Clinical trial NCT04435665
Conditions: Neurofibromatosis 1 Cutaneous Neurofibroma
Keywords: NFX-179
Sponsor: NFlection Therapeutics, Inc.
Start date: 2020-08-21; Completion date: 2021-04-14
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will enroll and treat subjects with cutaneous neurofibromas with NFX-179, a topical study drug. Eligible subjects will receive treatment for 28 days and be observed by a study doctor for approximately 56 days. Subjects will be randomly assigned to 1 of 4 treatment groups. 3 of the treatment groups will receive a specific dose NFX-179, and 1 group will receive placebo. The subject, study doctor, and NFlection Therapeutics will not know what treatment group each subject is assigned. Study participation requires at least 7 clinic visits, blood, urine, and tissue collection, images of the treated cutaneous neurofibromas, electrocardiograms, and information regarding the subject's medical and disease history.

Detailed description:

Arms: arm 1: NFX-179 Gel for topical administration, once daily for 28 days arm 2: NFX-179 Gel for topical administration, once daily for 28 days arm 3: NFX-179 Gel for topical administration, once daily for 28 days arm 4: Vehicle Gel, for topical administration, once daily for 28 days
Interventions: intervention 1: NFX-179 Gel intervention 2: Vehicle Gel
Intervention descriptions: intervention 1: gel for topical administration intervention 2: vehicle gel for topical administration

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Revised Protocol No. 1 
Date: 24-JUL-2020 
 
 
Page 1 of 78 
 
 
Supersedes: NEW 
CLINICAL STUDY REVISED PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Phase 2a 
Study to Determine Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamic Activity of NFX-179 Gel in Subjects with Cutaneous 
Neurofibromas 
 
Protocol No. NFX-179-NF1-201 
Revised Protocol Date: 24-JUL-2020 
Revised Protocol No.: 1 (incorporates Amendment Number 1) 
Supersedes: N/A 
Sponsor: NFlection Therapeutics  
714 Woodcrest Road,  
Wayne, PA 19087  
United States 
Medical Monitor: Guy Webster, M.D. Ph.D. 
24-hour telephone: (302) 559-8684 
Email: GWebster@Nflectionrx.com 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains proprietary and confidential information of NFlection Therapeutics. Acceptance of this 
document constitutes agreement by the recipient that no previously unpublished information contained herein 
will be published or disclosed without the prior written approval of NFlection Therapeutics with the exception 
that this document may be disclosed to study staff under your supervision who need to know the contents for 
conducting the study and to appropriate Institutional Review Boards /Ethics Committees under the condition that 
the staff have agreed to keep this information confidential. The foregoing shall not apply to disclosure required 
by governmental regulations or laws, however, NFlection Therapeutics shall be promptly notified of any such 
disclosure.
 
 
 


Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Revised Protocol No. 1 
Date: 24-JUL-2020 
 
 
Page 2 of 78 
 
 
Supersedes: NEW 
REVISED PROTOCOL INVESTIGATOR SIGNATURE PAGE 
Number: NFX-179-NF1-201 
Revised Protocol Number 1 (incorporates Amendment Number 1) 
 
INVESTIGATOR COMMITMENT: 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by NFlection to the investigational center staff under my supervision. I 
will discuss this material with them to ensure that they are fully informed about the 
Investigational Medicinal Product and the study protocol. 
I agree to conduct this clinical study according to the attached protocol, except when mutually 
agreed to with NFlection in writing. I also agree to conduct this study in compliance with all 
local regulatory requirements, Good Clinical Practices, as well as with the requirements of the 
appropriate Institutional Review Board(s) /Ethics Committee(s) and any other Institutional 
requirements. 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
 
 




Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Revised Protocol No. 1 
Date: 24-JUL-2020 
 
 
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Supersedes: NEW 
 
SYNOPSIS 
Name of Sponsor: 
NFlection Therapeutics, Inc.
Name of 
Investigational 
Product: 
NFX-179 Gel for topical application 
Name of Active 
Ingredient: 
NFX-179 
Title of Study: 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Phase 2a 
Study to Determine Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamic Activity of NFX-179 Gel in Subjects with Cutaneous 
Neurofibromas
Phase of Development: 
2a 
Investigational 
Centers: 
Approximately 6 United States investigational centers 
Study Period: 
Approximately 84 days 
Duration of Treatment: 
28 days of once-daily (QD) application to 5 Target cNF Tumors
Duration of Subject 
Participation: 
Approximately 84 days: 
 
Screening period: Up to 28 days 
 
Treatment period: 28 days 
 
Follow-up period: 28 days
Objectives: 
Primary Objectives: 
 
To determine the safety and tolerability of treatment with NFX-179 
Gel 0.05%, 0.15% and 0.50% when applied QD for 28 day 
 
To determine the pharmacodynamic activity of NFX-179 Gel as 
defined by suppression of phospho-ERK (p-ERK) levels in defined 
cutaneous neurofibroma (cNF) tumors for each NFX-179 Gel group 
compared with the Vehicle Gel group after 28 days of QD treatment. 
Secondary Objectives: 
 
To determine the effect of NFX-179 Gel defined as the percent change 
in neurofibroma volume after 28 days of QD treatment based on tumor 
volume derived from ruler measurements, ultrasound and digital 
imaging 
 
To determine the effect of NFX-179 Gel on the change from baseline 
in the Subject’s Self-Assessment after 28 days of QD treatment 
 
To determine the effect of NFX-179 Gel on the change from baseline 
in the Physician’s Tumor Assessment after 28 days of QD treatment. 
 
 
 


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Supersedes: NEW 
Endpoints: 
Primary Endpoints: 
 
Pharmacodynamic activity of NFX-179 Gel as defined by suppression 
of p-ERK levels in Target cNF Tumors in each NFX-179 Gel group 
compared with the Vehicle Gel group after 28 days of QD application  
 
Safety and tolerability of treatment with NFX-179 Gel (0.05%, 0.15% 
and 0.5.%) when applied QD for 28 days 
 
Assessment of adverse events (AEs)/serious adverse events (SAEs). 
Secondary Endpoints: 
 
Percent change in cNF tumor volume after 28 days of QD application 
 
Systemic exposure of NFX-179 Gel during the clinical study after 28 
days of QD application 
 
Change in Physician’s Tumor Assessment grade after 28 days of QD 
application 
 
Change in Subject’s Self-Assessment grade after 28 days of QD 
application. 
Number of Subjects: 
Approximately 48 subjects (≥ 18 years of age) with cNF tumors will be 
enrolled and randomized in the study. With a 1:1:1:1 randomization ratio, it is 
anticipated there will be: 
 
12 subjects randomized to receive NFX-179 Gel 0.05% 
 
12 subjects randomized to receive NFX-179 Gel 0.15% 
 
12 subjects randomized to receive NFX-179 Gel 0.50% 
 
12 subjects randomized to receive Vehicle Gel 
Study Design: 
This is a 28-day double-blind, randomized, vehicle-controlled, parallel-group 
phase 2a  study to determine the safety, tolerability, pharmacokinetics, and 
pharmacodynamic activity of 3 dose levels of NFX-179 Gel (0.05%, 0.15% and 
0.5.%) with that of vehicle  in subjects with NF1.  
 
The study drug will be applied topically QD to the 5 Target cNF Tumors for 28 
days.   
 
At Baseline, the investigator will select 6 Study cNF Tumors (5 Target cNF 
Tumors for treatment and 1 Untreated cNF Tumor) that are raised and have a 
diameter of at least 5mm and no larger than 10 mm and a height (thickness) of 
≥2mm. One of the Target cNF Tumors must be on the face. The Untreated 
cNF Tumor will NOT receive study medication applications. 
 
On Day 28 all 6 Study cNF Tumors will be excised for measurement of p-ERK 
levels. The excisions will be done 4 hours (+/- 1 hour) after the final study 
medication application.  
 
From the time of consent and for the duration of the study, subjects will be 
monitored for safety.   
 
The Target cNF Tumors will be evaluated for application site reactions at 
Visits 2 (Baseline), 3, 4 and 5 (End of Treatment).  
 
The Target cNF Tumor dimensions will be measured by the investigator at 
Visits 1 (screening), 2 and 5. 
 


