LSR score will be recorded at each 
visit. BOTE should not be considered an AE. When LSRs are clinically significant at the 
application site, the investigator should report the condition as an AE(s). 
At Baseline (at least 30 minutes after dosing) and Weeks 2 through 12, the investigators will rate 
LSRs on individual features including erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration. At Baseline (pre-dose) and Weeks 2 through 12, 
the investigators will rate BOTE signs using the BOTE Inflammation Score.  
The following tables describe the scoring parameters for the BOTE Inflammation Score and LSR 
score. 
Page 46/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 8/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
BOTE Inflammation Score 
Score 
Global Assessment 
Description 
0 
No inflammation 
No evidence of local inflammation 
1 
Mild 
Minimal erythema and/or edema 
2 
Moderate 
Definite erythema and/or edema with or 
without hemorrhagic crusting 
3 
Severe 
Erythema and edema with definite 
hemorrhagic crusting 
4 
Very severe 
Strong reaction spreading beyond the 
treated area, bullous reaction, erosions 
 
LSR Score 
Score 
Erythema 
Flaking/ 
Scaling 
Crusting 
Swelling 
Vesiculation/ 
Pustulation 
Erosion/ 
Ulceration 
0 
Not present 
Not 
present 
Not 
present 
Not 
present 
Not present 
Not 
present 
1 
Slightly 
pink 
Mild, 
limited 
Isolated 
crusting 
Minimal, 
limited 
Fine vesicles 
Superficial 
erosion 
2 
Pink or 
light red 
Moderate 
Crusting   
< 50% 
Mild, 
palpable 
Scant 
transudate or 
exudate 
Moderate 
erosion 
3 
Red, 
restricted to 
treatment 
area 
Coarse 
Crusting   
> 50% 
Moderate 
Moderate 
transudate or 
exudate 
Marked, 
extensive 
4 
Red 
extending 
outside 
treatment 
area 
Scaling 
extending 
outside 
treatment 
area 
Crusting 
extending 
outside 
treatment 
area 
Marked 
swelling 
extending 
outside 
treatment 
area 
Marked 
transudate or 
exudate 
Black 
eschar or 
ulceration 
Clinically significant LSRs that are reported as AEs and/or subject-reported intolerability (i.e., 
itching, pain) may result in an investigator-directed temporary treatment hold (drug holiday), and 
topical corticosteroids may be used to treat LSRs for up to 2 weeks. The subject may re-initiate 
study drug treatment prior to the next scheduled visit. Upon re-initiation of study drug treatment, 
if a subject develops worsening LSRs, allergic contact dermatitis may be suspected. The 
investigator may take photographs of the suspected allergic contact dermatitis and discuss 
possible confirmation of allergic contact dermatitis with the contract research organization’s 
Page 47/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 9/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
(CRO) medical monitor. The investigator should also discuss the necessity of patch testing with 
the subject/caregiver. The investigator will then discontinue the subject from study drug 
treatment and treat the area(s) with corticosteroids for up to 2 weeks. If the subject provides 
consent/assent, the investigator will consult with the CRO’s medical monitor to implement the 
process for patch testing.  
Adverse events will be assessed and collected after the initiation of study drug treatment through 
the end of the subject’s last visit. Treatment-related AEs will be followed up until resolution or 
up to 1 year after last treatment, whichever is sooner.  
Scar formation will be assessed starting at the Week 4 visit through Week 12 and again at 
Week 24. The investigator will map locations of the molluscum lesions at Baseline. Additional 
lesions identified through Week 12 will be added to the map. Using the map as a guidance, the 
investigator will assess the treated areas for scar/keloid formation. The investigator will count 
and record the number of active (raised, treatable) molluscum lesions per body area. If a new 
scar is noted after the subject treated with study drug, this will be considered an AE for the 
purposes of this study. In addition, keloid/hypertrophic scars will also be recorded as AEs.  
If a subject’s treatment is discontinued by the investigator or the subject because of an AE, that 
AE should be indicated as the reason for treatment discontinuation. All subjects will be 
encouraged to remain in the study throughout the 24-week study duration. 
When approximately 200 subjects (cumulative across studies MC301 and MC302) have 
completed 4 weeks of treatment, a data safety monitoring board (DSMB) will review all 
available unblinded safety data (including patch testing).  
5. DETERMINATION OF SAMPLE SIZE 
Approximately 340 subjects, 6 months of age and older, with a minimum of 3 and a maximum of 
70 MC lesions at Baseline will be randomized in a 2:1 (active:vehicle) scheme. The sample size 
assumptions for this study were informed by the completed Phase 2 study NI-MC201 of subjects 
2 years of age and older with between 3 and 70 MC lesions at Baseline. In the Intent-to-Treat 
(ITT) Population of the Phase 2 study, the observed rates of complete clearance at Week 12 were 
18% (12/66) for vehicle and 38% (18/48) for SB206 12% QD and the covariate-adjusted 
treatment difference was 18%.  
A sample size of 340 subjects (227 subjects in the SB206 12% QD group and 113 subjects in the 
vehicle group) will provide 94% power for a 2-sided alpha test of size 0.05 to detect an absolute 
difference of 18% when the vehicle response rate is 18%. This same sample size provides 93% 
power to detect a treatment difference of 18% when the vehicle response rate is 20% and 83% 
power when the treatment difference is 15% and the vehicle response rate is 20%.  
Since the intra-cluster correlation is estimated to be small (<10%) and the average size of 
households is expected to be capped at roughly 1.3, the sample size is still sufficient when 
considering the fact that the subjects within the household may not be independent. 
Page 48/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 10/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
6. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs. 
Unless otherwise noted, all statistical testing will be 2-sided and will be performed at the 0.05 
significance level. Tests will be declared statistically significant if the calculated P-value is 
≤0.05.  
Continuous variable summaries will include the number of subjects (n) with non-missing values, 
mean, standard deviation (SD), median, minimum, and maximum. Other statistics such as 
quartiles, confidence intervals (CIs), and number of missing values may be added as appropriate.  
Categorical variable summaries will include the frequency and percentage of subjects who are in 
the category or each possible value. In general, the denominator for the percentage calculation 
will be based upon the total number of subjects in the study population within each treatment 
group, unless otherwise specified. The denominator for by-visit displays will be the number of 
subjects in the relevant study population with non-missing data at each visit.  
All summary tables will be presented by treatment group. Baseline summaries will also include 
an overall summary column.  
Individual subject data obtained from the eCRFs and any derived data will generally be 
presented by subject in data listings. Additionally, a listing of the subjects requiring a narrative 
because they experience one of the following events: serious adverse event, death, discontinued 
the study due to an AE, hypertrophic or keloid scarring, unresolved scars, or LSR suggestive of 
allergic contact dermatitis will be presented.  
The analyses described in this plan are considered a priori, in that they have been defined prior to 
breaking the blind.  
Any analyses performed subsequent to breaking the blind will be considered post hoc and 
exploratory. Post hoc analyses will be labeled as such on the output and identified in the clinical 
study report. 
All analyses and tabulations will be performed using SAS software Version 9.4 or higher. 
Tables, listings, and figures will be presented in RTF format.  
The process for SAS program validation and quality control (QC) for programs and outputs is 
documented in the Synteract working instruction “SAS programming quality control.” 
Study-specific QC requirements can be found in Appendix C: SAS Programming QC 
Requirements. 
 
The study treatment period is defined from randomization through completion of Week 12/ET1 
visit and the safety follow-up period is from the completion of Week 12 through the completion 
of Week 24/ET2 visit. 
Page 49/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 11/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
 
After all subjects have completed their Week 12/ET1 visit, thus completing the Treatment Period 
of the study, the database through Week 12/ET1 will be frozen and unblinded for purposes of the 
primary analysis of efficacy and safety.  While this analysis is being prepared, the subjects will 
continue through Week 24/ET2. After all subjects have completed their Week 24/ET2 visit, the 
database will be locked and the follow-up data will be analyzed. 
7. NOTATION OF TREATMENT GROUPS AND VISITS 
Analysis visits 
 
Baseline is defined as the last nonmissing value recorded prior to the first application of study 
drug. If time is not recorded and the assessment was on the same day as the first application of 
study drug, then it will be assumed the assessment occurred prior to the application of study drug. 
The baseline record will have an analysis visit of “Baseline”. 
 
For all evaluations of all parameters, assessments will be analyzed according to the visit at which 
they occurred (i.e., per the eCRF visit label). In order to account for the fact that the Week 12 and 
Early Termination visits are collected on the same eCRF in the database, a check against the Study 
Exit form will be made to determine if the visit is a Week 12 or an Early Termination Visit. If the 
visit is an Early Termination visit, then the visit will be mapped according to the table below. If 
there is no corresponding Study Exit form on the same date, then it will be considered a Week 12 
visit. If there is no assessment in a given visit, then the following visit windows will be applied to 
determine if an unscheduled visit may be used: 
 
Visit 
Analysis Visit 
Target Study 
Day 
Study Day Analysis 
Window 
 
 
 
 
Week 2 (±3 days) 
Week 2 
15 
Day 12 to 22 
Week 4 (±5 days) 
Week 4 
29 
Day 23 to 43 
Week 8 (±5 days) 
Week 8 
57 
Day 44 to 71 
Week 12 (±5 days) 
Week 12 
85 
Day 72 to 98 
 
Days are measured from the date of randomization. Study days corresponding to measurements 
are calculated as: 
• Assessment date – date of randomization + 1, if assessment date is on or after the date of 
randomization. 
• Assessment date – date of randomization, if measurement date is before the date of 
randomization. 
In the event of multiple unscheduled records falling in the same analysis window, the assessment 
which is closest to the target study day will be chosen for analysis.  
Page 50/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 12/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
8. ANALYSIS POPULATIONS 
The following subject population will be used for disposition analyses:  
• The Enrolled Population will consist of all subjects who have a signed informed consent 
or assent. If a subject is randomly assigned to a treatment, then treatment assignment will 
be based on randomized treatment; otherwise, they will be deemed a screen failure and 
will only appear in the overall summary columns of output. 
The following subject population will be used for safety analyses:  
• The Safety Population will consist of all subjects who receive at least 1 application of 
study medication. Treatment assignment will be based on the treatment actually received. 
If a subject receives any amount of SB206, then they will be summarized in the SB206 
12% QD arm.  
The following subject populations will be used for efficacy analyses:  
• The ITT Population will consist of all subjects who are randomized. Treatment 
assignment will be based on the randomized treatment.  
• The Per-Protocol (PP) Population will consist of all subjects in the ITT Population who 
had no significant protocol deviations that impacted the analyses of efficacy endpoints. 
Final determination of subject inclusion in the PP Population will be made prior to 
unblinding. Treatment assignment will be based on the randomized treatment. 
9. STUDY POPULATION 
9.1 Subject Disposition 
Subject disposition information will be summarized for all subjects by treatment group. 
Summaries will include: the number of subjects screened, the number of subjects in each 
analysis population, the number of subjects where study treatment stopped, primary reason for 
study treatment stopped, the number of subjects completing 12 weeks of the study (defined as 
having an end of treatment reason of “Completed Treatment Per Protocol” or a reason of 
“Complete Clearance Prior to Week 12” and does not have a Study Exit date prior to the 
subject’s Week 12 visit date), the number of subjects completed the study, and the primary 
reason for discontinuation. 
 