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Supersedes: NEW 
Blood samples for complete blood count and serum chemistry and urine for 
urinalysis will be collected from subjects at Visits 1, 2 and 5.  
Blood samples for pharmacokinetic assessment of plasma levels of NFX-179 
will be collected at Visit 2 (Baseline) prior to the first study medication 
application and at Visit 5 (End of Treatment). 
Main Criteria for 
Inclusion: 
Select Inclusion Criteria: 
1. Subject is at least 18 years of age 
2. Subject must provide written informed consent prior to any study 
procedures  
3. Subject must have a clinical diagnosis of NF1 
4. Subject has 6 Study cNF Tumors (5 Target cNF Tumors [1 on 
the face; 4 on the anterior trunk or upper extremities] that will 
be treated with the assigned study medication;1 Untreated cNF 
Tumor on the anterior trunk or upper extremities) that each 
meet the following criteria: 
 Has, in the investigator’s opinion, a clinically typical 
appearance 
 Is dome shaped 
 Is not pedunculated 
 Is a discrete tumor 
 Is not irritated 
 Is not in an area subject to repeated trauma (e.g., area that 
is shaved, on the beltline, under a bra strap, etc.) 
 Does not have an active cutaneous infection 
 Has a diameter that is ≥5mm and ≤10mm 
 Has a height of ≥2mm 
 Is, when centered in the center of the provided template, 
the only cNF tumor visible 
 Is not within 5mm of the orbital rim. 
5. Subject is willing to have the 5 Target cNF Tumors and the 1 
Untreated cNF Tumor excised at the end of the treatment period  
6. Subject is willing to have hair in the area surrounding the Target cNF 
Tumors shaved, if necessary, to obtain photographs 
7. Subject is willing to minimize exposure of each Target cNF to natural 
and artificial ultraviolet radiation 
 
8. Subject is willing to forego treatment of the Target cNF Tumors, 
except protocol specified therapy, during the study 
9. Female subjects who are women of childbearing potential must have a 
negative urine pregnancy test result and be willing to use a protocol 
approved, contraceptive method for the duration of the study 
10. Subject is willing and able to follow all study instructions and to 
attend all study visits. 
 
 
 
 
 
 
 
 
 


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Supersedes: NEW 
 
Select Exclusion Criteria: 
1. Subject has applied any of the following topical products in the 
previous 30 days on or in proximity to any Study cNF Tumor that, in 
the investigator’s opinion, impairs evaluation of any the tumor or 
which exposes the subject to an unacceptable risk by study 
participation: 
 
Corticosteroids 
 
Retinoids (e.g., tazarotene, tretinoin, adapalene) 
 
> 5% of an alpha-hydroxy acid (e.g., glycolic acid, lactic 
acid) 
 
Fluorouracil  
 
Imiquimod 
2. Any Study cNF Tumor has ever been treated with an MEK inhibitor 
or a BRAF inhibitor 
3. The subject has used any of the following systemic medications in the 
noted time period:  
 
Retinoids (e.g., etretinate, isotretinoin) within the previous 90 
days 
 
MEK inhibitors within the previous 180 days 
 
BRAF inhibitors within the previous 180 days 
4. Subject has a history of hypersensitivity to any of the 
ingredients in the study medications 
5. Subject has any known intercurrent illness or physical 
condition that would, in the investigator’s opinion, impair 
evaluation of a Target cNF Tumor or which exposes the 
subject to an unacceptable risk by study participation 
6. Subject has, in the investigator’s opinion, clinically relevant history of 
liver disease, including viral hepatitis, current alcohol abuse, or 
cirrhosis 
7. Subject has a history of metastatic disease, or active cancer 
(excluding non-melanoma skin cancer, Stage I cervical 
cancer, ductal carcinoma in situ of the breast, or Stage 0 
chronic lymphocytic lymphoma) within the previous 5 years 
8. Subject has any condition (e.g., other skin conditions or 
diseases, metabolic dysfunction, physical examination 
findings, clinical laboratory findings) or situation (e.g., 
vacation, scheduled surgery) that would, in the investigator’s 
opinion, impair evaluation of a Target cNF Tumor or which 
exposes the subject to an unacceptable risk by study 
participation 
 
9. Subject has participated in an investigational drug trial in which 
administration of an investigational study medication occurred 
within the previous 30 days. 
No waivers to the exclusion criteria are permitted. 
Study Medication, 
Dosage and Mode of 
Administration 
NFX-179 Gel or Vehicle Gel for topical application QD for 28 days to 5 Target 
cNF Tumors: 
 
NFX-179 Gel 0.05% for topical administration, once daily for 28 days 
 
NFX-179 Gel 0.15% for topical administration, once daily for 28 days 
 
NFX-179 Gel 0.50% for topical administration, once daily for 28 days 
 
Vehicle Gel, for topical administration, once daily for 28 days 


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Supersedes: NEW 
Criteria for Evaluation 
Safety Assessments: 
Adverse Events: During the study, subjects will be assessed for the occurrence 
of new and ongoing AEs. Descriptions of AEs will include the date(s) of onset 
and resolution (if resolved), maximum severity, and seriousness, action taken 
regarding the study drug, corrective treatment, outcome, and the investigator’s 
assessment of causality.  
 
Safety Laboratory Tests: Routine safety laboratory tests (CBC/differential, 
serum chemistry, and urinalysis) will be performed at Visits 1, 2 and 5 Any 
out-of-range laboratory result that is considered clinically significant by the 
investigator will be recorded as an AE 
 
Electrocardiogram: A 12-lead ECG will be conducted at Visits 1, 2 and 5. ECG 
performance procedures will be standardized. The ECG results will be assessed 
for any clinically significant abnormality or relevant changes from baseline. 
 
Local Tolerability: Local tolerability on each Target cNF will be evaluated 
through assessment of selected signs (i.e., erythema, edema, scabbing/crusting, 
vesiculation and erosion) and symptoms (i.e., stinging, burning and pruritus) of 
local tolerability at Visits 2-5. 
 
Pregnancy Tests: All female subjects who are women of childbearing potential 
will have a urine pregnancy test performed at Visits 1, 2 and 5. 
 
Physical Examination and Vital Signs: A physical examination will be 
performed at the Screening visit. Vital signs will be measured at Visits 1, 2, 5 
and 7. 
 
Efficacy Assessments: 
Target cNF Tumor volume: At select sites the investigator will measure the 
volume of each Target cNF Tumor using a high frequency ultrasound at Visit 2 
(Baseline) and Visit 5 (end of treatment). 
 
Target cNF Tumor dimensions: The investigator will measure the diameter of 
each Target cNF Tumor using a ruler at Visit 1 (Screening), Visit 2 (Baseline) 
and Visit 5 (end of treatment). 
 
Physician’s Tumor Assessment: The investigator will assess a Physician’s 
Tumor Assessment, for each Target cNF Tumor at Visit 2 (Baseline) and Visit 
5 (end of treatment). 
 
Subject’s Self-Assessment: Each subject will assess a Subject’s Self-
Assessment, a Patient Reported Outcome, for each Target cNF Tumor at Visit 
2 (Baseline) and Visit 5 (end of treatment). 
 
Other Assessments: 
Demographics: 
Demographic characteristics will be reported for each subject will be collected 
at Visit 1 (Screening). 
 
 


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Supersedes: NEW 
PK: 
At select sites blood samples for assessment of NFX-179 levels will be 
collected at Visit 2 (Baseline), prior to the first study medication application, 
and at Visit 5 (end of treatment). 
 
Tumor excisions: At Visit 5 (end of treatment) the investigator will excise all 6 
Study cNF Tumors to assess for p-ERK levels. 
 
Standardized Photography: 
Standardized 3-dimensional color photographs to determine the volume, above 
the surrounding skin, of the 5 Target cNF Tumors will be taken at Visit 1, Visit 
2 (Baseline) and Visit 5 (end of treatment). 
  
Statistical Methods 
All subjects who are randomized and dispensed study drug will be included in 
the intent-to-treat (ITT) analysis set. All subjects who are randomized, receive 
at least 1 confirmed dose of study drug, and have at least 1 post-baseline safety 
assessment will be included in the safety population. Last observation carried 
forward (LOCF) will be used to impute efficacy data that are missing post-
baseline through Visit 5 (Week 4). Analyses will also be carried out on 
observed data. No imputations will be made for missing safety data. No 
adjustments for multiplicity will be made. 
 