A summary of the number of subjects in each center and each population will be presented.  
9.2 Eligibility 
A listing of subjects not fulfilling any eligibility criteria will be created. 
Page 51/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 13/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
9.3 Demographic and Baseline Characteristics 
Demographic variables include age, sex, ethnicity, and race. Age will be calculated in years 
relative to the informed consent date.  
Other baseline characteristics include lesion counts at baseline, site type (dermatologist vs other), 
number of sites and a breakdown of site type, number of randomly assigned subjects in 
household (1 subject vs 2 subjects), number of households and breakdown of household size, age 
at and time since initial clinical diagnosis of the current molluscum episode and age at and time 
since onset of symptoms of current molluscum episode. Descriptive statistics will be presented 
for ages and other continuous variables. Frequency counts and percentages will be presented for 
sex, ethnicity, race and other categorical variables. Demographic and baseline characteristics will 
be summarized for the Safety, ITT, and PP Populations.  
9.4 Extent of Exposure 
Study drug exposure will be summarized for each treatment using the total number of 
applications, the duration of treatment, and the number of subjects requiring a treatment 
interruption and modification. Duration of treatment is defined as the last application date minus 
the first application date plus 1. 
Study drug compliance will be summarized and calculated as follows: 
Compliance [%] = (Actual applications applied)/(Planned applications) ×100, where 
• Actual applications applied = Planned applications – the number of applications missed 
• Planned applications = Number of applications (days) planned up to the point of 
treatment discontinuation or date of Week 12 visit, whichever is later.  
This implies that if a subject treatment discontinues treatment prior to Week 12 due to complete 
clearance, then the number of applications takes this information into account and the subject is 
not penalized for having complete clearance.  
Compliance will be further summarized into 2 groups:  
1. Subjects who did not have any interruptions or modifications using the same formula as 
above, and 
2. Subjects with modifications or interruptions. For these subjects, an adjusted compliance 
will be calculated in the following manner: the actual applications applied will be the 
same as above but the planned applications will exclude the time where the subject has 
dosing interrupted.  
Page 52/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 14/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
9.5 Protocol Deviations 
Significant protocol deviations that could potentially affect the efficacy or safety conclusions of 
the study will be identified prior to database lock and unblinding of individual subject treatment 
information. Significant protocol deviations may include, but are not limited to: 
• Randomly assigned subjects who did not satisfy selected inclusion and exclusion criteria 
• Randomly assigned subjects who developed withdrawal criteria during the study but were 
not withdrawn 
• Subjects who were randomized incorrectly including subjects of the same household who 
are randomized to different treatments  
• Subjects who received the wrong treatment 
• Subjects where the subject/site staff were unproperly unblinded 
• Week 12 Lesion Count not performed 
• Subjects who received an excluded concomitant treatment. 
The decision on the criteria for whether a subject is excluded from the PP Population will be 
made during the data review meeting prior to unblinding and database lock. Reasons for 
exclusion of a subject from the analysis will be listed. 
A listing of all protocol deviations including the deviation designation (major or minor and 
significant or not), category, and indication of whether the deviation led to an exclusion of a 
subject from the PP Population will be presented in a data listing.   
Major and significant protocol deviations will be summarized by deviation category and 
treatment group.  
9.6 Medical History 
Medical history verbatim terms in the eCRFs will be mapped to system organ classes and 
preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0. 
Subject incidence of unique medical history terms by MedDRA system organ class and preferred 
term will be presented. The summary will be ordered by descending order of incidence of system 
organ class and preferred term within each system organ class. 
9.7 Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms in the eCRFs will be mapped to 
anatomical/therapeutic/chemical (ATC) class and preferred names using the WHODrug Global 
B3 (version March 2019). Prior medications are those medications started prior to the first 
application of study drug. Concomitant medications are those medications started on or after the 
date of first application of study drug or medications started prior to initial application of study 
Page 53/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 15/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
drug and continued during the study. A medication can be classified as both prior and 
concomitant. If it cannot be determined whether the medication was a prior (or concomitant) 
medication due to a partial start or stop date, then it will be counted as both prior and 
concomitant; see Appendix B for the imputation of missing dates algorithm. 
Prior and concomitant medications will be summarized for each treatment by WHODrug Global 
ATC class Level 3 and preferred name. These summaries will present the number and percentage 
of subjects using each medication. Subjects may have more than 1 medication per ATC class and 
preferred name. At each level of subject summarization, a subject is counted once if he/she 
reported 1 or more medications at that level. Each summary will be ordered by descending order 
of incidence of ATC class and preferred name within each ATC class. 
10. EFFICACY ANALYSES 
The primary efficacy analysis will be based on the ITT Population. Additional supportive 
efficacy analyses will be performed using the PP Population. 
10.1 Efficacy Endpoints 
The primary efficacy endpoint is the proportion of subjects with complete clearance of all 
treatable MC at Week 12.  
The secondary efficacy endpoint is the proportion of subjects with complete clearance of all 
treatable MC at Week 8.  
Complete clearance is defined as having a total number of lesions count of 0.  
The exploratory endpoints are the following: 
• Proportion of subjects with complete clearance of all treatable MC at Week 2 and Week 4 
visits 
• Proportion of subjects achieving at least a 95% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Proportion of subjects achieving at least a 90% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Proportion of subjects achieving at least a 75% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Percent change from Baseline in number of treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Change from Baseline in number of treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Proportion of subjects who have a recurrence of MC after the first visit at which complete 
clearance was observed, defined as the total lesion count being greater than 0 at any point 
after achieving a count of 0 
Page 54/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 16/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
• Time to complete clearance of all treatable MC, defined as the days between the date of 
first dose and the first date of clearance. Subjects who do not achieve complete clearance 
will be censored at the date of the last lesion count assessment.  
• Proportion of subjects with scarring, defined as an answer of Yes to either question on the 
Scarring/Keloid Assessment eCRF page: “Was the presence of a scar > 1 mm deep and/or 
5 mm wide noted?” or “Was the presence of a scar noted?”, after clearance of lesion(s) at 
each visit (Weeks 4, 8, 12, 24) 
• Proportion of subjects with keloid or hypertrophic scar, defined as an answer of Yes to 
the Scarring/Keloid Assessment eCRF page question “Was the presence of a keloid or 
hypertrophic scar noted?”, after clearance of lesion(s) at each visit (Weeks 4, 8, 12, 24) 
• Change from Baseline of the composite score from age-matched (at Baseline) 
Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index 
(CLDQI) assessment at Week 12 
• Subject-reported spread to household members as measured by any new occurrence of 
MC in household members of subjects at each visit (Weeks 2, 4, 8, 12, 16, 20, 24) 
10.2 Baseline Values 
Unless otherwise noted, baseline is defined as the last nonmissing value recorded prior to the 
first application of study drug. If time is not recorded and the assessment was on the same day as 
the first application of study drug, then it will be assumed the assessment occurred prior to the 
application of study drug. If a subject was randomized but not treated, then baseline is defined as 
the last nonmissing value on or before the date of randomization.  
10.3 Adjustments for Covariates 
The model for the primary efficacy will include adjustments for the following covariates: 
investigator type (dermatologist vs other), household number of randomized subjects (1 subject 
per household vs 2 subjects per household), age, and baseline lesion count. If there are not at 
least 3 responders and non-responders at each level of the stratification factors, then that 
stratification factor will be removed from the model. If there are fewer than 10 
responders/non-responders, then neither investigator type nor household number of randomized 
subjects will be included in the model.  
10.4 Handling of Dropouts or Missing Data 
In analyses based on response, a missing response will be considered a nonresponder.  
For a sensitivity analysis, subjects with missing lesion count at Week 12 but who demonstrated 
complete clearance at the last collected lesion assessment will be counted as responders.  
Page 55/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 17/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
10.5 Interim Analysis and Data Monitoring 
When approximately 200 subjects (cumulative across studies NI-MC301 and NI-MC302) have 
completed 4 weeks of treatment, a DSMB will review all available unblinded safety data 
(including patch testing). All responsibilities of the DSMB and details of the analysis and data to 
be reviewed is detailed in the DSMB charter. 
10.6 Examination of Subgroups 
Subgroup analyses of complete clearance at Week 12 for investigator type (dermatologist vs 
other) and household number of randomized subjects (1 subject per household vs 2 subjects per 
household), and will be presented in a forest plot for the ITT Population. An additional subgroup 
analysis of complete clearance at Week 12 for age (<1 year old, ≥1 to <2 years old, ≥2 to <6 
years old, ≥6 to <12 years old, ≥12 to <18 years old, ≥18 years old) and onset of MC symptoms 
duration prior to baseline (≤6 months vs >6 months) will be summarized descriptively for the 
ITT Population. 
10.7 Multiple Comparison/Multiplicity 
The familywise error rate with respect to the primary endpoint and secondary endpoint will be 
strongly controlled at the alpha=0.05 level using a fixed-sequence method testing strategy. If the 
primary endpoint is not statistically significant at the alpha=0.05 level, the secondary efficacy 
endpoint will be considered not significant. If the primary endpoint is statistically significant at 
the alpha=0.05 level, then the secondary efficacy endpoint will be analyzed. If the secondary 
efficacy endpoint fails to reach statistical significance at the alpha=0.05 level, it will be 
considered not statistically significant. 
10.8 Multicenter Studies 
This is a multicenter study, having approximately 35 centers participating in the study. The 
center effects will be investigated in the primary statistical analysis model by including the 
treatment by investigator type interaction. As exploratory analyses to examine the variability of 
the treatment effect across centers, the following analyses will be performed: 
• Pool the centers into self-standing center pools of at least 18 subjects. The pooling will 
sort by investigator type and number of randomized subjects. Then, the centers with 
fewer than 18 subjects will be pooled until the self-standing center pool is at least 18 
subjects. The treatment effect will be explored using a logistic model including treatment, 
household number of randomly assigned subjects, age, baseline lesion counts, and a strata 
statement which will include the pooling identified and examining the residual score 
statistics. To address treatment*center interaction, each pooling center will have a 
corresponding variable coded as 1 if on SB206 and 0 otherwise. Some pooled centers 
may have a p-value of less than 0.05 by chance since there will be multiple pooled 
centers. 
Page 56/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 18/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
• Pool the centers using the method above but the self-standing center pools will contain at 
least 12 subjects. This analysis should be interpreted with caution due to the small sample 
size within pooled centers. 
11. METHODS OF EFFICACY ANALYSIS 
11.1 Primary Efficacy Analysis 
The primary efficacy comparison will test the following hypotheses: 
H0: The proportion of subjects with complete clearance is equal between SB206 12% QD and 
Vehicle; 
H1: The proportion of subjects with complete clearance is different between SB206 12% QD 
and Vehicle.  
 
The primary efficacy model will be the following for 𝜋𝐻𝑖 as the probability of complete 
clearance for the ith subject in household H: 
 
𝜋𝐻𝑖= 
𝑒(𝛽0+𝛽1∗𝑋𝐻𝑖1 + 𝛽2∗𝑋𝐻𝑖2+ 𝛽3∗𝑋𝐻𝑖3+ 𝛽4∗𝑋𝐻𝑖4+ 𝛽5∗𝑋𝐻𝑖5 )
1 + 𝑒(𝛽0+𝛽1∗𝑋𝐻𝑖1 + 𝛽2∗𝑋𝐻𝑖2+ 𝛽3∗𝑋𝐻𝑖3+ 𝛽4∗𝑋𝐻𝑖4+ 𝛽5∗𝑋𝐻𝑖5 ) 
 
 
where H = Household, i = subject within the household, 𝛽0 is the intercept,  
𝑋𝐻𝑖1 = {1, 𝑖𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑖𝑠 𝑆𝐵206  
0, 𝑖𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑖𝑠 𝑉𝑒ℎ𝑐𝑖𝑙𝑒 
 
𝑋𝐻𝑖2 = {1, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎 2 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 ℎ𝑜𝑢𝑠𝑒ℎ𝑜𝑙𝑑
0, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎 1 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 ℎ𝑜𝑢𝑠𝑒ℎ𝑜𝑙𝑑 
 
𝑋𝐻𝑖3 = {1, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎 𝐷𝑒𝑟𝑚𝑎𝑡𝑜𝑙𝑜𝑔𝑦 𝑠𝑖𝑡𝑒
0, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎𝑛 𝑂𝑡ℎ𝑒𝑟 𝑠𝑖𝑡𝑒              
 
𝑋𝐻𝑖4is the subject’s baseline lesion count, and 𝑋𝐻𝑖4is the subject’s age at baseline; treatment will 
be included in the class statement with PARAM=REF and REF=Vehicle. The working 
correlation will have an exchangeable structure. The model will include a repeated statement for 
subject household with household ID in the class statement. Also, the data structure will be 
ordered according to household ID and subject ID in household. 
 
Treatment groups will be compared using a generalized estimating equation for logistic 
regression with an exchangeable working correlation structure. The model will include 
treatment, investigator type (dermatologist vs other), household number of randomly assigned 
subjects (1 subject per household vs 2 subjects per household), age, and baseline lesion count as 
factors. The odds ratio between SB206 12% and vehicle gel, 95% confidence intervals for the 
odds ratio, and P-value for the covariate-adjusted treatment comparison will be presented; 
Page 57/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 19/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
together with predicted proportions along with their associated 95% confidence interval. The 
difference in proportion confidence interval will be calculated using the following formula: 
 
(𝑝𝑆𝐵206 − 𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒) ± 𝑧0.025
∗∗ 𝑆𝐸 
 
Where the SE = 
√
𝑝𝑆𝐵206
2
(1 −𝑝𝑆𝐵206)2 𝑠𝑆𝐵206
2
+ 𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒
2
(1 −𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒)2 𝑠𝑉𝑒ℎ𝑖𝑐𝑙𝑒
2
−2𝑝𝑆𝐵206(1 −𝑝𝑆𝐵206)𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒 
(1 −𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒) ∗(𝑠𝑆𝐵206
2
+ 𝑠𝑉𝑒ℎ𝑖𝑐𝑙𝑒
2
− 𝑠𝑂𝑑𝑑𝑠 𝑅𝑎𝑡𝑖𝑜
2
2
)
 
The 𝑝𝑆𝐵206 and 𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒 are the transformed predicted log odds at the mean of the covariates, s2’s 
are the standard errors of the predicted log odds and the odds ratio.  
As a sensitivity analysis, the above primary analysis model will be applied to the PP Population. 
An additional sensitivity analysis counting subjects who discontinued prior to Week 12 or have a 
missing lesion count assessment but who demonstrated complete clearance at the last collected 
lesion assessment as responders will be presented. The impact of mis-stratifications may be 
explored via a sensitivity analysis.   
An analysis where the complete clearance response probability for each dropout prior to Week 
12 will be independently generated across the following scenarios (Vehicle response probability, 
SB206 response probability): 
 
(0.1, 0.1) 
(0.1, 0.0) 
 
 
 
(0.2, 0.2) 
(0.2, 0.1) 
(0.2, 0.0) 
 
 
(0.3, 0.3) 
(0.3, 0.2) 
(0.3, 0.1) 
(0.3, 0.0) 
 
(0.4, 0.4) 
(0.4, 0.3) 
(0.4, 0.2) 
(0.4, 0.1) 
(0.4, 0.0) 
 
The analysis will be produced 100 times and then the results for the estimated log odds ratio for 
treatment and its estimated standard error from each of the imputations will be combined using 
PROC MIANALYZE. 
An additional sensitivity analysis will be performed in a subset of the ITT population where only 
1 subject from each household is chosen to contribute to the model based on the subject with the 
highest number of baseline treatable MC and the oldest to break ties, if needed. A logistic 
regression model including treatment, investigator type, age, and baseline lesion counts will be 
utilized. 
11.2 Secondary Efficacy Analyses 
The secondary endpoint of the proportion of subjects with complete clearance of all treatable MC 
at Week 8 will be analyzed in the same manner as the primary endpoint. A sensitivity analysis 
using the PP Population will be provided.  
Page 58/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 20/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
11.3 Exploratory Analyses 
The exploratory endpoints based on the proportion of subjects achieving complete clearance or 
75%, 90%, or 95% reductions will be analyzed in the same manner as the primary endpoint.  
Since the within-household correlation is expected to be small and the change and percent 
change from Baseline in the number of treatable MC are exploratory, they will be analyzed using 
a repeated measures mixed model for the respective visits with the same covariates as the 
primary model together with visits and treatment by visit; an unstructured covariance matrix will 
be utilized. If the calculation of the percent change from baseline is influenced by outliers with 
calculated values >100%, then the influence of outliers will be avoided for analysis by censoring 
them so that all values were in the range of -100% to 100%. If the model fails to converge, then 
other correlation structures will be explored. 
Since the within-household correlation is expected to be small and time to first complete 
clearance of all MC is exploratory, it will be analyzed using Kaplan-Meier methods. The number 
and percentage of subjects achieving complete clearance, number and percentage of censored 
subjects, and Kaplan-Meier estimates of first quartile, median, and third quartile will be 
summarized by treatment group. Differences in Kaplan-Meier curves between the treatments will 
be tested for significance using a stratified log-rank test. 
The proportion of subjects with scarring and the proportion of subjects with keloid or 
hypertrophic scarring will be summarized descriptively at each visit. 
The change from Baseline of the composite score from age-matched (at Baseline) DLQI/CDLQI 
will be summarized descriptively and separately for each questionnaire. The scoring algorithms 
are detailed in Appendix A. The CDLQI will be examined in the following Week 12 response 
categories: complete clearance, 95% reduction in lesion counts, 90% reduction in lesion counts, 
and subjects who did not achieve complete clearance. Additionally, the changes from Baseline in 
the following subscales: Symptoms and Feelings, Daily Activities, Leisure, Work and School, 
Personal Relationships, and Treatment, for DLQI, and Symptoms and Feelings, Leisure, School 
or Holidays, Personal Relationships, Sleep, and Treatment, for CDLQI, and each question will be 
summarized descriptively. 
The subject-reported spread of MC to household members not in the study will be summarized 
descriptively including a breakdown of whether or not there was any spread and then a 
breakdown of the amount of spread within the household at each visit at the household level.  
12. OTHER ANALYSES 
The following analyses of BOTE vs lesion count/complete clearance will be presented: 
• Percent change from Baseline at Week 12 in relation to the highest BOTE score during 
treatment. 
• Complete clearance at Week 12 in relation to the highest BOTE score during treatment. 
Page 59/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 21/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
• Percent change from Baseline at each visit in relation to BOTE score at Week 2. 
• Complete clearance at each visit in relation to BOTE score at Week 2. 
In these analyses, the BOTE scores will be analyzed in the ITT Population as follows: 
1. Dichotomized: 
a. Score of 0 or 1: No to Mild 
b. Score of 2, 3, or 4: Moderate to Very Severe 
A shift table comparing the baseline BOTE score to each scheduled postbaseline assessment will 
be presented for the Safety Population.  
13. SAFETY ANALYSES 
All safety analyses will be based on the Safety Population. 
 