Safety: 
Safety Endpoints: 
 
Adverse events 
 
Local tolerability including:  
o 
erythema  
o 
edema  
o 
scabbing/crusting 
o 
vesiculation 
o 
erosion 
o 
stinging 
o 
burning 
o 
pruritis 
 
NFX-179 concentration levels in plasma 
 
Clinical laboratory assessments 
 
Statistical Analyses: 
The first primary objective is to determine the pharmacodynamic activity of 
NFX-179 Gel as defined by suppression of p-ERK levels in the Target cNF 
Tumors in the NFX-179 Gel treatment groups as compared to Vehicle Gel 
group after 28 days of QD treatment. This will be assessed by analyzing p-ERK 
levels at Visit 5 (Week 4). ANOVA models at the subject level will be used to 
compare mean p-ERK level between each active treatment group and the 
vehicle treatment group, with treatment as the independent factor. Within each 
subject, both the mean and the median p-ERK levels will first be calculated 
across all 5 tumors. The within-subject mean levels will be analyzed in the 
primary ANOVA model. The within-subject median levels will also be 
analyzed in a second ANOVA model to assess whether individual tumor outlier 
values may have an influence on the analysis. Mixed-model repeated measures 
ANOVA models will also be used to analyze p-ERK data at the tumor level. In 
addition, p-ERK levels from the untreated tumor for each subject will be used 


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in exploratory analyses to determine whether the inclusion of this reference 
level in analysis models may increase sensitivity. 
 
The second primary objective is to determine the safety and tolerability of 
treatment with NFX-179 Gel (0.05%, 0.15% and 0.50%) or Vehicle Gel 
applied QD for 28 days of treatment. The frequency of dermal safety and 
tolerability assessments including pain/burning, pruritus, erythema, edema, 
scabbing/crusting, and vesiculation/erosion will be summarized by treatment 
group and visit. All data will be listed. The third primary objective of 
evaluating adverse events will be based on summaries and listings of adverse 
events by treatment group, as described below under Safety Analyses. 
 
The first secondary objective is to determine the clinical efficacy of NFX-179 
Gel defined as the percent change in neurofibroma volume after 28 days of 
treatment based on tumor size derived from high frequency ultrasound 
measurements and 3D photographs. This will be analyzed analogously to the 
first primary endpoint.  Analyses will be conducted both on the tumor level and 
the subject level, as planned for the first primary endpoint. 
 
The second secondary objective is to measure systemic exposure of NFX-179 
gel during the clinical study. Plasma concentrations of NFX-179 will be 
summarized at Visit 5 (Weeks 4) by treatment group.  
 
The third and fourth secondary objectives are to determine the clinical efficacy 
of NFX-179 Gel defined as the change from baseline in the Subject’s Self-
Assessment grade and Physician’s Tumor Assessment grade, separately, after 
28 days of treatment. Appropriate mixed-model ANCOVAs will be used to 
compare, for each treated tumor, change from baseline grade between treatment 
groups, with treatment as the independent factor, baseline value as the 
covariate, and subject as the repeated factor. ANCOVA models will also be 
performed on the subject level after first calculating the within-subject mean 
values across treated tumors. In addition, for each assessment dichotomized 
analyses will be conducted on the proportion of tumors achieving a grade of 
Clear, and also the proportion of tumors achieving a grade of either Clear or 
Almost Clear, after 28 days of treatment. Treatment groups will be compared to 
vehicle using appropriate mixed-model logistic regression, as well as a Chi-
square analysis of within-subject averaged results across tumors. 
 
Safety Analyses: 
Subjects will be assessed for the occurrence of new and ongoing AEs. 
Descriptions of AEs will include the dates of onset and resolution (if resolved), 
maximum severity, seriousness, and action taken regarding the study drug, 
corrective treatment, outcome, and investigator’s assessment of causality. All 
AEs will be recorded and classified using terminology from the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported treatment-
emergent AEs (TEAEs), defined as any AE with an onset on or after the date of 
first study drug application, will be summarized by treatment group, the 
number of subjects reporting TEAEs, system organ class, preferred term, 
severity, and relationship to study drug. When summarizing TEAEs by severity 
or relationship to study drug, each subject will be counted only once within a 
system organ class or a preferred term using the event with the greatest severity 
or causality, respectively, within each category. All reported serious adverse 
events (SAEs) will be summarized by treatment group, the number of subjects 


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Supersedes: NEW 
reporting SAEs, system organ class, preferred term, severity, and relationship 
to study drug. 
 
All information pertaining to AEs noted during the study will be listed by 
subject and will include a verbatim description of the event as reported by the 
investigator, as well as the preferred term, system organ class, start date, stop 
date (if stopped), seriousness, severity, action taken regarding the study drug, 
corrective treatment, outcome and relationship to the study drug. In addition, a 
listing of subjects who prematurely discontinue from the study due to AEs will 
be provided as well as a listing of subjects who reported an SAE. 
 
Changes from baseline in safety laboratory values and vital sign measurements 
will be summarized with descriptive statistics for each treatment group at all 
applicable study visits. 
 
Shift tables will be presented for changes in safety laboratory values to 
summarize laboratory test results collected at Visits 1 (Screening), 2 (Baseline) 
and 5 (End of Treatment). Normal ranges established by the central laboratory 
will be used to determine the shifts. A listing of all out-of-range laboratory test 
results at any assessment time point will also be provided. Determination of 
clinical significance for all out-of-range laboratory values will be made by each 
investigator and included in the listing. In addition, a listing of all clinically 
significant laboratory test results will be provided. 
 
 
 


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Supersedes: NEW 
TABLE OF CONTENTS 
 
INVESTIGATOR SIGNATURE PAGE .................................................................................. 2 
PROTOCOL APPROVAL PAGE ............................................................................................ 3 
SYNOPSIS ................................................................................................................................... 4 
TABLE OF CONTENTS ......................................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................... 16 
1 
INTRODUCTION ........................................................................................................ 17 
1.1 
Study Rationale................................................................................................... 17 
1.2 
Background ......................................................................................................... 18 
1.2.1 
Nonclinical Experience ...................................................................... 18 
1.2.2 
Clinical Experience ............................................................................ 19 
1.3 
Risk Benefit Assessment .................................................................................... 19 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 20 
3 
STUDY OVERVIEW ................................................................................................... 20 
3.1 
Study Design ....................................................................................................... 20 
3.2 
Scientific Rationale for Study Design ................................................................ 21 
3.3 
Dose Selection Rationale .................................................................................... 22 
3.4 
End of Study Definition ...................................................................................... 22 
3.5 
Study Duration .................................................................................................... 22 
4 
STUDY POPULATION ............................................................................................... 23 
4.1 
Number of subjects ............................................................................................. 23 
4.2 
Study Entry Criteria ............................................................................................ 23 
4.2.1 
Inclusion Criteria ............................................................................... 23 
4.2.2 
Exclusion Criteria .............................................................................. 24 
4.3 
Subject identifier (SI) ......................................................................................... 25 
4.4 
Screen Failures ................................................................................................... 25 
4.5 
Early Termination Visit ...................................................................................... 26 
4.6 
Unscheduled Visit............................................................................................... 26 
4.7 
Lost to Follow-up ............................................................................................... 27 
4.8 
Subject discontinuation from the study .............................................................. 27 
4.9 
Replacement of subjects ..................................................................................... 28 
4.10 
Subject instructions............................................................................................. 28 
4.11 
Previous and Concomitant Therapies ................................................................. 29 
4.11.1 
Previous therapies .............................................................................. 29 
4.11.2 
Concomitant Therapies ...................................................................... 29 