A listing of all deaths will be presented. 
13.1 Adverse Events 
All AE summaries will be restricted to treatment-emergent AEs (TEAEs), which are defined as 
those AEs that occurred any time on or after the first in-clinical application of study drug through 
the last application of study medication and those existing AEs that worsened during this same 
period. If it cannot be determined whether the AE is treatment emergent due to a partial onset 
date, then it will be counted as such; see Appendix B for the imputation of missing dates 
algorithm. Verbatim terms in the eCRFs will be mapped to preferred terms and system organ 
classes using the MedDRA Version 22.0.  
Each AE summary will be displayed by treatment group. Summaries that are displayed by 
system organ classes and preferred terms will be ordered by descending order of incidence of 
system organ class and preferred term within each system organ class. Summaries of the 
following types will be presented: 
• Overall summary of TEAEs that contain an overview of each item below. 
• Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system 
organ class and preferred term.  
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
maximum severity. At each level of subject summarization, a subject is classified 
according to the maximum severity if the subject reported 1 or more events. Adverse 
events with missing severity will be considered severe for this summary. 
Page 60/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 22/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and closest 
relationship to study drug (Related/Not Related). Related AEs are those reported as 
“Definite,” “Probable,” or “Possible,” and unrelated AEs are those reported as “Unlikely” 
or “Unrelated.” At each level of subject summarization, a subject is classified according 
to the closest relationship if the subject reported 1 or more events. Adverse events with a 
missing relationship will be considered related for this summary. 
• Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA system organ class and preferred term.  
• Subject incidence of TEAEs leading to study drug discontinuation by MedDRA system 
organ class and preferred term. 
• Subject incidence of TEAEs leading to death as an outcome by MedDRA system organ 
class and preferred term. 
Separate listings of all AEs, all SAEs and all AEs leading to study drug discontinuation will be 
provided.  
13.2 Local Skin Reaction 
The LSR composite score will be calculated by summing up all the numerical responses (0-4) to 
each individual parameter for a composite score that ranges between 0 and 24. The change from 
Baseline of the LSR composite score will be summarized descriptively. A table summarizing 
each LSR parameter (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and 
erosion/ulceration) score at each scheduled postbaseline assessment will be presented. 
Additionally, a shift table comparing the baseline score for each LSR parameter to each 
scheduled postbaseline assessment will be presented for the Safety Population. 
13.3 Events of Special Interest 
Events of Special Interest will include subjects with any TEAE where the preferred term contains 
“application site”, subjects with at least 1 post-baseline occurrence of moderate BOTE 
inflammation score, or subjects with at least 1 post-baseline LSR component score ≥ 1. A 
summary including the number and percentage of subjects with at least 1 event of special 
interest, AEs of interest by MedDRA system organ class and preferred term, at least 1 moderate 
BOTE inflammation score, and any LSR component score ≥ 1 will be provided for the Safety 
Population. The analysis will also be repeated with the LSR criteria revised to include any post-
baseline LSR component (excluding erythema) score ≥ 1 and erythema score ≥ 2. 
13.4 Urine Pregnancy Test 
Urine pregnancy test results will be included in a data listing only.  
Page 61/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 23/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
13.5 Physical Examination 
A shift table summarizing the shift from Baseline to end of treatment in normal/abnormal will be 
presented.  
13.6 Patch Testing 
A table summarizing any patch testing results by time point may be presented.  
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The following modifications and/or clarifications to the methodology specified in the protocol 
will be: 
• The DLQI and CDLQI will be summarized separately 
• The order of the exploratory endpoints was updated 
• The Mean percent change in baseline endpoint was updated to be more generic in order 
to analyze the median in the case of skewness 
• Proportion of subjects with 90% and 95% clearance exploratory endpoints were added in 
order to provide additional clinically meaningful categories for analysis 
 
 
Page 62/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 24/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
15. REFERENCES 
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for industry ICH E9: Statistical principles 
for clinical trials. September 1998 [cited 2019 May 20]. Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
073137.pdf 
 
Cardiff University. Dermatology Life Quality Index. April 1992 [cited 2019 May 20]. Available 
from: https://www.cardiff.ac.uk/medicine/resources/quality-of-life-questionnaires/dermatology-
life-quality-index 
 
Cardiff University. Children’s Dermatology Life Quality Index. April 1992 [cited 2019 May 20]. 
Available from: https://www.cardiff.ac.uk/medicine/resources/quality-of-life-
questionnaires/childrens-dermatology-life-quality-index 
Page 63/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 25/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
16. APPENDICES 
Appendix A: Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) Scoring 
DLQI: 
Question 
Scoring 
Subscale 
1. Over the last week, how itchy, sore, 
painful or stinging has you skin been? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all = 0 
Symptoms and 
Feelings 
2. Over the last week, how embarrassed 
or self conscious have you been because 
of your skin? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all = 0 
Symptoms and 
Feelings 
3. Over the last week, how has your skin 
interfered with you going shopping or 
looking after your home or garden? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Daily Activities 
4. Over the last week, how much has 
your skin influenced the clothes you 
wear? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Daily Activities 
5. Over the last week, how much has 
your skin affected any social or leisure 
activities? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Leisure 
6. Over the last week, how much has 
your skin made it difficult for you to do 
any sport? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Leisure 
7. Over the last week, has your skin 
prevented you from working or 
studying? 
 
If “No”, over the last week how much 
has your skin been a problem at work or 
studying? 
Yes = 3 
No 
Not Relevant = 0 
 
A lot = 2 
A little = 1 
Not at all = 0 
Work and School 
8. Over the last week, how much has 
your skin created problems with your 
partner or any of your close friends or 
relatives? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Personal 
Relationships 
 
Page 64/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 26/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Question 
Scoring 
Subscale 
9. Over the last week, how much has 
your skin caused any sexual difficulties? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Personal 
Relationships 
10. Over the last week, how much of a 
problem has the treatment for your skin 
been, for example by making your home 
messy, or by taking up time? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Treatment 
Note: DLQI is administered in subjects ≥ 16 years old. 
 
 
The DLQI composite score is then the sum of the scores to all 10 questions and will range from 0 
to 30. If 1 question is unanswered, this is allocated a score of 0 and the DLQI score is then 
summed. If 2 or more questions are unanswered, the questionnaire is not scored.  
The subscales will be expressed as percentages of the maximum score: 
 
Subscale 
Maximum Score 
Symptoms and Feelings 
6 
Daily Activities 
6 
Leisure 
6 
Work and School 
3 
Personal Relationships 
6 
Treatment 
3 
 
 
 
Page 65/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 27/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
CDLQI: 
Question 
Scoring 
Subscale 
1. Over the last week, how itchy, 
“scratchy”, sore, or painful has your skin 
been? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Symptoms and 
Feelings 
2. Over the last week, how embarrassed or 
self conscious, upset or sad have you been 
because of your skin? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Symptoms and 
Feelings 
3. Over the last week, how has your skin 
affected your friendships? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Personal 
Relationships 
4. Over the last week, how much have you 
changed or worn different or special 
clothes/shoes because of your skin? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
5. Over the last week, how much has your 
skin trouble affected going out, playing, or 
doing hobbies? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
6. Over the last week, how much have you 
avoided swimming or other sports because 
of your skin trouble? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
7. Last week, was it school time? If school 
time: Over the last week, how much did 
your skin problem affect your school work? 
 
Was it holiday time? If holiday time: Over 
the last week, has your skin problem 
interfered with your enjoyment of the 
holiday? 
Prevented school = 3 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
School or 
Holidays 
8. Over the last week, how much trouble 
have you had because of your skin with 
other people calling you names, teasing, 
bullying, asking questions or avoiding 
you? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Personal 
Relationships 
 
 
 
Page 66/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 28/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
 
Question 
Scoring 
Subscale 
9. Over the last week, how much has 
your sleep been affected by your skin 
problem? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Sleep 
10. Over the last week, how much of a 
problem has the treatment for your skin 
been? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Treatment 
Note: CDLQI is administered in subjects 4 years old up to 16 years old. 
 
The CDLQI composite score is then the sum of the scores to all 10 questions and will range from 
0 to 30. If a question is unanswered, this is allocated a score of 0 and the CDLQI score is then 
summed.  
The subscales will be expressed as percentages of the maximum score: 
 
Subscale 
Maximum Score 
Symptoms and Feelings 
6 
Leisure 
9 
School or Holidays 
3 
Personal Relationships 
6 
Sleep 
3 
Treatment 
3 
 
 
 
Page 67/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 29/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Appendix B: Presentation of Data and Programming Specifications 
General  
• Specialized text styles, such as bold, italics, borders, and shading will not be used in 
tables, figures, and data listings unless they add significant value to the table, figure, or 
data listing. 
• Only standard keyboard characters are to be used in tables and data listings. 
• Special characters, such as nonprintable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
• Hexadecimal character representations are allowed (e.g., µ, , ß). 
• All footnotes will be left justified and at the bottom of a page. Footnotes must be used 
sparingly and must add value to the table, figure, or data listing. 
 
Tables 
• Formal organization of tabulations may be changed during programming, if appropriate, 
e.g., tables for the different variables may be combined into a single table, or tables with 
more than 1 variable may be split into several tables. 
• Means and medians will be presented to 1 more decimal place than the raw data. 
Standard deviations will be presented to 2 more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
• Percentages will be presented to the tenths place. 
• For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the subjects discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0. 
Categories with zero counts will not have zero percentages displayed. 
• Lower and upper confidence interval values must be presented to 1 decimal place more 
than the raw/derived data (i.e., to the same number of decimal places as the mean). 
• Percentiles (e.g., 25%, 75%) must be presented to 1 decimal place more than the 
raw/derived data. 
• For all inferential analyses, P values will be rounded to 4 decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P values less than 0.0001 will be 
presented as “<0.0001.” 
• The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source table number(s) if applicable (in case aggregated 
results like mean or median are plotted) or the source listing(s) (in case individual responses are 
plotted) and/or source dataset(s) (e.g., AdaM).  
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
Page 68/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 30/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Figures 
• Legends will be used for all figures with more than 1 variable or item displayed. 
Treatment group sizes (n=xx) will be included, as appropriate. 
• Figures will be in black and white but can be in color to add value to the clarity and 
readability of a figure. Lines must be wide enough to see the line after being copied. 
• For box plots, the horizontal line will represent the median, + represents the group mean, 
the length of the box represents the interquartile range (25th-75th percentiles), and the 
whiskers will represent the minimum and maximum. 
• The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source listing number(s) and/or source dataset(s) (e.g., AdaM).  
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
 
Listings 
• Formal organization of the listing may be changed during programming, if appropriate, 
e.g., additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints. 
• If not otherwise specified, all data listings will be sorted by sequence/treatment, center, 
subject number, visit, and date/time, as appropriate.  
• All date values will be presented in a SAS date (e.g., 29AUG2001) format.  
• All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26). Seconds will only be reported if they were measured as part of 
the study. 
• The last footnote will be 
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
 
 
 
Page 69/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 31/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Missing or incomplete dates (i.e., AEs, concomitant medications, and start dates of current 
molluscum episode and initial diagnosis) 
The most conservative approach will be systematically considered. If the AE onset date is 
missing/incomplete, it is assumed to have occurred during the study treatment phase (i.e., 
considered a TEAE) except if the partial onset date or other data, such as the stop date, indicates 
differently. Similarly, a medication with partial start and stop dates could be considered as both a 
prior and concomitant treatment. 
 
The following algorithms will be applied to missing and incomplete start and stop dates: 
 
Start Dates 
• If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first application of study drug, provided the start month and year are 
the same as the first application of study drug and the stop date is either after the first 
application of study drug or completely missing. Otherwise, the missing day portion will 
be estimated as “01.” 
• If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first application of study drug, provided the start year 
is the same as the first application of study drug and the stop date is either after the first 
application of study drug or completely missing. Otherwise, the event will be assumed to 
start on the first day of the given year (e.g., ??-???-2013 is estimated as 01-JAN-2013) or 
the subject’s date of birth, whichever is latest. 
• If the start date is completely missing and the stop date is either after the application of 
study drug or completely missing, the start date will be estimated to be the first day of 
study drug application. Otherwise, the start date will be estimated to be the first day of 
the same year as the stop date or the subject’s date of birth, whichever is latest. All other 
non-AE and non-concomitant medication day calculations where only partial dates are 
available will be handled as follows: the first day of the month will be used in the 
calculations if the day part of a start date is missing while January 1 will be employed if 
both the month and day parts of a start date are missing. 
 
Stop Dates 
• If only the day of resolution is unknown, the day will be assumed to be the last day of the 
month (e.g., ??-JAN-2013 will be treated as 31-JAN-2013).  
• If both the day and month of resolution are unknown, the event will be assumed to have 
ceased on the last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013).  
• If the stop date is completely missing and the event is not continuing, the event will be 
assumed to be after first application of study drug and will be imputed using the last 
known date on the study. 
 
For the start dates of current molluscum episode and initial diagnosis, the day will be estimated 
as “01” if only day is missing. If both month and day are missing, then it will be estimated as 
“01-JUN-YYYY” or the subject’s date of birth, whichever is latest. 
Page 70/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 32/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
 
If the start date of current molluscum episode is partial, then the following imputation will be 
made: 
• If only the day is unknown, the day will be assumed to be the first day of the month or 
the date of birth, whichever is later. 
• If the day and month are missing, then the start date will be estimated to be June 1st or the 
date of birth, whichever is later. 
 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• Days – A duration expressed in days between 1 date (date1) and another later date (date2) is 
calculated using the formulas noted below: 
Duration in days = date2 – date1 + 1. 
• Months – A duration expressed in months will be calculated as (later date – earlier date + 
1)/(30.4167). 
• Years – A duration expressed in years will be calculated as (later date – earlier date + 
1)/(365). 
• Change from Baseline – Change from Baseline will be calculated as follows: 
Change from Baseline = postbaseline value – baseline value. 
• Percent change from Baseline – Change from Baseline will be calculated as follows: 
Percent change from Baseline = (postbaseline value – baseline value)/baseline value  
× 100. 
 
 
Page 71/120


 
 
Novan, Inc.  
 
Statistical Analysis Plan 
NI-MC302 
 
18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 33/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Appendix C: SAS Programming QC Requirements  
Derived datasets are independently programmed by two programmers. The separate datasets 
produced by the 2 programmers must match 100%. Detailed specifications for the derived 
datasets are documented in the study analysis dataset specifications provided to the client at 
study conclusion. 
Tables are independently reprogrammed by a second programmer for numeric results.  
Listings are checked for consistency against corresponding tables, figures, and derived datasets. 
Figures are checked for consistency against corresponding tables and listings, or independently 
reprogrammed if there are no corresponding tables or listings. 
The entire set of TLFs is checked for completeness and consistency prior to its delivery to the 
client by the lead biostatistician and a senior level, or above, reviewer.
Page 72/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                     18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 34/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Appendix D:  List of Tables, Figures, and Listings 
The following proposal for section 14 and 16.2 is completed according to ICH E3 guidelines. The ICH heading numbers and description are in bold. 
Minor changes from this planned index do not need to be amended in the SAP.  
 
Formal organization of tabulations may be changed during programming, if appropriate, e.g., tables for the different variables may be combined into 
a single table, or tables with more than 1 variable may be split into several tables. 
 
The shells for the outputs below are contained in the file titled “Novan NI-MC302 SAP TLFs Version 2.0”. 
  