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4.11.3 
Prohibited therapies ........................................................................... 29 
4.12 
Study Medications .............................................................................................. 30 
4.12.1 
Study medication identity .................................................................. 30 
4.12.2 
Study medication packaging and labeling ......................................... 30 
4.12.3 
Method of study medication assignment ............................................ 31 
4.12.4 
Subject randomization ....................................................................... 32 
4.12.5 
Dispensing and collecting study medication ..................................... 32 
4.12.6 
Weighing study medication ............................................................... 33 
4.12.7 
Route of Administration, frequency and treatment period ................ 33 
4.12.8 
Study medication application............................................................. 34 
4.12.9 
Dose Modification ............................................................................. 35 
4.12.10 
Accountability .................................................................................... 35 
4.12.11 
Return and disposition of study medication ...................................... 35 
4.13 
Blinding .............................................................................................................. 36 
4.13.1 
Verification of blinding ..................................................................... 36 
4.13.2 
Unblinding the study medication ....................................................... 36 
4.14 
Study medication adherence ............................................................................... 36 
4.15 
Other study supplies ........................................................................................... 37 
5 
STUDY VISITS AND PROCEDURES ...................................................................... 38 
5.1 
Schedule of Events ............................................................................................. 38 
5.2 
Study Visits......................................................................................................... 39 
5.2.1 
Visit 1/Day -28 to 0 (Screening) ........................................................ 39 
5.2.2 
Visit 2/Day 1 (Randomization; start of QD treatment) ...................... 39 
5.2.3 
Visits 3 and 4/Days 8 and 15 (QD Treatment) .................................. 41 
5.2.4 
Visit 5/Day 29 (End of Treatment; start of no treatment follow-up) . 41 
5.2.5 
Visit 6/Day ≥36 to ≤50 (Excision wound care) ................................. 43 
5.2.6 
Visit 7/Day 57 (End of study, early termination) .............................. 43 
5.3 
Study cNF tumor identification .......................................................................... 43 
6 
STUDY ASSESSMENTS ............................................................................................. 48 
6.1 
Safety assessments .............................................................................................. 48 
6.1.1 
Adverse Event Assessments .............................................................. 48 
6.1.2 
Clinical Laboratory Evaluations ........................................................ 48 
6.1.3 
Local Tolerability Assessment........................................................... 49 
6.1.4 
Medical history .................................................................................. 51 
6.1.5 
Physical Examination ........................................................................ 52 
6.1.6 
Vital Signs.......................................................................................... 52 


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6.1.7 
Urine pregnancy tests......................................................................... 53 
6.1.8 
Electrocardiogram .............................................................................. 53 
6.2 
Efficacy Assessments ......................................................................................... 54 
6.2.1 
Target cNF dimensions ...................................................................... 54 
6.2.2 
Target cNF ultrasounds ...................................................................... 55 
6.2.3 
Subject’s Self-Assessment (SSA) ...................................................... 55 
6.2.4 
Physician’ Tumor Assessment (PTA) ............................................... 56 
6.3 
Other Assessments .............................................................................................. 57 
6.3.1 
Demographics .................................................................................... 57 
6.3.2 
Pharmacokinetic blood samples......................................................... 57 
6.3.3 
Study cNF Tumor excision for p-ERK levels .................................... 58 
6.3.4 
Standardized photography ................................................................. 59 
6.4 
Total Blood Volume ........................................................................................... 60 
7 
ADVERSE EVENTS .................................................................................................... 60 
7.1 
Definitions .......................................................................................................... 61 
7.1.1 
Adverse Event (AE) ........................................................................... 61 
7.1.2 
Serious Adverse Event (SAE) ............................................................ 62 
7.1.3 
Unexpected Adverse Event ................................................................ 62 
7.1.4 
Adverse Events of Special Interest .................................................... 63 
7.2 
Reporting Adverse Events .................................................................................. 63 
7.2.1 
Adverse event reporting period .......................................................... 63 
7.3 
Assessment of Adverse Events ........................................................................... 63 
7.3.1 
Severity of Adverse Events ................................................................ 63 
7.3.2 
Relationship to Study Medication ..................................................... 64 
7.4 
Procedures for reporting non-serious adverse events ......................................... 64 
7.5 
Procedures for reporting serious adverse events ................................................ 65 
7.6 
Pregnancy ........................................................................................................... 66 
7.6.1 
Woman of Childbearing Potential (WOCBP) ................................... 66 
7.6.2 
Protocol approved methods of birth control ...................................... 66 
8 
STATISTICAL METHODOLOGY ........................................................................... 68 
8.1 
Sample Size Determination ................................................................................ 68 
8.2 
Randomization .................................................................................................... 68 
8.3 
Statistical Analyses ............................................................................................. 68 
8.3.1 
General Approach .............................................................................. 68 
8.3.2 
Baseline Assessment .......................................................................... 69 
8.3.3 
Efficacy Analyses .............................................................................. 69 


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8.3.4 
Safety Analyses.................................................................................. 71 
8.4 
Missing Data ....................................................................................................... 72 
8.5 
Sub-Group Analyses ........................................................................................... 72 
9. 
TRAINING, DATA HANDLING AND RECORD KEEPING ................................ 73 
9.1. 
Training .............................................................................................................. 73 
9.2. 
Data Collection ................................................................................................... 73 
9.3. 
Data Management ............................................................................................... 73 
9.4. 
Study Monitoring ................................................................................................ 74 
9.5. 
Source Documentation ....................................................................................... 74 
9.6. 
Inspection of Records ......................................................................................... 75 
9.7. 
Retention of Records .......................................................................................... 75 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE.......................................... 76 
11. 
ETHICS ......................................................................................................................... 77 
11.1. Ethics Review ..................................................................................................... 77 
11.2. Ethical Conduct of the Study .............................................................................. 77 
11.3. Written Informed Consent .................................................................................. 77 
11.4. Study Conduct and Protocol Amendments ......................................................... 77 
11.5. Regulatory Documents ....................................................................................... 78 
11.6. Contractual Requirements .................................................................................. 78 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
cNF 
Cutaneous neurofibromas 
CR 
Clinically Relevant 
CRF 
Case Report Form 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization 
IRB 
Institutional Review Board 
LDH 
Lactic Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCR 
Not Clinically Relevant 
NF1 
Neurofibromatosis type 1 
NFlection 
NFlection Therapeutics 
PK 
Pharmacokinetic 
PRO 
Patient Reported Outcome 
PTA 
Physician’s Tumor Assessment 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI 
Subject Identifier 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSA 
Subject’s Self-Assessment 
TEAE 
Treatment Emergent Adverse Event 
US 
United States 
WHO 
World Health Organization 


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1 
INTRODUCTION 
Neurofibromatosis type I (NF1) is an autosomal dominant development syndrome caused by 
germline mutations in the NF1 gene on chromosome 17. The NF1 gene is responsible for 
production of a protein called neurofibromin that is involved in the RAS pathway (RASopathy) 
and which is needed for normal function in many human cell types. NF1 is one of the most 
common genetic disorders, is not limited by a person’s race or sex, and causes tumors along the 
nervous system which can grow anywhere on the body.  
 
A mutation or deletion of one allele of the NF1 gene is enough for the development of NF1, 
although presentation varies widely. It is an age specific disease; most signs of NF1 occur as the 
person ages and has hormonal changes. As of 2015, there were at least 100,000 people in the 
U.S. who have been diagnosed with NF1. A common symptom of NF1 are benign skin tumors 
called neurofibromas.  
 
The severity of NF1 varies widely, and little is known about what causes a person to have more 
severe or less severe cases. Sixty percent of people with NF1 have mild cases, with few signs 
and symptoms that have very little effect in their day-to-day lives. Forty percent of NF1 patients 
have moderate to severe cases, which manifest as several signs and symptoms that affect the 
person's quality of life. Even in this last group, signs and symptoms are rarely life-threatening.  
 
Cutaneous neurofibromas are a common manifestation of NF1. The gene product neurofibromin 
negatively regulates RAS activity and acts as a tumor suppressor by preventing the activation of 
downstream signaling pathways such as the RAF/MEK/ERK pathway.  
NFlection. 
 
1.1 
Study Rationale 
NFlection tested the efficacy of a topical formulation of a novel MEK inhibitor (NFX-179) in an 
ex vivo model by using human cutaneous neurofibroma explants. Dose dependent suppression of 
the shared biomarker, p-ERK, by NFX-179 (0.5%, 1.0%, 1.5%) was observed in human 
cutaneous neurofibroma explants. p-ERK suppression was not observed in neurofibroma 
explants treated with the vehicle formulation.  


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Western Blot analysis of p-ERK level showed complete suppression of p-ERK by all three 
dosages of NFX-179 in the top sections of the explant and a dose dependent suppression in the 
bottom sections. 
 
Taken together, these data clearly demonstrate that NFX-179 (0.5%, 1.0%, 1.5%) can penetrate 
human epidermis and suppress p-ERK in human cutaneous neurofibroma explants.  
 
This clinical study is designed to evaluate the safety and efficacy of NFX-179 after 28 days of 
once-daily (QD) application in subjects with NF1 tumors. 
 
1.2 
Background 
1.2.1 Nonclinical Experience 
NFX-179 was well tolerated in the rat following a single oral administration of doses up to 1000 
mg/kg.  Following multiple dosing for up to 21 days NFX-179 was well tolerated at up to 300 
mg/kg/day (the highest dose tested).  
 
In the rat, following subcutaneous administration NFX-179 was well tolerated with single doses 
up to 300 mg/kg. Following multiple dosing for up to 14 days, one main study animal (100 
mg/kg) and one TK animal (300 mg/kg) were pre-terminally euthanized on Day 12 due to poor 
clinical condition of the skin.  Lesions, lumps and discoloration were noted at the dosing site. 
Macroscopic examination revealed dermal dark discoloration with numerous red dermal scabs at 
last dosing site associated with thickening and SC mottling, but the cause of poor condition could 
not be identified. 
 
After a single subcutaneous dose, the systemic exposure was low relative to oral administration 
and increased in a less than proportional manner with dose.  The very low exposure suggests that 
the dose remains in the skin as a depot and may be released very slowly.  
 
Over 21 days of subcutaneous administration there was an increase in exposure so that it was 
similar to that seen following repeated oral administration. 
 


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In a 7-day dermal study, NFX-179 (0, 0.15, 1.0 and 1.5%) were administered at a dose volume of 
1 mL/kg/dose. In this study there was very slight erythema and very slight edema were noted in a 
single animal at both 1% and 1.5% formulations on Days 7 and 8. 
 
Systemic exposure following dermal administration was low after single dose increasing on 
repeat dosing. 
 
NFX-179 was assessed in a 28-day study.  Minipigs received 0, 0.5, 1.0 or 1.5% at a dose 
volume of 2 mL/kg/day.  Following the onset of dermal lesions and clinical signs in the majority 
of the study animals (including controls), treatment of the animals was stopped following 5 to 9 
days of dosing (depending on replicates).  The observations recorded included but were not 
limited to slight to severe erythema; brown skin rash and discoloration; elevated body 
temperature; elevated neutrophil counts.  These clinical signs were seen in all animals, including 
controls receiving vehicle only. 
 
The clinical observations were considered to be due to the inherent irritancy of the vehicle 
formulation (1+ erythema) which caused unexpected reactions and then due to residency of 
NFX-179 in the skin and associated pharmacological effects reducing the ability of the skin to 
recover from the reactions to the vehicle. 
 
Details of the non-clinical studies for NFX-179 are presented in the Investigators Brochure. 
 
1.2.2 Clinical Experience 
No human clinical studies have been conducted with NFX-179. 
 
1.3 
Risk Benefit Assessment 
Detailed information about benefits and potential risks of NFX-179 may be found in the 
Investigators Brochure (IB). The benefit risk ratio is considered favorable. 
 
 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives of this study include: 
 Primary objectives: 
o To determine the safety and tolerability of treatment with NFX-179 Gel 0.05%, 
0.15% and 0.50% when applied once daily (QD) for 28 days 
o To determine the pharmacodynamic activity of NFX-179 Gel as defined by 
suppression of phospho-ERK (p-ERK) levels in defined cutaneous 
neurofibroma (cNF) tumors for each NFX-179 Gel group compared with the 
Vehicle Gel group after 28 days of QD treatment. 
 Secondary objectives: 
o To determine the effect of NFX-179 Gel defined as the percent change in 
neurofibroma volume after 28 days of QD treatment based on tumor volume 
derived from ruler measurements, ultrasound and digital imaging 
o To determine the effect of NFX-179 Gel on the change from baseline in the 
Subject’s Self-Assessment grade after 28 days of QD treatment 
o To determine the effect of NFX-179 Gel on the change from baseline in the 
Physician’s Tumor Assessment grade after 28 days of QD treatment. 
 
The endpoints being evaluated include: 
 Primary endpoints include: 
o Pharmacodynamic activity of NFX-179 Gel as defined by suppression of p-
ERK levels in Target cNF Tumors in each NFX-179 Gel group compared with 
the Vehicle Gel group after 28 days of QD application 
o Safety and tolerability of treatment with NFX-179 gel (0.05%, 0.15% and 
0.50%) when applied QD for 28 days 
o Assessment of adverse events (AEs)/serious adverse events (SAEs). 
 Secondary endpoints include: 
o Percent change in cNF tumor volume after 28 days of QD application 
o Systemic exposure of NFX-179 Gel during the clinical study after 28 days of 
QD application 
o Change in Subject’s Self-Assessment grade after 28 days of QD application 
o Change in Physician’s Tumor Assessment grade after 28 days of QD 
application. 
 
3 
STUDY OVERVIEW 
3.1 
Study Design 
This study of NFX-179 is a double-blind, randomized, vehicle-controlled, parallel-group 
study, evaluating safety, tolerability, pharmacokinetics and pharmacodynamic activity in 
subjects with cutaneous neurofibromas. 
 
At Visit 1, the investigator will identify 6 cNF tumors (Study cNF Tumors) that fulfill the 
enrollment criteria. The 5 Target cNF Tumors are for treatment with the assigned study 


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medication. One of the 5 Target cNF Tumors must be on the face, and 4 Target cNF Tumors 
must be on the anterior trunk or upper extremities. The 1 Untreated cNF Tumor must be on 
the anterior trunk or upper extremities and will not receive study medication applications.  
At select sites the Target cNF Tumors will be measured using high frequency ultrasound to 
determine volume throughout the study. The assigned study medication will be applied the 
Target cNF Tumors once daily (QD) during the 28-day treatment period. 
 
At Visit 2 (Day 1) eligible subjects will be randomized and will begin the 28-day QD 
treatment period. 
 
Subjects will be seen at Visits 3 and 4 (Days 8 and 15) for follow-up visits during the 
treatment period. At Visit 5 (Day 29) subjects will be seen for the last treatment period visit, 
will have the 5 Target cNF Tumors and the 1 Untreated cNF Tumor excised 4 (±1) hours after 
the last study medication application, and will start a 28-day no treatment follow-up period. 
Subjects will be seen at Visit 6 (Day 36-50) for follow-up care of the Visit 5 excision wounds. 
Subjects will be seen for Visit 7 (Day 57) for an end of study visit.  
 
No topical treatments other than the study medication will be applied to any of the Study cNF 
Tumors for the duration of the study.  
 
3.2 
Scientific Rationale for Study Design 
NFX-179 is formulated as a gel for topical administration. Since application of a gel can be 
expected to have an effect on the treated cNF tumors, use of a vehicle gel is deemed necessary 
in this study to differentiate any effects due to the vehicle from the active substance. Use of a 
vehicle also allows to control any effect that participation in the clinical study may introduce 
as a result of a more careful or otherwise different management of the cNF. Finally, use of a 
vehicle controls bias in those safety and efficacy assessments that rely on subjective 
judgement by the subject or the investigator. 
 
Systemic absorption of NFX-179 following single topical application to the 5 Target cNF 
Tumors is expected to be extremely low, based on serum values observed in animal studies 
presented in the IB. However, to confirm that systemic exposure of NFX-179 is low in human 


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subjects as well, blood samples will be taken to assess NFX-179 serum levels throughout the 
study. 
 
3.3 
Dose Selection Rationale 
The selection of dose, dosing interval and duration has taken into account the results of the 
nonclinical pharmacology, PK and toxicology studies, which are presented in the IB. 
The QD topical application frequency at the proposed concentrations is expected to result in 
continuous exposure at efficacious levels in a safe range. Further details on the dose selection 
rationale are provided in the NFX-179 IB. 
 
3.4 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last subject in the study 
globally. 
 
If NFlection, Medical Monitor or designee, monitor, or appropriate regulatory officials 
indicate that the study should be halted or that a study site should be terminated, this action 
may be taken after appropriate consultation between NFlection and the appropriate parties. 
NFlection has the right to terminate this study at any time for any reason. Conditions that may 
warrant termination of the study include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study. 
 A decision by NFlection to suspend or discontinue testing, evaluation, or 
development of the product. 
 
3.5 
Study Duration 
The duration of study participation for each subject is anticipated to be a maximum of 88 
days. Including a 28-day screening period, a 28-day treatment period and a 28-day no-
treatment follow-up period. The last study visit has a window of ±4 days.  
 