TABLES, FIGURES, AND GRAPHS  
Table 
Number 
 
Table Title 
Analysis Population 
14 
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE 
TEXT 
 
14.1 
DEMOGRAPHIC DATA 
 
14.1.1.1 
Subject Disposition 
Enrolled 
14.1.1.2 
Enrollment by Site 
ITT 
14.1.2.1 
Demographic and Baseline Characteristics  
Safety 
14.1.2.2 
Demographic and Baseline Characteristics 
ITT 
14.1.2.3 
Demographic and Baseline Characteristics 
PP 
14.1.3.1 
Study Drug Exposure 
Safety 
14.1.3.2 
Study Drug Compliance 
Safety 
14.1.4 
Significant and Major Protocol Deviations 
ITT 
14.1.5 
Medical History 
ITT 
14.1.6.1 
Prior Medications 
ITT 
14.1.6.2 
Concomitant Medications 
ITT 
14.2 
Efficacy data 
 
14.2.1.1 
Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.2 
Complete Clearance Lesion Count Response at Week 12 
PP 
Page 73/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                     18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 35/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Table 
Number 
 
Table Title 
Analysis Population 
14.2.1.3 
Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.4 
Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
PP 
14.2.1.6 
Proportion of Subjects with Complete Clearance at Week 12 by Subgroup 
ITT 
14.2.1.7 
Dropout Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.8 
One Subject Per Household Sensitivity Analysis: Complete Clearance Lesion Count Response at 
Week 12 
ITT 
14.2.1.9 
Exploratory Analysis of the Variability of Treatment Effect of Complete Clearance Lesion 
Count Response at Week 12 Across Pools of at Least 17 Subjects 
ITT 
14.2.1.10 
Exploratory Analysis of the Variability of Treatment Effect of Complete Clearance Lesion 
Count Response at Week 12 Across Pools of at Least 10 Subjects 
ITT 
14.2.2.1 
Complete Clearance Lesion Count Response at Week 8 
ITT 
14.2.2.2 
Complete Clearance Lesion Count Response at Week 8 
PP 
14.2.3.1 
Complete Clearance Lesion Count Response at Weeks 2 and 4 
ITT 
14.2.3.2.1 
Summary of a 95% Reduction in Lesion Counts from Baseline Response by Visit 
ITT 
14.2.3.2.2 
Summary of a 90% Reduction in Lesion Counts from Baseline Response by Visit 
ITT 
14.2.3.2.3 
Summary of a 75% Reduction in Lesion Counts from Baseline Response by Visit 
ITT 
14.2.3.3.1 
Percent Change from Baseline in Lesion Count by Visit 
ITT 
14.2.3.4.1 
Change from Baseline in Lesion Count by Visit 
ITT 
14.2.3.5 
Summary of Recurrence after Complete Clearance 
ITT 
14.2.3.6.1 
Kaplan-Meier Estimates of Time to Complete Clearance (Days) from Start of Dosing 
ITT 
14.2.3.7 
Summary of Scarring and Keloid by Visit 
ITT 
14.2.3.8.1 
Summary of the Dermatology Life Quality Index (DLQI) and Subscales by Visit 
ITT 
14.2.3.8.2 
Summary of the Dermatology Life Quality Index (DLQI) Individual Questions by Visit 
ITT 
14.2.3.8.3.1 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT 
14.2.3.8.3.2 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Complete 
Responders at Week 12  
14.2.3.8.3.3 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Subjects with at 
least a 95% Reduction in 
Page 74/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                     18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 36/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Table 
Number 
 
Table Title 
Analysis Population 
Lesion Counts at Week 
12 
14.2.3.8.3.4 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Subjects with at 
least a 90% Reduction in 
Lesion Counts at Week 
12 
14.2.3.8.3.5 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Subjects who did 
not Achieve Complete 
Clearance at Week 12 
14.2.3.8.4 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) Individual Questions by 
Visit 
ITT 
14.2.3.9 
Summary of Increase in Subject-Reported Spread to Household Members by Visit 
ITT 
14.2.3.10.1 
Summary of Lesion Counts by Highest Dichotomized BOTE Score 
ITT 
14.2.3.10.3 
Percent Change from Baseline in Lesion Count over Time by Dichotomized Week 2 BOTE 
Score 
ITT 
14.2.3.10.4 
Summary of Complete Clearance by Visit and Dichotomized Week 2 BOTE Score 
ITT 
14.2.3.10.5 
Summary of the Beginning of the End (BOTE) Inflammation Score Results by Visit 
Safety 
14.3 
Safety data 
 
14.3.1 
Displays of Adverse Events 
 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety 
14.3.1.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.4 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug 
Safety 
14.3.1.5 
Summary of Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
Safety 
14.3.1.6 
Summary of Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
Safety 
Page 75/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                     18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 37/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Table 
Number 
 
Table Title 
Analysis Population 
14.3.1.7 
Summary of Treatment-Emergent Adverse Events Leading to Death by System Organ Class and 
Preferred Term 
Safety 
14.3.2 
Listings of deaths, other serious and significant adverse events 
 
14.3.2.1 
Listing of Serious Adverse Events 
Safety 
14.3.2.2 
Listing of Adverse Events Leading to Study Drug Discontinuation 
Safety 
14.3.2.3 
Listing of Deaths 
Safety 
14.3.6 
Other safety data 
 
14.3.6.1.1 
Summary of Local Skin Reaction (LSR) Composite Score by Visit 
Safety 
14.3.6.1.2 
Summary of Local Skin Reaction (LSR) Score Results by Visit 
Safety 
14.3.6.1.3 
Shift Summary of Local Skin Reaction (LSR) Score Results by Visit 
Safety 
14.3.6.2 
Summary of Events of Special Interest 
Safety 
14.3.6.3 
Summary of Physical Examination Findings 
Safety 
14.3.6.4 
Summary of Patch Testing Results 
Safety 
 
  
 
 
Page 76/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                     18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 38/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
 
Figure 
Number 
 
Figure Title 
Analysis Population 
14.2.1.5 
Forest Plot: Odds Ratio (95% CI) of the Proportion of Subjects with Complete Clearance at 
Week 12 
ITT 
14.2.3.3.2 
Percent Change from Baseline in Lesion Count over Time by Treatment Group 
ITT 
14.2.3.4.2 
Mean Change from Baseline in Lesion Count over Time by Treatment Group 
ITT 
14.2.3.6.2 
Kaplan-Meier Plot of Time to Complete Clearance (Days) from Start of Dosing 
ITT 
14.2.3.10.2 
Plot of Complete Clearance at Week 12 by Highest Dichotomized Categorized BOTE Score 
ITT 
 
 
Page 77/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                     18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 39/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
Section 16.2: List of Data Listings 
 
ICH Listing 
Number 
 
Listing Title 
Analysis 
Population 
16.1.7 
Subject Randomization 
ITT 
16.2 
SUBJECT DATA LISTINGS 
 
16.2.1 
Discontinued subjects 
 
16.2.1.1 
Subject disposition 
Enrolled 
16.2.2 
Protocol deviations 
 
16.2.2.1 
Protocol Deviations  
ITT 
16.2.2.2 
Inclusion/Exclusion Criteria 
Enrolled 
16.2.3 
Subjects excluded from the efficacy analysis 
 
16.2.3.1 
Analysis Populations 
Enrolled 
16.2.4 
Demographic data 
 
16.2.4.1 
Demographic and Baseline Characteristics 
ITT 
16.2.4.2 
Patch Testing Consent/Assent 
Enrolled 
16.2.4.3 
Medical History 
ITT 
16.2.4.4 
Prior and Concomitant Medications 
ITT 
16.2.5 
Compliance and/or drug concentration data  
 
16.2.5.1 
Study Drug Administration 
Safety 
16.2.5.2 
Study Drug Accountability 
Safety 
16.2.5.3 
Treatment Adjustment 
Safety 
16.2.5.4 
Treatment Compliance 
Safety 
16.2.6 
Individual efficacy response data 
 
16.2.6.1 
Lesion Counts 
ITT 
16.2.6.2 
Lesion Count Derived Efficacy Variables and Time to Complete Clearance 
ITT 
16.2.6.3 
Scarring/Keloid Assessment 
ITT 
16.2.6.4 
Dermatology Life Quality Index (DLQI) and Subscales 
ITT 
16.2.6.5 
Children’s Dermatology Life Quality Index (CDLQI) and Subscales 
ITT 
16.2.6.6 
Household Transmission 
ITT 
16.2.7 
Adverse events listings 
 
Page 78/120


 
 
 
Novan, Inc.  
                                                                                                 Statistical Analysis Plan 
NI-MC302 
                                                                                                                     18Nov2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 40/40 
CONFIDENTIAL 
Novan NI-MC302 SAP Version 2.0 
ICH Listing 
Number 
 
Listing Title 
Analysis 
Population 
16.2.7.1 
All Adverse Events 
Safety 
16.2.8  
Listing of individual laboratory measurements by subject, when required by regulatory authorities 
 
16.2.8.1 
Urine Pregnancy Test 
Safety 
16.2.9 
Other data 
 
16.2.9.1 
Beginning-of-the-End (BOTE) Inflammation Score 
Safety 
16.2.9.2 
Local Skin Reactions (LSR) 
Safety 
16.2.9.3 
Physical Examination 
Safety 
16.2.9.4 
Patch Testing 
Safety 
16.2.9.5 
Telephone Contact 
ITT 
16.2.9.6 
Subjects who Require a Narrative  
ITT 
  
Page 79/120


 
 
 
Statistical Analysis Plan 
 
Novan, Inc.  
NI-MC302 
 
A Phase 3 Multi-Center, Randomized, Double-Blind, Vehicle-Controlled, Parallel Group 
Study Comparing the Efficacy and Safety of SB206 and Vehicle Gel Once Daily in the 
Treatment of Molluscum Contagiosum 
Protocol Version: 26Mar2019 
 
 
 
Sponsor:  
 
Novan, Inc.  
4105 Hopson Road 
Morrisville, NC 27560 
 
 
Prepared by:  
Christopher Tait 
5909 Sea Otter Place, Suite 100 
Carlsbad, CA 92010 
 
 
Version 
Date 
Version 1 
10 Sep 2019 
Version 2 
18 Nov 2019 
Version 3 
12 Dec 2019 
 
 
 
 
 
Page 80/120


Page 81/120


TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................................. 6 
2. 
STUDY DOCUMENTS ......................................................................................................... 6 
3. 
STUDY OBJECTIVES .......................................................................................................... 6 
4. 
STUDY DESIGN AND PLAN .............................................................................................. 6 
5. 
DETERMINATION OF SAMPLE SIZE ............................................................................ 9 
6. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................. 10 
7. 
NOTATION OF TREATMENT GROUPS AND VISITS ............................................... 11 
8. 
ANALYSIS POPULATIONS .............................................................................................. 12 
9. 
STUDY POPULATION....................................................................................................... 12 
9.1 
SUBJECT DISPOSITION .................................................................................................. 12 
9.2 
ELIGIBILITY.................................................................................................................. 12 
9.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 13 
9.4 
EXTENT OF EXPOSURE ................................................................................................. 13 
9.5 
PROTOCOL DEVIATIONS .............................................................................................. 14 
9.6 
MEDICAL HISTORY ...................................................................................................... 14 
9.7 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................. 14 
10. EFFICACY ANALYSES ..................................................................................................... 15 
10.1 EFFICACY ENDPOINTS .................................................................................................. 15 
10.2 BASELINE VALUES ....................................................................................................... 16 
10.3 ADJUSTMENTS FOR COVARIATES ................................................................................ 16 
10.4 HANDLING OF DROPOUTS OR MISSING DATA ............................................................. 16 
10.5 INTERIM ANALYSIS AND DATA MONITORING ............................................................. 17 
10.6 EXAMINATION OF SUBGROUPS .................................................................................... 18 
10.7 MULTIPLE COMPARISON/MULTIPLICITY ..................................................................... 18 
10.8 MULTICENTER STUDIES ............................................................................................... 18 
11. METHODS OF EFFICACY ANALYSIS .......................................................................... 18 
11.1 PRIMARY EFFICACY ANALYSIS ................................................................................... 18 
11.2 SECONDARY EFFICACY ANALYSES ............................................................................. 20 
11.3 EXPLORATORY ANALYSES .......................................................................................... 20 
12. OTHER ANALYSES ........................................................................................................... 21 
13. SAFETY ANALYSES .......................................................................................................... 22 
13.1 ADVERSE EVENTS ........................................................................................................ 22 
13.2 LOCAL SKIN REACTION ............................................................................................... 23 
13.3 EVENTS OF SPECIAL INTEREST .................................................................................... 23 
13.4 URINE PREGNANCY TEST ............................................................................................ 23 
13.5 PHYSICAL EXAMINATION ............................................................................................ 24 
13.6 PATCH TESTING ........................................................................................................... 24 
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................ 24 
15. REFERENCES ..................................................................................................................... 25 
16. APPENDICES ...................................................................................................................... 26 
Page 82/120


APPENDIX A: DERMATOLOGY LIFE QUALITY INDEX (DLQI) AND CHILDREN’S 
DERMATOLOGY LIFE QUALITY INDEX (CDLQI) SCORING ............................. 26 
APPENDIX B: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS .................... 30 
APPENDIX C: SAS PROGRAMMING QC REQUIREMENTS ....................................................... 34 
APPENDIX D:  LIST OF TABLES, FIGURES, AND LISTINGS ...................................................... 35 
Page 83/120


LIST OF ABBREVIATIONS 
Abbreviation 
Full Notation 
AE 
adverse event 
ATC 
anatomical/therapeutic/chemical 
BOTE 
beginning of the end 
CDLQI 
Children’s Dermatology Life Quality Index 
CRO 
contract research organization 
DLQI 
Dermatology Life Quality Index 
DSMB 
data safety monitoring board 
eCRF 
electronic case report form 
ICH 
International Council for Harmonisation 
ITT 
Intent-to-Treat 
LSR 
local skin reaction 
MC 
molluscum contagiosum 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per-Protocol 
QC 
quality control 
QD 
once daily 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
 
  
 