The planned duration of the study from first subject first visit to last subject last visit is planned 
to be approximately 64 weeks.  The study end date is the date of the last subject’s last visit.  
 
 


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4 
STUDY POPULATION 
This study will enroll male and female subjects aged 18 years and older, with a clinical 
diagnosis of NF1. 
  
4.1 
Number of subjects 
Approximately 56 subjects will be randomized to 1 of the 4 study medication treatment 
groups at approximately 6 United States (US) investigational centers with the goal of at least 
48 subjects completing the study. 
 
4.2 
Study Entry Criteria 
4.2.1 Inclusion Criteria 
In order to be eligible to participate in this study, the subject must fulfill all the following 
criteria: 
1. Subject is at least 18 years of age 
2. Subject must provide written informed consent prior to any study procedures  
3. Subject must have a clinical diagnosis of NF1 
4. Subject has 6 Study cNF Tumors (5 Target cNF Tumors [1 on the face; 4 on the 
anterior trunk or upper extremities] that will be treated with the assigned study 
medication;1 Untreated cNF Tumor on the anterior trunk or upper extremities) that 
each meet the following criteria: 
 Has, in the investigator’s opinion, a clinically typical appearance 
 Is dome shaped 
 Is not pedunculated 
 Is a discrete tumor 
 Is not irritated 
 Is not in an area subject to repeated trauma (e.g., area that is shaved, on the 
beltline, under a bra strap, etc.) 
 Does not have an active cutaneous infection 
 Has a diameter that is ≥5mm and ≤10mm 
 Has a height of ≥2mm 
 Is, when centered in the center of the provided template, the only cNF tumor 
visible 
 Is not within 5mm of the orbital rim. 
5. Subject is willing to have the 5 Target cNF Tumors and the 1 Untreated cNF Tumor 
excised at the end of the treatment period  
6. Subject is willing to have hair in the area surrounding the Target cNF Tumors shaved, if 
necessary, to obtain photographs 
7. Subject is willing to minimize exposure of each Target cNF to natural and artificial 
ultraviolet radiation 
 
 


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8. Subject is willing to forego treatment of the Target cNF Tumors, except protocol 
specified therapy, during the study 
9. Female subjects who are women of childbearing potential must have a negative urine 
pregnancy test result and be willing to use a protocol approved, contraceptive method for 
the duration of the study 
10. Subject is willing and able to follow all study instructions and to attend all study visits. 
 
No waivers to the inclusion criteria are permitted. 
 
4.2.2 Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from participation in this 
study: 
1. Subject has applied any of the following topical products in the previous 30 days on or in 
proximity to any Study cNF Tumor that, in the investigator’s opinion, impairs evaluation 
of any the tumor or which exposes the subject to an unacceptable risk by study 
participation: 
 Corticosteroids 
 Retinoids (e.g., tazarotene, tretinoin, adapalene) 
 > 5% of an alpha-hydroxy acid (e.g., glycolic acid, lactic acid) 
 Fluorouracil  
 Imiquimod 
2. Any Study cNF Tumor has ever been treated with an MEK inhibitor or a BRAF inhibitor 
3. The subject has used any of the following systemic medications in the noted time period:  
 Retinoids (e.g., etretinate, isotretinoin) within the previous 90 days 
 MEK inhibitors within the previous 180 days 
 BRAF inhibitors within the previous 180 days 
4. Subject has a history of hypersensitivity to any of the ingredients in the study 
medications 
5. Subject has any known intercurrent illness or physical condition that would, in 
the investigator’s opinion, impair evaluation of a Target cNF Tumor or which 
exposes the subject to an unacceptable risk by study participation 
6. Subject has, in the investigator’s opinion, clinically relevant history of liver disease, 
including viral hepatitis, current alcohol abuse, or cirrhosis 
7. Subject has a history of metastatic disease, or active cancer (excluding non-
melanoma skin cancer, Stage I cervical cancer, ductal carcinoma in situ of the 
breast, or Stage 0 chronic lymphocytic lymphoma) within the previous 5 years 
8. Subject has any condition (e.g., other skin conditions or diseases, metabolic 
dysfunction, physical examination findings, clinical laboratory findings) or 
situation (e.g., vacation, scheduled surgery) that would, in the investigator’s 
opinion, impair evaluation of a Target cNF Tumor or which exposes the subject to 
an unacceptable risk by study participation 
 
 


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9. Subject has participated in an investigational drug trial in which administration of an 
investigational study medication occurred within the previous 30 days. 
 
No waivers to the exclusion criteria are permitted. 
 
4.3 
Subject identifier (SI) 
At Visit 1 (Screening) the investigator or designee will assign a unique four-digit subject 
identifier (SI) to each subject.  
 
The SI format will be NN-NN where the first 2 digits are the investigational center site number 
(using leading zeroes as appropriate) assigned by NFlection. The final 2 digits are the subject 
number and must be assigned in ascending numerical order, without omitting or repeating any 
number, starting with 01 at each investigational center. For example, the SI for the second 
subject that signs an informed consent at site number 04 would be 04-02.  
 
The subject will be identified using the SI in all study documentation for the duration of the 
study. 
 
4.4 
Screen Failures 
A subject who consents to participate in the study but is not subsequently randomized to study 
medication will be considered a screen failure.  
 
A minimal set of screening failure information is required to ensure appropriate reporting of 
screen failure subjects and to respond to queries from regulatory authorities. For detailed 
screening failure requirements please refer to the case report form (CRF) completion 
guidelines. 
 
Individuals whose screening data do not meet the criteria for participation in this study (i.e., 
screen failure) may be rescreened after consultation of the Medical Monitor. If the subject will 
be rescreened, a new SI will be created. 
 
 
 


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4.5 
Early Termination Visit 
The investigator should complete the following study procedures for subjects who 
prematurely discontinue from the study: 
 For subjects who are randomized and discontinue from the study prior to Visit 5 
complete the Visit 5 procedures except Study Tumor excision 
 For subjects who complete Visit 5 and discontinue from the study prior to Visit 6 
complete the Visit 6 procedures 
 For subjects who complete Visit 6 and discontinue from the study prior to Visit 7 
complete the Visit 7 procedures. 
 
Detailed instructions for documenting subjects who prematurely discontinue from the study 
will be included in the CRF guidelines. 
 
4.6 
Unscheduled Visit 
The investigator may see a subject for an unscheduled study visit at any time it is, in the 
investigator’s opinion, necessary. 
 
At unscheduled visits, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health since the 
previous visit and report all AEs as appropriate 
2. Query the subject about any changes in her/his concomitant therapies since the previous 
visit and report changes as appropriate 
3. Review the study instructions with the subject 
4. Schedule the next study visit. 
 
Complete other study procedures that are, in the investigator’s opinion, appropriate for the 
visit. Detailed instructions for documenting unscheduled visits will be included in the CRF 
guidelines. 
 
 
 


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4.7 
Lost to Follow-up 
A subject who appears to be unavailable for scheduled visits and is unable to be contacted by 
the study site will be considered lost to follow-up. 
The following actions must be taken if a subject repeatedly fails to return to the study site for 
a required study visit: 
 The investigator or designee must attempt to contact the subject and reschedule the 
missed visit as soon as possible and counsel the subject on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the subject 
wishes to and/or should continue in the study. 
 Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
 Should the subject continue to be unreachable, she/he will be considered to 
have withdrawn from the study. 
 
4.8 
Subject discontinuation from the study 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason.  
 
The investigator may remove a subject from the study if, in the investigator's opinion, it is not in 
the best interest of the subject to continue the study. The investigator must remove a subject from 
the study if the subject experiences: 
 A Serious Adverse Event the investigator defines as related to the study medication, 
regardless of the intensity of the event 
 A non-serious adverse event the investigator defines as related to study medication that 
has a severity of severe and requires treatment to resolve.  
 
Examples of other reasons subjects may be discontinued from the study are a change in 
compliance with an inclusion or exclusion criterion, occurrence of AEs, occurrence of pregnancy 
or use of a prohibited therapy. Notification of discontinuation will immediately (within 24 hours) 
be made to the NFlection study monitor.  
 
All withdrawn subjects with ongoing AEs will be followed as appropriate. 
 
The study may be discontinued at the discretion of NFlection. Some examples of reasons for 


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discontinuation are the occurrence of the following: 
 
Increased frequency, severity or duration of known AEs 
 
Medical, regulatory or ethical reasons affecting the continued performance 
of the study 
 
Difficulties in the recruitment of subjects. 
 