Page 84/120


1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Novan, Inc. protocol version 1.0 [A Phase 3 Multi-Center, 
Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Study Comparing the Efficacy 
and Safety of SB206 and Vehicle Gel Once Daily in the Treatment of Molluscum Contagiosum]. 
The purpose of this plan is to provide specific guidelines from which the statistical analyses will 
proceed. Any deviations from this plan will be documented in the clinical study report. 
2. STUDY DOCUMENTS 
The following study documents are used for the preparation of the statistical analysis plan (SAP): 
• Protocol version 1.0, 26Mar2019 
• Annotated electronic case report form (eCRF) version 2.0, 30Jul2019 
• Data management plan version 2.0, 23Aug2019 
3. STUDY OBJECTIVES 
The objective of the study is to evaluate the efficacy and safety of SB206 12% once daily (QD) 
for the treatment of molluscum contagiosum (MC). 
4. STUDY DESIGN AND PLAN 
This is a Phase 3 multi-center, randomized, double-blind, vehicle-controlled, parallel group study 
to be conducted in approximately 340 subjects ≥6 months of age with MC. After obtaining 
informed consent/assent, subjects who satisfy entry criteria will be randomized to a 2:1 
(active:vehicle) scheme. Subjects receiving current treatment for MC at the time of the Screening 
Visit will enter a washout period of up to 14 days prior to randomization. In the event no 
washout period is required, Screening and Baseline visit activities may be combined into a single 
visit. At randomization, subjects will be stratified into 4 strata corresponding to the cross-
classification of household number of randomly assigned subjects (1 subject per household vs 2 
subjects per household) and investigator type (dermatologist vs other). Households randomizing 
2 subjects will receive the same treatment assignment for both subjects. Up to 2 subjects from 
the same household may be randomly assigned on the same day, if both individually meet all 
inclusion and exclusion criteria. For subjects in the same household, Screening can occur on 
different days; however, the baseline visit must occur on the same day. 
Subjects or their caregivers will apply SB206 12% or Vehicle Gel QD for a minimum of 4 weeks 
and up to 12 weeks to all lesions identified at Baseline and new treatable lesions that arise during 
the course of the study. Subjects or their caregivers will continue to treat the area until the next 
scheduled visit even if the lesion(s) clear. If the investigator determines all lesions are cleared at 
a clinic visit, the treatment may stop. At Weeks 2, 4, 8 and 12, the investigator will count and 
record the number of active (raised, treatable) molluscum lesions per body area. At Weeks 2, 4, 
Page 85/120


and 8, the investigator will determine if new lesions have occurred since the last visit, and the 
subject or caregiver will be instructed by the investigator to re-initiate treatment. If treatment is 
stopped due to clearance, subjects will continue regularly scheduled visits through Week 24. 
Subjects will visit the clinic at Screening/Baseline, Week 2, Week 4, Week 8, Week 12, and 
Week 24. Subjects will be contacted via phone on Day 2 to collect subject information on early 
dose reactions. At Weeks 16 and 20, subjects will be contacted via phone to capture information 
regarding MC recurrence and adverse events (AEs); at Week 24, the subject will be seen at the 
site for a final study visit to assess scarring, keloid, and MC recurrence. Subjects who 
discontinue the study prior to the Week 12 visit due to AEs or other reasons will be asked to 
complete the Week 12 visit assessments: this will be recorded as an Early Termination (ET1) 
visit. No study drug treatment will be provided after the Week 12 visit. Subjects who discontinue 
from the study after Week 12 but prior to Week 24 will be asked to come to the site to complete 
Week 24 assessments; this will be recorded as an ET2 visit. 
Safety assessments include local skin reactions (LSRs), AE collection, including scarring/keloid, 
and urine pregnancy tests. Safety assessments will be completed at specified site visits through 
Week 12. After Week 12, safety information for ongoing AEs and new AEs will be collected, 
along with information regarding household MC occurrence. 
Inflammatory reactions around the MC has been associated with imminent resolution of MC 
(sometimes referred to as “beginning-of-the-end” [“BOTE”] sign). The investigator (or 
designated evaluator) will assess the presence and overall degree of inflammatory reactions at 
MC lesions at Baseline (before dosing) and Weeks 2 through 12. In most cases, clinical features 
can differentiate between BOTE and LSR. BOTE may be associated with itch, but not pain. 
BOTE is usually asymptomatic, self-limited, and localized to individual MC lesions and does not 
require discontinuation of study treatment or additional treatment. LSR is generally more diffuse, 
associated with significant itch or tenderness, may necessitate discontinuation of study treatment, 
and may need treatment for symptomatic relief (e.g., a topical corticosteroid or topical 
anesthetic). For very severe LSR, systemic corticosteroids may be considered. Investigators will 
assess the treatment area at each scheduled visit and use their medical judgement to differentiate 
between BOTE and LSRs. BOTE Inflammation Score and LSR score will be recorded at each 
visit. BOTE should not be considered an AE. When LSRs are clinically significant at the 
application site, the investigator should report the condition as an AE(s). 
At Baseline (at least 30 minutes after dosing) and Weeks 2 through 12, the investigators will rate 
LSRs on individual features including erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration. At Baseline (pre-dose) and Weeks 2 through 12, 
the investigators will rate BOTE signs using the BOTE Inflammation Score.  
The following tables describe the scoring parameters for the BOTE Inflammation Score and LSR 
score. 
Page 86/120


BOTE Inflammation Score 
Score 
Global Assessment 
Description 
0 
No inflammation 
No evidence of local inflammation 
1 
Mild 
Minimal erythema and/or edema 
2 
Moderate 
Definite erythema and/or edema with or 
without hemorrhagic crusting 
3 
Severe 
Erythema and edema with definite 
hemorrhagic crusting 
4 
Very severe 
Strong reaction spreading beyond the 
treated area, bullous reaction, erosions 
 
LSR Score 
Score 
Erythema 
Flaking/ 
Scaling 
Crusting 
Swelling 
Vesiculation/ 
Pustulation 
Erosion/ 
Ulceration 
0 
Not present 
Not 
present 
Not 
present 
Not 
present 
Not present 
Not 
present 
1 
Slightly 
pink 
Mild, 
limited 
Isolated 
crusting 
Minimal, 
limited 
Fine vesicles 
Superficial 
erosion 
2 
Pink or 
light red 
Moderate 
Crusting   
< 50% 
Mild, 
palpable 
Scant 
transudate or 
exudate 
Moderate 
erosion 
3 
Red, 
restricted to 
treatment 
area 
Coarse 
Crusting   
> 50% 
Moderate 
Moderate 
transudate or 
exudate 
Marked, 
extensive 
4 
Red 
extending 
outside 
treatment 
area 
Scaling 
extending 
outside 
treatment 
area 
Crusting 
extending 
outside 
treatment 
area 
Marked 
swelling 
extending 
outside 
treatment 
area 
Marked 
transudate or 
exudate 
Black 
eschar or 
ulceration 
Clinically significant LSRs that are reported as AEs and/or subject-reported intolerability (i.e., 
itching, pain) may result in an investigator-directed temporary treatment hold (drug holiday), and 
topical corticosteroids may be used to treat LSRs for up to 2 weeks. The subject may re-initiate 
study drug treatment prior to the next scheduled visit. Upon re-initiation of study drug treatment, 
if a subject develops worsening LSRs, allergic contact dermatitis may be suspected. The 
investigator may take photographs of the suspected allergic contact dermatitis and discuss 
possible confirmation of allergic contact dermatitis with the contract research organization’s 
Page 87/120


(CRO) medical monitor. The investigator should also discuss the necessity of patch testing with 
the subject/caregiver. The investigator will then discontinue the subject from study drug 
treatment and treat the area(s) with corticosteroids for up to 2 weeks. If the subject provides 
consent/assent, the investigator will consult with the CRO’s medical monitor to implement the 
process for patch testing.  
Adverse events will be assessed and collected after the initiation of study drug treatment through 
the end of the subject’s last visit. Treatment-related AEs will be followed up until resolution or 
up to 1 year after last treatment, whichever is sooner.  
Scar formation will be assessed starting at the Week 4 visit through Week 12 and again at 
Week 24. The investigator will map locations of the molluscum lesions at Baseline. Additional 
lesions identified through Week 12 will be added to the map. Using the map as a guidance, the 
investigator will assess the treated areas for scar/keloid formation. The investigator will count 
and record the number of active (raised, treatable) molluscum lesions per body area. If a new 
scar is noted after the subject treated with study drug, this will be considered an AE for the 
purposes of this study. In addition, keloid/hypertrophic scars will also be recorded as AEs.  
If a subject’s treatment is discontinued by the investigator or the subject because of an AE, that 
AE should be indicated as the reason for treatment discontinuation. All subjects will be 
encouraged to remain in the study throughout the 24-week study duration. 
When approximately 200 subjects (cumulative across studies MC301 and MC302) have 
completed 4 weeks of treatment, a data safety monitoring board (DSMB) will review all 
available unblinded safety data (including patch testing).  
5. DETERMINATION OF SAMPLE SIZE 
Approximately 340 subjects, 6 months of age and older, with a minimum of 3 and a maximum of 
70 MC lesions at Baseline will be randomized in a 2:1 (active:vehicle) scheme. The sample size 
assumptions for this study were informed by the completed Phase 2 study NI-MC201 of subjects 
2 years of age and older with between 3 and 70 MC lesions at Baseline. In the Intent-to-Treat 
(ITT) Population of the Phase 2 study, the observed rates of complete clearance at Week 12 were 
18% (12/66) for vehicle and 38% (18/48) for SB206 12% QD and the covariate-adjusted 
treatment difference was 18%.  
A sample size of 340 subjects (227 subjects in the SB206 12% QD group and 113 subjects in the 
vehicle group) will provide 94% power for a 2-sided alpha test of size 0.05 to detect an absolute 
difference of 18% when the vehicle response rate is 18%. This same sample size provides 93% 
power to detect a treatment difference of 18% when the vehicle response rate is 20% and 83% 
power when the treatment difference is 15% and the vehicle response rate is 20%.  
Since the intra-cluster correlation is estimated to be small (<10%) and the average size of 
households is expected to be capped at roughly 1.3, the sample size is still sufficient when 
considering the fact that the subjects within the household may not be independent. 
Page 88/120


6. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs. 
Unless otherwise noted, all statistical testing will be 2-sided and will be performed at the 0.05 
significance level. Tests will be declared statistically significant if the calculated P-value is 
≤0.05.  
Continuous variable summaries will include the number of subjects (n) with non-missing values, 
mean, standard deviation (SD), median, minimum, and maximum. Other statistics such as 
quartiles, confidence intervals (CIs), and number of missing values may be added as appropriate.  
Categorical variable summaries will include the frequency and percentage of subjects who are in 
the category or each possible value. In general, the denominator for the percentage calculation 
will be based upon the total number of subjects in the study population within each treatment 
group, unless otherwise specified. The denominator for by-visit displays will be the number of 
subjects in the relevant study population with non-missing data at each visit.  
All summary tables will be presented by treatment group. Baseline summaries will also include 
an overall summary column.  
Individual subject data obtained from the eCRFs and any derived data will generally be 
presented by subject in data listings. Additionally, a listing of the subjects requiring a narrative 
because they experience one of the following events: serious adverse event, death, discontinued 
the study due to an AE, hypertrophic or keloid scarring, unresolved scars, or LSR suggestive of 
allergic contact dermatitis will be presented.  
The analyses described in this plan are considered a priori, in that they have been defined prior to 
breaking the blind.  
Any analyses performed subsequent to breaking the blind will be considered post hoc and 
exploratory. Post hoc analyses will be labeled as such on the output and identified in the clinical 
study report. 
All analyses and tabulations will be performed using SAS software Version 9.4 or higher. 
Tables, listings, and figures will be presented in RTF format.  
The process for SAS program validation and quality control (QC) for programs and outputs is 
documented in the Synteract working instruction “SAS programming quality control.” 
Study-specific QC requirements can be found in Appendix C: SAS Programming QC 
Requirements. 
 
The study treatment period is defined from randomization through completion of Week 12/ET1 
visit and the safety follow-up period is from the completion of Week 12 through the completion 
of Week 24/ET2 visit. 
Page 89/120


 
After all subjects have completed their Week 12/ET1 visit, thus completing the Treatment Period 
of the study, the database through Week 12/ET1 will be frozen and unblinded for purposes of the 
primary analysis of efficacy and safety.  While this analysis is being prepared, the subjects will 
continue through Week 24/ET2. After all subjects have completed their Week 24/ET2 visit, the 
database will be locked and the follow-up data will be analyzed. 
7. NOTATION OF TREATMENT GROUPS AND VISITS 
Analysis visits 
 
Baseline is defined as the last nonmissing value recorded prior to the first application of study 
drug. If time is not recorded and the assessment was on the same day as the first application of 
study drug, then it will be assumed the assessment occurred prior to the application of study drug. 
The baseline record will have an analysis visit of “Baseline”. 
 
For all evaluations of all parameters, assessments will be analyzed according to the visit at which 
they occurred (i.e., per the eCRF visit label). In order to account for the fact that the Week 12 and 
Early Termination visits are collected on the same eCRF in the database, a check against the Study 
Exit form will be made to determine if the visit is a Week 12 or an Early Termination Visit. If the 
visit is an Early Termination visit, then the visit will be mapped according to the table below. If 
there is no corresponding Study Exit form on the same date, then it will be considered a Week 12 
visit. If there is no assessment in a given visit, then the following visit windows will be applied to 
determine if an unscheduled visit may be used: 
 
Visit 
Analysis Visit 
Target Study 
Day 
Study Day Analysis 
Window 
 
 
 
 
Week 2 (±3 days) 
Week 2 
15 
Day 12 to 22 
Week 4 (±5 days) 
Week 4 
29 
Day 23 to 43 
Week 8 (±5 days) 
Week 8 
57 
Day 44 to 71 
Week 12 (±5 days) 
Week 12 
85 
Day 72 to 98 
 
Days are measured from the date of randomization. Study days corresponding to measurements 
are calculated as: 
• Assessment date – date of randomization + 1, if assessment date is on or after the date of 
randomization. 
• Assessment date – date of randomization, if measurement date is before the date of 
randomization. 
In the event of multiple unscheduled records falling in the same analysis window, the assessment 
which is closest to the target study day will be chosen for analysis.  
Page 90/120


8. ANALYSIS POPULATIONS 
The following subject population will be used for disposition analyses:  
• The Enrolled Population will consist of all subjects who have a signed informed consent 
or assent. If a subject is randomly assigned to a treatment, then treatment assignment will 
be based on randomized treatment; otherwise, they will be deemed a screen failure and 
will only appear in the overall summary columns of output. 
The following subject population will be used for safety analyses:  
• The Safety Population will consist of all subjects who receive at least 1 application of 
study medication. Treatment assignment will be based on the treatment actually received. 
If a subject receives any amount of SB206, then they will be summarized in the SB206 
12% QD arm.  
The following subject populations will be used for efficacy analyses:  
• The ITT Population will consist of all subjects who are randomized. Treatment 
assignment will be based on the randomized treatment.  
• The Per-Protocol (PP) Population will consist of all subjects in the ITT Population who 
had no significant protocol deviations that impacted the analyses of efficacy endpoints. 
Final determination of subject inclusion in the PP Population will be made prior to 
unblinding. Treatment assignment will be based on the randomized treatment. 
9. STUDY POPULATION 
9.1 Subject Disposition 
Subject disposition information will be summarized for all subjects by treatment group. 
Summaries will include: the number of subjects screened, the number of subjects in each 
analysis population, the number of subjects where study treatment stopped, primary reason for 
study treatment stopped, the number of subjects completing 12 weeks of the study (defined as 
having an end of treatment reason of “Completed Treatment Per Protocol” or a reason of 
“Complete Clearance Prior to Week 12” and does not have a Study Exit date prior to the 
subject’s Week 12 visit date), the number of subjects completed the study, and the primary 
reason for discontinuation. 
 
A summary of the number of subjects in each center and each population will be presented.  
9.2 Eligibility 
A listing of subjects not fulfilling any eligibility criteria will be created. 
Page 91/120


9.3 Demographic and Baseline Characteristics 
Demographic variables include age, sex, ethnicity, and race. Age will be calculated in years 
relative to the informed consent date.  
Other baseline characteristics include lesion counts at baseline, site type (dermatologist vs other), 
number of sites and a breakdown of site type, number of randomly assigned subjects in 
household (1 subject vs 2 subjects), number of households and breakdown of household size, age 
at and time since initial clinical diagnosis of the current molluscum episode and age at and time 
since onset of symptoms of current molluscum episode. Descriptive statistics will be presented 
for ages and other continuous variables. Frequency counts and percentages will be presented for 
sex, ethnicity, race and other categorical variables. Demographic and baseline characteristics will 
be summarized for the Safety, ITT, and PP Populations.  
9.4 Extent of Exposure 
Study drug exposure will be summarized for each treatment using the total number of 
applications, the duration of treatment, and the number of subjects requiring a treatment 
interruption and modification. Duration of treatment is defined as the last application date minus 
the first application date plus 1. 
Study drug compliance will be summarized and calculated as follows: 
Compliance [%] = (Actual applications applied)/(Planned applications) ×100, where 
• Actual applications applied = Planned applications – the number of applications missed 
• Planned applications = Number of applications (days) planned up to the point of 
treatment discontinuation or date of Week 12 visit, whichever is later.  
This implies that if a subject treatment discontinues treatment prior to Week 12 due to complete 
clearance, then the number of applications takes this information into account and the subject is 
not penalized for having complete clearance.  
Compliance will be further summarized into 2 groups:  
1. Subjects who did not have any interruptions or modifications using the same formula as 
above, and 
2. Subjects with modifications or interruptions. For these subjects, an adjusted compliance 
will be calculated in the following manner: the actual applications applied will be the 
same as above but the planned applications will exclude the time where the subject has 
dosing interrupted.  
Page 92/120


9.5 Protocol Deviations 
Significant protocol deviations that could potentially affect the efficacy or safety conclusions of 
the study will be identified prior to database lock and unblinding of individual subject treatment 
information. Significant protocol deviations may include, but are not limited to: 
• Randomly assigned subjects who did not satisfy selected inclusion and exclusion criteria 
• Randomly assigned subjects who developed withdrawal criteria during the study but were 
not withdrawn 
• Subjects who were randomized incorrectly including subjects of the same household who 
are randomized to different treatments  
• Subjects who received the wrong treatment 
• Subjects where the subject/site staff were unproperly unblinded 
• Week 12 Lesion Count not performed 
• Subjects who received an excluded concomitant treatment. 
The decision on the criteria for whether a subject is excluded from the PP Population will be 
made during the data review meeting prior to unblinding and database lock. Reasons for 
exclusion of a subject from the analysis will be listed. 
A listing of all protocol deviations including the deviation designation (major or minor and 
significant or not), category, and indication of whether the deviation led to an exclusion of a 
subject from the PP Population will be presented in a data listing.   
Major and significant protocol deviations will be summarized by deviation category and 
treatment group.  
9.6 Medical History 
Medical history verbatim terms in the eCRFs will be mapped to system organ classes and 
preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0. 
Subject incidence of unique medical history terms by MedDRA system organ class and preferred 
term will be presented. The summary will be ordered by descending order of incidence of system 
organ class and preferred term within each system organ class. 
9.7 Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms in the eCRFs will be mapped to 
anatomical/therapeutic/chemical (ATC) class and preferred names using the WHODrug Global 
B3 (version March 2019). Prior medications are those medications started prior to the first 
application of study drug. Concomitant medications are those medications started on or after the 
date of first application of study drug or medications started prior to initial application of study 
Page 93/120


drug and continued during the study. A medication can be classified as both prior and 
concomitant. If it cannot be determined whether the medication was a prior (or concomitant) 
medication due to a partial start or stop date, then it will be counted as both prior and 
concomitant; see Appendix B for the imputation of missing dates algorithm. 
Prior and concomitant medications will be summarized for each treatment by WHODrug Global 
ATC class Level 3 and preferred name. These summaries will present the number and percentage 
of subjects using each medication. Subjects may have more than 1 medication per ATC class and 
preferred name. At each level of subject summarization, a subject is counted once if he/she 
reported 1 or more medications at that level. Each summary will be ordered by descending order 
of incidence of ATC class and preferred name within each ATC class. 
10. EFFICACY ANALYSES 
The primary efficacy analysis will be based on the ITT Population. Additional supportive 
efficacy analyses will be performed using the PP Population. 
10.1 Efficacy Endpoints 
The primary efficacy endpoint is the proportion of subjects with complete clearance of all 
treatable MC at Week 12.  
The secondary efficacy endpoint is the proportion of subjects with complete clearance of all 
treatable MC at Week 8.  
Complete clearance is defined as having a total number of lesions count of 0.  
The exploratory endpoints are the following: 
• Proportion of subjects with complete clearance of all treatable MC at Week 2 and Week 4 
visits 
• Proportion of subjects achieving at least a 95% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Proportion of subjects achieving at least a 90% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Proportion of subjects achieving at least a 75% reduction from Baseline in the number of 
all treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Percent change from Baseline in number of treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Change from Baseline in number of treatable MC at each visit (Weeks 2, 4, 8, 12) 
• Proportion of subjects who have a recurrence of MC after the first visit at which complete 
clearance was observed, defined as the total lesion count being greater than 0 at any point 
after achieving a count of 0 
Page 94/120


• Time to complete clearance of all treatable MC, defined as the days between the date of 
first dose and the first date of clearance. Subjects who do not achieve complete clearance 
will be censored at the date of the last lesion count assessment.  
• Proportion of subjects with scarring, defined as an answer of Yes to either question on the 
Scarring/Keloid Assessment eCRF page: “Was the presence of a scar > 1 mm deep and/or 
5 mm wide noted?” or “Was the presence of a scar noted?”, after clearance of lesion(s) at 
each visit (Weeks 4, 8, 12, 24) 
• Proportion of subjects with keloid or hypertrophic scar, defined as an answer of Yes to 
the Scarring/Keloid Assessment eCRF page question “Was the presence of a keloid or 
hypertrophic scar noted?”, after clearance of lesion(s) at each visit (Weeks 4, 8, 12, 24) 
• Change from Baseline of the composite score from age-matched (at Baseline) 
Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index 
(CLDQI) assessment at Week 12 
• Subject-reported spread to household members as measured by any new occurrence of 
MC in household members of subjects at each visit (Weeks 2, 4, 8, 12, 16, 20, 24) 
10.2 Baseline Values 
Unless otherwise noted, baseline is defined as the last nonmissing value recorded prior to the 
first application of study drug. If time is not recorded and the assessment was on the same day as 
the first application of study drug, then it will be assumed the assessment occurred prior to the 
application of study drug. If a subject was randomized but not treated, then baseline is defined as 
the last nonmissing value on or before the date of randomization.  
10.3 Adjustments for Covariates 
The model for the primary efficacy will include adjustments for the following covariates: 
investigator type (dermatologist vs other), household number of randomized subjects (1 subject 
per household vs 2 subjects per household), age, and baseline lesion count. If there are not at 
least 3 responders and non-responders at each level of the stratification factors, then that 
stratification factor will be removed from the model. If there are fewer than 10 
responders/non-responders, then neither investigator type nor household number of randomized 
subjects will be included in the model.  
10.4 Handling of Dropouts or Missing Data 
In analyses based on response, a missing response will be considered a nonresponder.  
For a sensitivity analysis, subjects with missing lesion count at Week 12 but who demonstrated 
complete clearance at the last collected lesion assessment will be counted as responders.  
Page 95/120


An additional sensitivity analysis using multiple imputation will be performed to address 
subjects with missing lesion count at Week 12. A monotone imputation model will be utilized in 
the following steps: 
1. The lesion count data will be imputed to follow a monotone missing data pattern using 
the Markov chain Monte Carlo method for 10 imputations. 
2. Each of the 10 imputations will then be imputed a further 10 times using a monotone 
regression method to impute the remaining missing data and the Week 12 lesion count 
using lesion count assessments at Weeks 2, 4, and 8, treatment group, investigator type 
(dermatologist vs other), household number of randomized subjects (1 subject per 
household vs 2 subjects per household), age, and baseline lesion count as covariates. 
3. Complete Clearance at Week 12 will be re-derived based on the imputed values and then 
analyzed using the primary analysis model. The results of the 100 analyses will be 
transformed into a normal statistic and combined into a single analysis using PROC 
MIANALYZE. 
The ROUND and MINIMUM options will be utilized in Steps 1 and 2 to ensure imputed values 
are non-negative integers. The seed to be used is 20191212. 
For subjects with a missing lesion count at Week 12 and were identified as “Lost to Follow-up” 
by the investigator and captured on the Study Exit eCRF, the following sensitivity analysis will 
be performed. These lost to follow-up subjects will be contacted to obtain a patient reported 
outcome of MC disease status at the end of their study participation of either ‘Resolved’, 
‘Resolving’, ‘Unchanged’, or ‘Worsening’. A reported response endpoint will be derived in the 
following manner: 
• If a subject has a Week 12 lesion count assessment, then the subject will be deemed a 
responder if the count was 0. 
• If the subject did not have a Week 12 lesion count assessment and the response to the 
disease status as ‘Resolved’ or ‘Resolving’, then the subject will be deemed a responder. 
• Otherwise, the subject will be deemed a non-responder. 
The reported response will be analyzed in the same manner as the primary endpoint. A list of the 
patient reported outcome of MC disease status will be provided. 
10.5 Interim Analysis and Data Monitoring 
When approximately 200 subjects (cumulative across studies NI-MC301 and NI-MC302) have 
completed 4 weeks of treatment, a DSMB will review all available unblinded safety data 
(including patch testing). All responsibilities of the DSMB and details of the analysis and data to 
be reviewed is detailed in the DSMB charter. 
Page 96/120


10.6 Examination of Subgroups 
Subgroup analyses of complete clearance at Week 12 for investigator type (dermatologist vs 
other) and household number of randomized subjects (1 subject per household vs 2 subjects per 
household), and will be presented in a forest plot for the ITT Population. An additional subgroup 
analysis of complete clearance at Week 12 for age (<1 year old, ≥1 to <2 years old, ≥2 to <6 
years old, ≥6 to <12 years old, ≥12 to <18 years old, ≥18 years old) and onset of MC symptoms 
duration prior to baseline (≤6 months vs >6 months) will be summarized descriptively for the 
ITT Population. 
10.7 Multiple Comparison/Multiplicity 
The familywise error rate with respect to the primary endpoint and secondary endpoint will be 
strongly controlled at the alpha=0.05 level using a fixed-sequence method testing strategy. If the 
primary endpoint is not statistically significant at the alpha=0.05 level, the secondary efficacy 
endpoint will be considered not significant. If the primary endpoint is statistically significant at 
the alpha=0.05 level, then the secondary efficacy endpoint will be analyzed. If the secondary 
efficacy endpoint fails to reach statistical significance at the alpha=0.05 level, it will be 
considered not statistically significant. 
10.8 Multicenter Studies 
This is a multicenter study, having approximately 35 centers participating in the study. The 
center effects will be investigated in the primary statistical analysis model by including the 
treatment by investigator type interaction. As exploratory analyses to examine the variability of 
the treatment effect across centers, the following analyses will be performed: 
• Pool the centers into self-standing center pools of at least 18 subjects. The pooling will 
sort by investigator type and number of randomized subjects. Then, the centers with 
fewer than 18 subjects will be pooled until the self-standing center pool is at least 18 
subjects. The treatment effect will be explored using a logistic model including treatment, 
household number of randomly assigned subjects, age, baseline lesion counts, and a strata 
statement which will include the pooling identified and examining the residual score 
statistics. To address treatment*center interaction, each pooling center will have a 
corresponding variable coded as 1 if on SB206 and 0 otherwise. Some pooled centers 
may have a p-value of less than 0.05 by chance since there will be multiple pooled 
centers. 
• Pool the centers using the method above but the self-standing center pools will contain at 
least 12 subjects. This analysis should be interpreted with caution due to the small sample 
size within pooled centers. 
11. METHODS OF EFFICACY ANALYSIS 
11.1 Primary Efficacy Analysis 
The primary efficacy comparison will test the following hypotheses: 
Page 97/120


H0: The proportion of subjects with complete clearance is equal between SB206 12% QD and 
Vehicle; 
H1: The proportion of subjects with complete clearance is different between SB206 12% QD 
and Vehicle.  
 
The primary efficacy model will be the following for 𝜋𝐻𝑖 as the probability of complete 
clearance for the ith subject in household H: 
 
𝜋𝐻𝑖= 
𝑒(𝛽0+𝛽1∗𝑋𝐻𝑖1 + 𝛽2∗𝑋𝐻𝑖2+ 𝛽3∗𝑋𝐻𝑖3+ 𝛽4∗𝑋𝐻𝑖4+ 𝛽5∗𝑋𝐻𝑖5 )
1 + 𝑒(𝛽0+𝛽1∗𝑋𝐻𝑖1 + 𝛽2∗𝑋𝐻𝑖2+ 𝛽3∗𝑋𝐻𝑖3+ 𝛽4∗𝑋𝐻𝑖4+ 𝛽5∗𝑋𝐻𝑖5 ) 
 
 
where H = Household, i = subject within the household, 𝛽0 is the intercept,  
𝑋𝐻𝑖1 = {1, 𝑖𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑖𝑠 𝑆𝐵206  
0, 𝑖𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑖𝑠 𝑉𝑒ℎ𝑐𝑖𝑙𝑒 
 
𝑋𝐻𝑖2 = {1, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎 2 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 ℎ𝑜𝑢𝑠𝑒ℎ𝑜𝑙𝑑
0, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎 1 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 ℎ𝑜𝑢𝑠𝑒ℎ𝑜𝑙𝑑 
 
𝑋𝐻𝑖3 = {1, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎 𝐷𝑒𝑟𝑚𝑎𝑡𝑜𝑙𝑜𝑔𝑦 𝑠𝑖𝑡𝑒
0, 𝑖𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑠 𝑓𝑟𝑜𝑚 𝑎𝑛 𝑂𝑡ℎ𝑒𝑟 𝑠𝑖𝑡𝑒              
 
𝑋𝐻𝑖4is the subject’s baseline lesion count, and 𝑋𝐻𝑖4is the subject’s age at baseline; treatment will 
be included in the class statement with PARAM=REF and REF=Vehicle. The working 
correlation will have an exchangeable structure. The model will include a repeated statement for 
subject household with household ID in the class statement. Also, the data structure will be 
ordered according to household ID and subject ID in household. 
 