4.9 
Replacement of subjects 
Subject enrollment will continue until approximately 56 subjects have been randomized. 
Subjects who are randomized and do not complete the study will not be replaced. 
 
4.10 Subject instructions 
At Visit 1, an investigational center staff member will dispense a Subject Instruction sheet to 
each subject. 
 
During the entire duration of the study subjects must:  
 Continue to use her/his routine cleansers and cosmetics 
 Not apply any non-study topical products to any Target cNF within 18 hours prior to a 
study visit 
 Avoid exposing each Target cNF to excessive natural (e.g., sunlight) or artificial (e.g., 
tanning beds) ultraviolet radiation and use her/his routine sunscreen if excessive exposure 
cannot be avoided 
 Bring the subject instruction sheet to every visit. 
 
During the 4-week treatment period, subjects must: 
 Apply the study medication to each Target cNF as directed, once daily, with 24 (±6) 
hours between applications 
 Not apply the study medication to any open wounds or obviously infected skin 
 For Visits 3 and 4 do not apply the study medication within 18 hours prior to the visit  
 Prior to Visit 5 perform the study medication application 24 (±6) hours prior to the 
visit  
 Not wash or submerge a Target cNF Tumor for at least 6 hours after a study medication 
application 
 Not apply any topical products to a Target cNF for at least 6 hours after a study 
medication application 
 Not allow anyone else to use your study medication 
 Keep the study medication away from children 
 Store the study medication at room temperature 
 Bring all study medication tubes to every visit 
 Bring the subject instruction sheet to every visit. 


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4.11 Previous and Concomitant Therapies 
4.11.1 Previous therapies 
At Visit 1, the investigator or designee will question the subject to ensure they have not used any 
excluded therapies. 
 
4.11.2 Concomitant Therapies 
Concomitant therapies are any new or existing therapy received from Visit 1 until discharge from 
the study.  
 
Concomitant therapies include drug (e.g., prescription, over-the-counter) and non-drug (e.g., 
chiropractic, physical therapy, energy-based treatments) therapies. Subjects will refrain from 
receipt of any therapy in compliance with the inclusion/exclusion criteria. Subjects should refrain 
from changing the use of any concomitant therapies during the study.  
 
All new or modified concomitant therapies used during the study must be recorded. 
 
Any new or modified concomitant therapy must be considered to determine if it is related to an 
AE. An AE must be reported unless the therapy is modified for non-medical reasons (e.g., health 
insurance purposes), it is for prophylaxis (e.g., vaccinations), it is for the Visit 5 excision of, or 
post-excision management of the Study cNF Tumors following the investigator’s standard of 
care. 
 
4.11.3 Prohibited therapies 
Subjects must not use any systemic therapy for cNF and must not use any topical cNF therapy 
on the Untreated cNF Tumor and must not use any topical cNF therapy other than the study 
medication, on any Target cNF Tumor. 
 
During this study, subjects are prohibited from using therapies listed in the exclusion criteria. 
The investigator should notify the NFlection Medical Monitor immediately (within 24 hours) if 
any prohibited therapies are required to ensure subject safety. 
 
Starting at Visit 2 subjects must avoid applying any topical product to any Target cNF Tumor for 
at least 6 hours after any study medication application. 


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4.12 Study Medications 
The study medications are faint yellow, water clear gels and are indistinguishable in physical 
appearance. Study medications must be maintained in a secure area with limited access under 
appropriately controlled and monitored storage conditions at each investigational center.  
 
4.12.1 Study medication identity 
 
Study Medication Information
Name 
NFX-179 Gel 
0.50%
NFX-179 Gel 
0.15%
NFX-179 Gel 
0.05%
NFX-179 Gel 
Vehicle
Manufacturer 
MedPharm Limited 
Unit 1, Chancellor Court, 50 Occam Road, Surrey Research Park 
Guildford, Surrey GU2 7AB United Kingdom
Active ingredient 
2-((2-fluoro-4-iodophenyl) amino)-N-(2-
hydroxyethoxy)-1-methyl-1H-pyrrolo[2,3-b] 
pyridine-3-carboxamide
None 
Active 
concentration
0.50% 
0.15% 
0.05% 
0% 
Storage 
conditions
59°F to 77°F (15°C to 25°C) 
 
The investigator or designee must confirm appropriate storage temperature was maintained 
during shipment for all study medication received and any discrepancies must be reported to 
NFlection and resolved before the study medication is dispensed. 
 
4.12.2 Study medication packaging and labeling 
The study medications will be packaged in identical appearing white plastic tubes that each 
contain 30 grams of study medication. 
 
One Subject Kit that contains 2 tubes of study medication will be prepared for each subject. 
 
Subject Kits will be labeled with a two-part, three-panel label. One part of the label remains 
affixed to the Subject Kit and the second part, a two-panel tear-off, is separated when the Subject 
Kit is first dispensed to the subject. 
 
 
 


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The affixed label part and the first panel of the tear-off label part show at least the following: 
 Subject Kit number (Subject Kit number is also the randomization number) 
 Protocol number 
 Space to enter the SI 
 Space to enter the date randomized 
 Storage conditions 
 NFlection information. 
 
The second panel of the tear-off part is a blinded label (e.g., scratch-off panel or equivalent) 
which when opened identifies the study medication in the Subject Kit. The blinded label should 
be opened only in a medical emergency. 
 
Each study medication tube will be labeled with a one-part label that remains attached to the tube 
and shows at least the following:  
 Subject Kit number 
 Protocol number 
 Tube number 
 Space to enter the SI 
 Space to enter the date dispensed 
 Directions for use 
 Investigational drug warning 
 
4.12.3 Method of study medication assignment 
Prior to the study start NFlection, or a designated third party, will generate a list of 
randomization numbers that will be provided to the assigned vendor for study medication 
labeling. The randomization number is also the Subject Kit number. 
The randomization list will be stored with access limited to the appropriate personnel for the 
study medication labeling. The randomization list will be made available as appropriate to 
unblind the database. 
 
 
 


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4.12.4 Subject randomization 
At Visit 2, the investigator will determine the subject’s eligibility for randomization to study 
medication. To be eligible for randomization the subject must: 
 Continue to fulfill all the inclusion criteria and none of the exclusion criteria 
 If a Woman of Childbearing Potential (WOCBP), has a negative urine pregnancy test 
result at Visit 1 and Visit 2 
 Have clinical laboratory test results for all measured analytes at Visit 1 and all results 
are either within the range of normal for the laboratory or, any abnormal results, are 
defined as Not Clinically Relevant (NCR) by the investigator 
 Have Visit 1 ECG results that are defined as Normal.  
 
The investigator or designee will assign study medication to eligible subjects by selecting the 
Subject Kits in chronological sequence in ascending numerical order starting with the lowest 
available Subject Kit number. The investigator will not omit or reuse any Subject Kit number. 
 
4.12.5 Dispensing and collecting study medication 
The study medication must be dispensed only to study subjects, only at investigational centers 
specified on the Form FDA 1572 (or its equivalent) and only by authorized personnel as required 
by applicable regulations and guidelines. 
 
At Visit 2, after a subject is randomized, locate the Subject Kit with the lowest available number 
and complete the label. 
 
Next locate the unused study medication tube with the lowest available number and complete the 
label. Weigh the study medication tube. Dispense one study medication tube to the subject for 
use in the first study medication application. 
 
The subject must bring all dispensed study medication tubes with them to all visits. 
 
At Visits 3 and 4, examine the study medication tubes dispensed to the subject, collect any tube 
that contains no useable study medication, weigh the tube and dispense a new tube, if required, 
following the instructions above.  
 
At Visit 5, collect all study medication tubes from the subject and weigh each tube.30 grams (1 


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tube) of study medication tube is enough to complete the study medication applications for the 
duration of the study. 
 
The investigational center staff member should make every effort to obtain all dispensed and 
unused study medication. Two documented telephone contacts followed by a registered letter to 
the subject are adequate follow-up efforts. If these efforts fail, the reason for the failure must be 
noted on the appropriate line of the study medication inventory CRF.  
 
All unused and un-dispensed study medication should be held for inspection by NFlection’s 
study monitor. Upon completion of the study all study medication will be returned to NFlection 
or a designated third party by the monitor using a traceable method. 
 