Treatment groups will be compared using a generalized estimating equation for logistic 
regression with an exchangeable working correlation structure. The model will include 
treatment, investigator type (dermatologist vs other), household number of randomly assigned 
subjects (1 subject per household vs 2 subjects per household), age, and baseline lesion count as 
factors. The odds ratio between SB206 12% and vehicle gel, 95% confidence intervals for the 
odds ratio, and P-value for the covariate-adjusted treatment comparison will be presented; 
together with predicted proportions along with their associated 95% confidence interval. The 
difference in proportion confidence interval will be calculated using the following formula: 
 
(𝑝𝑆𝐵206 − 𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒) ± 𝑧0.025
∗∗ 𝑆𝐸 
 
Where the SE = 
Page 98/120


√
𝑝𝑆𝐵206
2
(1 −𝑝𝑆𝐵206)2 𝑠𝑆𝐵206
2
+ 𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒
2
(1 −𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒)2 𝑠𝑉𝑒ℎ𝑖𝑐𝑙𝑒
2
−2𝑝𝑆𝐵206(1 −𝑝𝑆𝐵206)𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒 
(1 −𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒) ∗(𝑠𝑆𝐵206
2
+ 𝑠𝑉𝑒ℎ𝑖𝑐𝑙𝑒
2
− 𝑠𝑂𝑑𝑑𝑠 𝑅𝑎𝑡𝑖𝑜
2
2
)
 
The 𝑝𝑆𝐵206 and 𝑝𝑉𝑒ℎ𝑖𝑐𝑙𝑒 are the transformed predicted log odds at the mean of the covariates, s2’s 
are the standard errors of the predicted log odds and the odds ratio.  
As a sensitivity analysis, the above primary analysis model will be applied to the PP Population. 
An additional sensitivity analysis counting subjects who discontinued prior to Week 12 or have a 
missing lesion count assessment but who demonstrated complete clearance at the last collected 
lesion assessment as responders will be presented. The impact of mis-stratifications may be 
explored via a sensitivity analysis.   
An analysis where the complete clearance response probability for each dropout prior to Week 
12 will be independently generated across the following scenarios (Vehicle response probability, 
SB206 response probability): 
 
(0.1, 0.1) 
(0.1, 0.0) 
 
 
 
(0.2, 0.2) 
(0.2, 0.1) 
(0.2, 0.0) 
 
 
(0.3, 0.3) 
(0.3, 0.2) 
(0.3, 0.1) 
(0.3, 0.0) 
 
(0.4, 0.4) 
(0.4, 0.3) 
(0.4, 0.2) 
(0.4, 0.1) 
(0.4, 0.0) 
 
The analysis will be produced 100 times and then the results for the estimated log odds ratio for 
treatment and its estimated standard error from each of the imputations will be combined using 
PROC MIANALYZE. 
An additional sensitivity analysis will be performed in a subset of the ITT population where only 
1 subject from each household is chosen to contribute to the model based on the subject with the 
highest number of baseline treatable MC and the oldest to break ties, if needed. A logistic 
regression model including treatment, investigator type, age, and baseline lesion counts will be 
utilized. 
11.2 Secondary Efficacy Analyses 
The secondary endpoint of the proportion of subjects with complete clearance of all treatable MC 
at Week 8 will be analyzed in the same manner as the primary endpoint. A sensitivity analysis 
using the PP Population will be provided.  
11.3 Exploratory Analyses 
The exploratory endpoints based on the proportion of subjects achieving complete clearance or 
75%, 90%, or 95% reductions will be analyzed in the same manner as the primary endpoint.  
Page 99/120


Since the within-household correlation is expected to be small and the change and percent 
change from Baseline in the number of treatable MC are exploratory, they will be analyzed using 
a repeated measures mixed model for the respective visits with the same covariates as the 
primary model together with visits and treatment by visit; an unstructured covariance matrix will 
be utilized. If the calculation of the percent change from baseline is influenced by outliers with 
calculated values >100%, then the influence of outliers will be avoided for analysis by censoring 
them so that all values were in the range of -100% to 100%. If the model fails to converge, then 
other correlation structures will be explored. 
Since the within-household correlation is expected to be small and time to first complete 
clearance of all MC is exploratory, it will be analyzed using Kaplan-Meier methods. The number 
and percentage of subjects achieving complete clearance, number and percentage of censored 
subjects, and Kaplan-Meier estimates of first quartile, median, and third quartile will be 
summarized by treatment group. Differences in Kaplan-Meier curves between the treatments will 
be tested for significance using a stratified log-rank test. 
The proportion of subjects with scarring and the proportion of subjects with keloid or 
hypertrophic scarring will be summarized descriptively at each visit. 
The change from Baseline of the composite score from age-matched (at Baseline) DLQI/CDLQI 
will be summarized descriptively and separately for each questionnaire. The scoring algorithms 
are detailed in Appendix A. The CDLQI will be examined in the following Week 12 response 
categories: complete clearance, 95% reduction in lesion counts, 90% reduction in lesion counts, 
and subjects who did not achieve complete clearance. Additionally, the changes from Baseline in 
the following subscales: Symptoms and Feelings, Daily Activities, Leisure, Work and School, 
Personal Relationships, and Treatment, for DLQI, and Symptoms and Feelings, Leisure, School 
or Holidays, Personal Relationships, Sleep, and Treatment, for CDLQI, and each question will be 
summarized descriptively. 
The subject-reported spread of MC to household members not in the study will be summarized 
descriptively including a breakdown of whether or not there was any spread and then a 
breakdown of the amount of spread within the household at each visit at the household level.  
12. OTHER ANALYSES 
The following analyses of BOTE vs lesion count/complete clearance will be presented: 
• Percent change from Baseline at Week 12 in relation to the highest BOTE score during 
treatment. 
• Complete clearance at Week 12 in relation to the highest BOTE score during treatment. 
• Percent change from Baseline at each visit in relation to BOTE score at Week 2. 
• Complete clearance at each visit in relation to BOTE score at Week 2. 
In these analyses, the BOTE scores will be analyzed in the ITT Population as follows: 
Page 100/120


1. Dichotomized: 
a. Score of 0 or 1: No to Mild 
b. Score of 2, 3, or 4: Moderate to Very Severe 
A shift table comparing the baseline BOTE score to each scheduled postbaseline assessment will 
be presented for the Safety Population.  
13. SAFETY ANALYSES 
All safety analyses will be based on the Safety Population. 
 
A listing of all deaths will be presented. 
13.1 Adverse Events 
All AE summaries will be restricted to treatment-emergent AEs (TEAEs), which are defined as 
those AEs that occurred any time on or after the first in-clinical application of study drug through 
the last application of study medication and those existing AEs that worsened during this same 
period. If it cannot be determined whether the AE is treatment emergent due to a partial onset 
date, then it will be counted as such; see Appendix B for the imputation of missing dates 
algorithm. Verbatim terms in the eCRFs will be mapped to preferred terms and system organ 
classes using the MedDRA Version 22.0.  
Each AE summary will be displayed by treatment group. Summaries that are displayed by 
system organ classes and preferred terms will be ordered by descending order of incidence of 
system organ class and preferred term within each system organ class. Summaries of the 
following types will be presented: 
• Overall summary of TEAEs that contain an overview of each item below. 
• Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system 
organ class and preferred term.  
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
maximum severity. At each level of subject summarization, a subject is classified 
according to the maximum severity if the subject reported 1 or more events. Adverse 
events with missing severity will be considered severe for this summary. 
Page 101/120


• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and closest 
relationship to study drug (Related/Not Related). Related AEs are those reported as 
“Definite,” “Probable,” or “Possible,” and unrelated AEs are those reported as “Unlikely” 
or “Unrelated.” At each level of subject summarization, a subject is classified according 
to the closest relationship if the subject reported 1 or more events. Adverse events with a 
missing relationship will be considered related for this summary. 
• Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA system organ class and preferred term.  
• Subject incidence of TEAEs leading to study drug discontinuation by MedDRA system 
organ class and preferred term. 
• Subject incidence of TEAEs leading to death as an outcome by MedDRA system organ 
class and preferred term. 
Separate listings of all AEs, all SAEs and all AEs leading to study drug discontinuation will be 
provided.  
13.2 Local Skin Reaction 
The LSR composite score will be calculated by summing up all the numerical responses (0-4) to 
each individual parameter for a composite score that ranges between 0 and 24. The change from 
Baseline of the LSR composite score will be summarized descriptively. A table summarizing 
each LSR parameter (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and 
erosion/ulceration) score at each scheduled postbaseline assessment will be presented. 
Additionally, a shift table comparing the baseline score for each LSR parameter to each 
scheduled postbaseline assessment will be presented for the Safety Population. 
13.3 Events of Special Interest 
Events of Special Interest will include subjects with any TEAE where the preferred term contains 
“application site”, subjects with at least 1 post-baseline occurrence of moderate BOTE 
inflammation score, or subjects with at least 1 post-baseline LSR component score ≥ 1. A 
summary including the number and percentage of subjects with at least 1 event of special 
interest, AEs of interest by MedDRA system organ class and preferred term, at least 1 moderate 
BOTE inflammation score, and any LSR component score ≥ 1 will be provided for the Safety 
Population. The analysis will also be repeated with the LSR criteria revised to include any post-
baseline LSR component (excluding erythema) score ≥ 1 and erythema score ≥ 2. 
13.4 Urine Pregnancy Test 
Urine pregnancy test results will be included in a data listing only.  
Page 102/120


13.5 Physical Examination 
A shift table summarizing the shift from Baseline to end of treatment in normal/abnormal will be 
presented.  
13.6 Patch Testing 
A table summarizing any patch testing results by time point may be presented.  
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The following modifications and/or clarifications to the methodology specified in the protocol 
will be: 
• The DLQI and CDLQI will be summarized separately 
• The order of the exploratory endpoints was updated 
• The Mean percent change in baseline endpoint was updated to be more generic in order 
to analyze the median in the case of skewness 
• Proportion of subjects with 90% and 95% clearance exploratory endpoints were added in 
order to provide additional clinically meaningful categories for analysis 
• Additional sensitivity analyses were added to examine the impact of missing data 
including  
o An analysis based on multiple imputation 
o An analysis based on a reported response endpoint 
 
 
Page 103/120


15. REFERENCES 
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for industry ICH E9: Statistical principles 
for clinical trials. September 1998 [cited 2019 May 20]. Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
073137.pdf 
 
Cardiff University. Dermatology Life Quality Index. April 1992 [cited 2019 May 20]. Available 
from: https://www.cardiff.ac.uk/medicine/resources/quality-of-life-questionnaires/dermatology-
life-quality-index 
 
Cardiff University. Children’s Dermatology Life Quality Index. April 1992 [cited 2019 May 20]. 
Available from: https://www.cardiff.ac.uk/medicine/resources/quality-of-life-
questionnaires/childrens-dermatology-life-quality-index 
Page 104/120


16. APPENDICES 
Appendix A: Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) Scoring 
DLQI: 
Question 
Scoring 
Subscale 
1. Over the last week, how itchy, sore, 
painful or stinging has you skin been? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all = 0 
Symptoms and 
Feelings 
2. Over the last week, how embarrassed 
or self conscious have you been because 
of your skin? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all = 0 
Symptoms and 
Feelings 
3. Over the last week, how has your skin 
interfered with you going shopping or 
looking after your home or garden? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Daily Activities 
4. Over the last week, how much has 
your skin influenced the clothes you 
wear? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Daily Activities 
5. Over the last week, how much has 
your skin affected any social or leisure 
activities? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Leisure 
6. Over the last week, how much has 
your skin made it difficult for you to do 
any sport? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Leisure 
7. Over the last week, has your skin 
prevented you from working or 
studying? 
 
If “No”, over the last week how much 
has your skin been a problem at work or 
studying? 
Yes = 3 
No 
Not Relevant = 0 
 
A lot = 2 
A little = 1 
Not at all = 0 
Work and School 
8. Over the last week, how much has 
your skin created problems with your 
partner or any of your close friends or 
relatives? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Personal 
Relationships 
 
Page 105/120


Question 
Scoring 
Subscale 
9. Over the last week, how much has 
your skin caused any sexual difficulties? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Personal 
Relationships 
10. Over the last week, how much of a 
problem has the treatment for your skin 
been, for example by making your home 
messy, or by taking up time? 
Very much = 3 
A lot = 2 
A little = 1 
Not at all/Not Relevant = 0 
Treatment 
Note: DLQI is administered in subjects ≥ 16 years old. 
 
 
The DLQI composite score is then the sum of the scores to all 10 questions and will range from 0 
to 30. If 1 question is unanswered, this is allocated a score of 0 and the DLQI score is then 
summed. If 2 or more questions are unanswered, the questionnaire is not scored.  
The subscales will be expressed as percentages of the maximum score: 
 
Subscale 
Maximum Score 
Symptoms and Feelings 
6 
Daily Activities 
6 
Leisure 
6 
Work and School 
3 
Personal Relationships 
6 
Treatment 
3 
 
 
 
Page 106/120


CDLQI: 
Question 
Scoring 
Subscale 
1. Over the last week, how itchy, 
“scratchy”, sore, or painful has your skin 
been? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Symptoms and 
Feelings 
2. Over the last week, how embarrassed or 
self conscious, upset or sad have you been 
because of your skin? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Symptoms and 
Feelings 
3. Over the last week, how has your skin 
affected your friendships? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Personal 
Relationships 
4. Over the last week, how much have you 
changed or worn different or special 
clothes/shoes because of your skin? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
5. Over the last week, how much has your 
skin trouble affected going out, playing, or 
doing hobbies? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
6. Over the last week, how much have you 
avoided swimming or other sports because 
of your skin trouble? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Leisure 
7. Last week, was it school time? If school 
time: Over the last week, how much did 
your skin problem affect your school work? 
 
Was it holiday time? If holiday time: Over 
the last week, has your skin problem 
interfered with your enjoyment of the 
holiday? 
Prevented school = 3 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
School or 
Holidays 
8. Over the last week, how much trouble 
have you had because of your skin with 
other people calling you names, teasing, 
bullying, asking questions or avoiding 
you? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Personal 
Relationships 
 
 
 
Page 107/120


 
Question 
Scoring 
Subscale 
9. Over the last week, how much has 
your sleep been affected by your skin 
problem? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Sleep 
10. Over the last week, how much of a 
problem has the treatment for your skin 
been? 
Very much = 3 
Quite a lot = 2 
Only a little = 1 
Not at all = 0 
Treatment 
Note: CDLQI is administered in subjects 4 years old up to 16 years old. 
 
The CDLQI composite score is then the sum of the scores to all 10 questions and will range from 
0 to 30. If a question is unanswered, this is allocated a score of 0 and the CDLQI score is then 
summed.  
The subscales will be expressed as percentages of the maximum score: 
 
Subscale 
Maximum Score 
Symptoms and Feelings 
6 
Leisure 
9 
School or Holidays 
3 
Personal Relationships 
6 
Sleep 
3 
Treatment 
3 
 
 
 
Page 108/120


Appendix B: Presentation of Data and Programming Specifications 
General  
• Specialized text styles, such as bold, italics, borders, and shading will not be used in 
tables, figures, and data listings unless they add significant value to the table, figure, or 
data listing. 
• Only standard keyboard characters are to be used in tables and data listings. 
• Special characters, such as nonprintable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
• Hexadecimal character representations are allowed (e.g., µ, , ß). 
• All footnotes will be left justified and at the bottom of a page. Footnotes must be used 
sparingly and must add value to the table, figure, or data listing. 
 
Tables 
• Formal organization of tabulations may be changed during programming, if appropriate, 
e.g., tables for the different variables may be combined into a single table, or tables with 
more than 1 variable may be split into several tables. 
• Means and medians will be presented to 1 more decimal place than the raw data. 
Standard deviations will be presented to 2 more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
• Percentages will be presented to the tenths place. 
• For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the subjects discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0. 
Categories with zero counts will not have zero percentages displayed. 
• Lower and upper confidence interval values must be presented to 1 decimal place more 
than the raw/derived data (i.e., to the same number of decimal places as the mean). 
• Percentiles (e.g., 25%, 75%) must be presented to 1 decimal place more than the 
raw/derived data. 
• For all inferential analyses, P values will be rounded to 4 decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P values less than 0.0001 will be 
presented as “<0.0001.” 
• The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source table number(s) if applicable (in case aggregated 
results like mean or median are plotted) or the source listing(s) (in case individual responses are 
plotted) and/or source dataset(s) (e.g., AdaM).  
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
Page 109/120


Figures 
• Legends will be used for all figures with more than 1 variable or item displayed. 
Treatment group sizes (n=xx) will be included, as appropriate. 
• Figures will be in black and white but can be in color to add value to the clarity and 
readability of a figure. Lines must be wide enough to see the line after being copied. 
• For box plots, the horizontal line will represent the median, + represents the group mean, 
the length of the box represents the interquartile range (25th-75th percentiles), and the 
whiskers will represent the minimum and maximum. 
• The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source listing number(s) and/or source dataset(s) (e.g., AdaM).  
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
 
Listings 
• Formal organization of the listing may be changed during programming, if appropriate, 
e.g., additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints. 
• If not otherwise specified, all data listings will be sorted by sequence/treatment, center, 
subject number, visit, and date/time, as appropriate.  
• All date values will be presented in a SAS date (e.g., 29AUG2001) format.  
• All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26). Seconds will only be reported if they were measured as part of 
the study. 
• The last footnote will be 
- 
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date (e.g., data cut off, database lock) is the date stamp of the data snapshot 
used. 
 
 
 
Page 110/120


Missing or incomplete dates (i.e., AEs, concomitant medications, and start dates of current 
molluscum episode and initial diagnosis) 
The most conservative approach will be systematically considered. If the AE onset date is 
missing/incomplete, it is assumed to have occurred during the study treatment phase (i.e., 
considered a TEAE) except if the partial onset date or other data, such as the stop date, indicates 
differently. Similarly, a medication with partial start and stop dates could be considered as both a 
prior and concomitant treatment. 
 
The following algorithms will be applied to missing and incomplete start and stop dates: 
 
Start Dates 
• If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first application of study drug, provided the start month and year are 
the same as the first application of study drug and the stop date is either after the first 
application of study drug or completely missing. Otherwise, the missing day portion will 
be estimated as “01.” 
• If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first application of study drug, provided the start year 
is the same as the first application of study drug and the stop date is either after the first 
application of study drug or completely missing. Otherwise, the event will be assumed to 
start on the first day of the given year (e.g., ??-???-2013 is estimated as 01-JAN-2013) or 
the subject’s date of birth, whichever is latest. 
• If the start date is completely missing and the stop date is either after the application of 
study drug or completely missing, the start date will be estimated to be the first day of 
study drug application. Otherwise, the start date will be estimated to be the first day of 
the same year as the stop date or the subject’s date of birth, whichever is latest. All other 
non-AE and non-concomitant medication day calculations where only partial dates are 
available will be handled as follows: the first day of the month will be used in the 
calculations if the day part of a start date is missing while January 1 will be employed if 
both the month and day parts of a start date are missing. 
 
Stop Dates 
• If only the day of resolution is unknown, the day will be assumed to be the last day of the 
month (e.g., ??-JAN-2013 will be treated as 31-JAN-2013).  
• If both the day and month of resolution are unknown, the event will be assumed to have 
ceased on the last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013).  
• If the stop date is completely missing and the event is not continuing, the event will be 
assumed to be after first application of study drug and will be imputed using the last 
known date on the study. 
 
For the start dates of current molluscum episode and initial diagnosis, the day will be estimated 
as “01” if only day is missing. If both month and day are missing, then it will be estimated as 
“01-JUN-YYYY” or the subject’s date of birth, whichever is latest. 
Page 111/120


 
If the start date of current molluscum episode is partial, then the following imputation will be 
made: 
• If only the day is unknown, the day will be assumed to be the first day of the month or 
the date of birth, whichever is later. 
• If the day and month are missing, then the start date will be estimated to be June 1st or the 
date of birth, whichever is later. 
 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• Days – A duration expressed in days between 1 date (date1) and another later date (date2) is 
calculated using the formulas noted below: 
Duration in days = date2 – date1 + 1. 
• Months – A duration expressed in months will be calculated as (later date – earlier date + 
1)/(30.4167). 
• Years – A duration expressed in years will be calculated as (later date – earlier date + 
1)/(365). 
• Change from Baseline – Change from Baseline will be calculated as follows: 
Change from Baseline = postbaseline value – baseline value. 
• Percent change from Baseline – Change from Baseline will be calculated as follows: 
Percent change from Baseline = (postbaseline value – baseline value)/baseline value  
× 100. 
 
 
Page 112/120


Appendix C: SAS Programming QC Requirements  
Derived datasets are independently programmed by two programmers. The separate datasets 
produced by the 2 programmers must match 100%. Detailed specifications for the derived 
datasets are documented in the study analysis dataset specifications provided to the client at 
study conclusion. 
Tables are independently reprogrammed by a second programmer for numeric results.  
Listings are checked for consistency against corresponding tables, figures, and derived datasets. 
Figures are checked for consistency against corresponding tables and listings, or independently 
reprogrammed if there are no corresponding tables or listings. 
The entire set of TLFs is checked for completeness and consistency prior to its delivery to the 
client by the lead biostatistician and a senior level, or above, reviewer.
Page 113/120


Appendix D:  List of Tables, Figures, and Listings 
The following proposal for section 14 and 16.2 is completed according to ICH E3 guidelines. The ICH heading numbers and description are in bold. 
Minor changes from this planned index do not need to be amended in the SAP.  
 
Formal organization of tabulations may be changed during programming, if appropriate, e.g., tables for the different variables may be combined into 
a single table, or tables with more than 1 variable may be split into several tables. 
 
The shells for the outputs below are contained in the file titled “Novan NI-MC302 SAP TLFs Version 2.0”. 
  
TABLES, FIGURES, AND GRAPHS  
Table 
Number 
 
Table Title 
Analysis Population 
14 
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE 
TEXT 
 
14.1 
DEMOGRAPHIC DATA 
 
14.1.1.1 
Subject Disposition 
Enrolled 
14.1.1.2 
Enrollment by Site 
ITT 
14.1.2.1 
Demographic and Baseline Characteristics  
Safety 
14.1.2.2 
Demographic and Baseline Characteristics 
ITT 
14.1.2.3 
Demographic and Baseline Characteristics 
PP 
14.1.3.1 
Study Drug Exposure 
Safety 
14.1.3.2 
Study Drug Compliance 
Safety 
14.1.4 
Significant and Major Protocol Deviations 
ITT 
14.1.5 
Medical History 
ITT 
14.1.6.1 
Prior Medications 
ITT 
14.1.6.2 
Concomitant Medications 
ITT 
14.2 
Efficacy data 
 
14.2.1.1 
Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.2 
Complete Clearance Lesion Count Response at Week 12 
PP 
Page 114/120


Table 
Number 
 
Table Title 
Analysis Population 
14.2.1.3 
Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.4 
Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
PP 
14.2.1.6 
Proportion of Subjects with Complete Clearance at Week 12 by Subgroup 
ITT 
14.2.1.7 
Dropout Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 12 
ITT 
14.2.1.8 
One Subject Per Household Sensitivity Analysis: Complete Clearance Lesion Count Response at 
Week 12 
ITT 
14.2.1.9 
Exploratory Analysis of the Variability of Treatment Effect of Complete Clearance Lesion 
Count Response at Week 12 Across Pools of at Least 17 Subjects 
ITT 
14.2.1.10 
Exploratory Analysis of the Variability of Treatment Effect of Complete Clearance Lesion 
Count Response at Week 12 Across Pools of at Least 10 Subjects 
ITT 
14.2.1.11 
Multiple Imputation Sensitivity Analysis: Complete Clearance Lesion Count Response at Week 
12 
 
14.2.1.12 
Patient Reported Response Sensitivity Analysis: Complete Clearance Lesion Count Response at 
Week 12 
 
14.2.2.1 
Complete Clearance Lesion Count Response at Week 8 
ITT 
14.2.2.2 
Complete Clearance Lesion Count Response at Week 8 
PP 
14.2.3.1 
Complete Clearance Lesion Count Response at Weeks 2 and 4 
ITT 
14.2.3.2.1 
Summary of a 95% Reduction in Lesion Counts from Baseline Response by Visit 
ITT 
14.2.3.2.2 
Summary of a 90% Reduction in Lesion Counts from Baseline Response by Visit 
ITT 
14.2.3.2.3 
Summary of a 75% Reduction in Lesion Counts from Baseline Response by Visit 
ITT 
14.2.3.3.1 
Percent Change from Baseline in Lesion Count by Visit 
ITT 
14.2.3.4.1 
Change from Baseline in Lesion Count by Visit 
ITT 
14.2.3.5 
Summary of Recurrence after Complete Clearance 
ITT 
14.2.3.6.1 
Kaplan-Meier Estimates of Time to Complete Clearance (Days) from Start of Dosing 
ITT 
14.2.3.7 
Summary of Scarring and Keloid by Visit 
ITT 
14.2.3.8.1 
Summary of the Dermatology Life Quality Index (DLQI) and Subscales by Visit 
ITT 
14.2.3.8.2 
Summary of the Dermatology Life Quality Index (DLQI) Individual Questions by Visit 
ITT 
14.2.3.8.3.1 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT 
Page 115/120


Table 
Number 
 
Table Title 
Analysis Population 
14.2.3.8.3.2 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Complete 
Responders at Week 12  
14.2.3.8.3.3 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Subjects with at 
least a 95% Reduction in 
Lesion Counts at Week 
12 
14.2.3.8.3.4 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Subjects with at 
least a 90% Reduction in 
Lesion Counts at Week 
12 
14.2.3.8.3.5 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) and Subscales by Visit 
ITT: Subjects who did 
not Achieve Complete 
Clearance at Week 12 
14.2.3.8.4 
Summary of the Children’s Dermatology Life Quality Index (CDLQI) Individual Questions by 
Visit 
ITT 
14.2.3.9 
Summary of Increase in Subject-Reported Spread to Household Members by Visit 
ITT 
14.2.3.10.1 
Summary of Lesion Counts by Highest Dichotomized BOTE Score 
ITT 
14.2.3.10.3 
Percent Change from Baseline in Lesion Count over Time by Dichotomized Week 2 BOTE 
Score 
ITT 
14.2.3.10.4 
Summary of Complete Clearance by Visit and Dichotomized Week 2 BOTE Score 
ITT 
14.2.3.10.5 
Summary of the Beginning of the End (BOTE) Inflammation Score Results by Visit 
Safety 
14.3 
Safety data 
 
14.3.1 
Displays of Adverse Events 
 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety 
14.3.1.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.4 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug 
Safety 
Page 116/120


Table 
Number 
 
Table Title 
Analysis Population 
14.3.1.5 
Summary of Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
Safety 
14.3.1.6 
Summary of Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
Safety 
14.3.1.7 
Summary of Treatment-Emergent Adverse Events Leading to Death by System Organ Class and 
Preferred Term 
Safety 
14.3.2 
Listings of deaths, other serious and significant adverse events 
 
14.3.2.1 
Listing of Serious Adverse Events 
Safety 
14.3.2.2 
Listing of Adverse Events Leading to Study Drug Discontinuation 
Safety 
14.3.2.3 
Listing of Deaths 
Safety 
14.3.6 
Other safety data 
 
14.3.6.1.1 
Summary of Local Skin Reaction (LSR) Composite Score by Visit 
Safety 
14.3.6.1.2 
Summary of Local Skin Reaction (LSR) Score Results by Visit 
Safety 
14.3.6.1.3 
Shift Summary of Local Skin Reaction (LSR) Score Results by Visit 
Safety 
14.3.6.2 
Summary of Events of Special Interest 
Safety 
14.3.6.3 
Summary of Physical Examination Findings 
Safety 
14.3.6.4 
Summary of Patch Testing Results 
Safety 
 
  
 
 
Page 117/120


 
Figure 
Number 
 
Figure Title 
Analysis Population 
14.2.1.5 
Forest Plot: Odds Ratio (95% CI) of the Proportion of Subjects with Complete Clearance at 
Week 12 
ITT 
14.2.3.3.2 
Percent Change from Baseline in Lesion Count over Time by Treatment Group 
ITT 
14.2.3.4.2 
Mean Change from Baseline in Lesion Count over Time by Treatment Group 
ITT 
14.2.3.6.2 
Kaplan-Meier Plot of Time to Complete Clearance (Days) from Start of Dosing 
ITT 
14.2.3.10.2 
Plot of Complete Clearance at Week 12 by Highest Dichotomized Categorized BOTE Score 
ITT 
 
 
Page 118/120


Section 16.2: List of Data Listings 
 
ICH Listing 
Number 
 
Listing Title 
Analysis 
Population 
16.1.7 
Subject Randomization 
ITT 
16.2 
SUBJECT DATA LISTINGS 
 
16.2.1 
Discontinued subjects 
 
16.2.1.1 
Subject disposition 
Enrolled 
16.2.2 
Protocol deviations 
 
16.2.2.1 
Protocol Deviations  
ITT 
16.2.2.2 
Inclusion/Exclusion Criteria 
Enrolled 
16.2.3 
Subjects excluded from the efficacy analysis 
 
16.2.3.1 
Analysis Populations 
Enrolled 
16.2.4 
Demographic data 
 
16.2.4.1 
Demographic and Baseline Characteristics 
ITT 
16.2.4.2 
Patch Testing Consent/Assent 
Enrolled 
16.2.4.3 
Medical History 
ITT 
16.2.4.4 
Prior and Concomitant Medications 
ITT 
16.2.5 
Compliance and/or drug concentration data  
 
16.2.5.1 
Study Drug Administration 
Safety 
16.2.5.2 
Study Drug Accountability 
Safety 
16.2.5.3 
Treatment Adjustment 
Safety 
16.2.5.4 
Treatment Compliance 
Safety 
16.2.6 
Individual efficacy response data 
 
16.2.6.1 
Lesion Counts 
ITT 
16.2.6.2 
Lesion Count Derived Efficacy Variables and Time to Complete Clearance 
ITT 
16.2.6.3 
Scarring/Keloid Assessment 
ITT 
16.2.6.4 
Dermatology Life Quality Index (DLQI) and Subscales 
ITT 
16.2.6.5 
Children’s Dermatology Life Quality Index (CDLQI) and Subscales 
ITT 
16.2.6.6 
Household Transmission 
ITT 
16.2.6.7 
Patient Reported Outcome of Molluscum Contagiosum Disease Status 
ITT 
Page 119/120


ICH Listing 
Number 
 
Listing Title 
Analysis 
Population 
16.2.7 
Adverse events listings 
 
16.2.7.1 
All Adverse Events 
Safety 
16.2.8  
Listing of individual laboratory measurements by subject, when required by regulatory authorities 
 
16.2.8.1 
Urine Pregnancy Test 
Safety 
16.2.9 
Other data 
 
16.2.9.1 
Beginning-of-the-End (BOTE) Inflammation Score 
Safety 
16.2.9.2 
Local Skin Reactions (LSR) 
Safety 
16.2.9.3 
Physical Examination 
Safety 
16.2.9.4 
Patch Testing 
Safety 
16.2.9.5 
Telephone Contact 
ITT 
16.2.9.6 
Subjects who Require a Narrative  
ITT 
  
Page 120/120