4.12.6 Weighing study medication 
An investigational center staff member will weigh each study medication tube when dispensed 
using the provided scale (or equivalent). The study medication container weight must be reported 
in grams (g) to the nearest 0.1g.  
 
An investigational center staff member will weigh each study medication tube when returned. 
Study medication tubes that are examined and not collected from the subject because they 
contain useable study medication do not need to be weighed. 
 
The study medication tube weights must be noted on the appropriate CRF.  
 
The scale used to weigh the study medication tubes must be calibrated, according to the 
instructions provided for the scale, and the calibration documented, each day the scale is used, 
prior to use. Any scale that does not pass the calibration test must not be used to weigh the study 
medication. 
 
4.12.7 Route of Administration, frequency and treatment period 
The study medications are applied topically to each Target cNF Tumor, once daily for 28 
days. 


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4.12.8 Study medication application 
The study medications are for external, topical use on each Target cNF Tumor only and on the 
appropriate study subject only.  
 
To perform a study medication application the subject should: 
 Wash her/his hands before starting the application 
 Avoid applying the study medication any open wounds or obviously infected skin  
 Apply an amount of the assigned study medication sufficient to cover each Target cNF 
with a thin layer of the medication 
 Gently rub in the study medication until no visible accumulation is evident 
 Wash her/his hands after completing the application 
 
The subject must apply study medication to the entire area of each Target cNF Tumor limiting 
exposure to the un-affected skin surrounding the tumor. 
 
At Visit 2, an investigational center staff member will instruct the subject on the proper 
application technique The staff member will observe the subject’s study medication application 
to ensure proper application technique and record the time the subject completes the application 
to the last Target cNF Tumor as the Application Completion Time. The staff member will 
monitor the subject for adverse events for at least 20 minutes after the Application Completion 
Time. The subjects are to continue QD application of the assigned study medication to each 
Target cNF Tumor for 4 weeks with 24 (±6) hours between applications.  
 
At Visit 5, the study medication application will be performed by the subject as part of the visit 
procedures at the investigational center. Record the time the subject completes the application to 
the last Target cNF Tumor as the Application Completion Time. The study medication tubes will 
be collected after the application at this visit. 
 
For Visits 3 and 4 subjects should not apply the study medication within 18 hours prior to the 
study visit.  
 
Prior to Visit 5 subjects must be instructed to perform the study medication application 24 
(±6) hours prior to the visit.  
 


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After completing a study medication application, a subject should not: 
 Wash or submerse any Target cNF Tumor for at least 6 hours 
 Apply any topical products (e.g., cosmetics, emollient/moisturizer, sunscreens) to any 
Target cNF Tumor for at least 6 hours. 
 
4.12.9 Dose Modification 
Subjects should not modify the study medication application procedure or frequency. All 
application modifications must be reported on the appropriate CRF page. 
 
If any significant study medication intolerance or safety issue occurs, after consulting with the 
NFlection’s Medical Monitor, the investigator or designee may direct the subject to reduce the 
study medication application frequency. If the subject cannot perform QD applications to all 
Target cNF Tumors for more than 4 consecutive days, the subject must be removed from the 
study. 
 
4.12.10 Accountability 
The investigator or designee will maintain an accurate record of the receipt of the study 
medications as shipped by NFlection or designee, including the date received and the condition of 
the study medications. One copy of this receipt will be returned to NFlection when the contents of 
the study medication shipment have been verified and one copy maintained in the study file. In 
addition, an accurate study medication disposition record will be kept, specifying the amount 
dispensed to each subject and the date of dispensing. This inventory record will be available for 
inspection at any time. At the completion of the study, the original inventory record will be 
available for review by NFlection upon request. 
 
4.12.11 Return and disposition of study medication 
At the completion of the study, all unused study medication will be returned to NFlection or 
designee for disposal per NFlection’s or designee’s written instructions. 
 
 
 


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4.13 Blinding 
4.13.1 Verification of blinding 
Blinding of the study medications is important for validity of this study. This study uses a 
double-blind design. The study medications are indistinguishable in appearance, packaging and 
labeling. 
 
4.13.2 Unblinding the study medication 
Blinding is important for validity of this study; however, the blind may be broken in the event of 
a medical emergency in which knowledge of the study medication identity is critical to the 
management of the subject’s course of treatment. Before breaking the blind, the investigator 
should determine that the information is necessary (i.e., that it will alter the subject’s immediate 
course of treatment). In many cases, particularly when the emergency is clearly not study 
medication-related, the problem may be effectively managed by assuming that the subject is 
receiving active study medication without the need for unblinding.  
 
If deemed necessary to break the blind for a study subject, attempt to contact the NFlection 
Medical Monitor to obtain concurrence. If it is not possible to contact the Medical Monitor 
beforehand, contact her/him as soon as possible after breaking the blind for a subject. 
 
To identify a subject’s study medication, locate the second panel of the Subject Kit tear-off label 
attached to the subject’s CRF and follow the unblinding instructions on the label. Record the date 
of unblinding, the reason for unblinding and the initials of the investigational center staff 
member who performed the unblinding in the subject’s CRF. 
 
Any subject whose blind has been broken must be discharged from the study.  
 
4.14 Study medication adherence 
Adherence with the study medication application frequency will be monitored by questioning 
the subject regarding adherence at each visit and by measuring the weight of the study 
medication tubes when dispensed to the subject and when collected from the subject. 
 
 
 


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4.15 Other study supplies 
In addition to the equipment and supplies provided for procedures, such as blood sampling, 
ultrasound measures and photography, NFlection, or designee, will provide the following 
items to each investigational center prior to the initiation of subject enrollment: 
 Rulers for measuring each Study cNF Tumor 
 Scales for weighing the study medication tubes 
 Supplies for tissue excision processing and storage. 
 
 


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5 
STUDY VISITS AND PROCEDURES 
5.1 
Schedule of Events 
Visit 
1 
Screening 
2 
Randomization 
3, 4 
Treatment 
5 
End of 
treatment 
6 
Excision 
wound care 
7 
End of 
study 
Protocol 
section 
Day 
-28 to 0 
1 
8, 15 
29 
36-50 
57 
Informed consent 
X 
 
 
 
 
 
11.3 
Subject identifier (SI) 
X 
 
 
 
 
 
4.3 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
4.2 
Demographics 
X 
 
 
 
 
 
6.3.1 
Medical history 
X 
X 
 
 
 
 
6.1.4 
Physical examination 
X 
 
 
 
 
 
6.1.4 
Vital signs 
X 
X 
 
X 
 
X 
6.1.6 
Clinical laboratory samples 
X 
X 
 
X 
 
 
6.1.2 
Electrocardiogram (ECG) 
X 
X 
 
X 
 
 
6.1.8 
Study/Target cNF Tumor location 
identification 
X 
X 
X 
X 
 
 
5.3 
Study/Target cNF Tumor 
dimensions 
X 
X 
 
X 
 
 
6.2.1 
Local tolerability assessment 
(LTA) 
 
X 
X 
X 
 
 
6.1.3 
Physician’s Tumor Assessment 
(PTA) 
 
X 
 
X 
 
 
6.2.4 
Subject’s Self-Assessment (SSA) 
 
X 
 
X 
 
 
6.2.3 
Ultrasound (select sites) 
 
X 
 
X 
 
 
6.2.2 
Photography 
X 
X 
 
X 
 
 
6.3.4 
Study cNF Tumor excision 
 
 
 
X 
 
 
6.3.3 
Excision wound care 
 
 
 
 
X 
 
6.3.3 
Pharmacokinetic samples (select 
sites) 
 
X 
 
X 
 
 
6.3.2 
Urine pregnancy test 
X 
X 
 
X 
 
 
6.1.7 
Screening 
 
 
 
 
 
 
5.2.1 
Randomization 
 
X 
 
 
 
 
4.12.4 
Dispense/collect/weigh study 
medication 
 
X 
X 
X 
 
 
4.12.5/ 
4.12.6 
Once-daily (QD) application 
  
 
 
 
4.12.8 
No treatment follow-up 
 
 
 
 
 
5.2.4 
Subject instructions 
X 
X 
X 
X 
X 
 
4.10 
Concomitant therapies 
X 
X 
X 
X 
X 
X 
4.11.2 
Adverse events 
 
X 
X 
X 
X 
X 
7 
 
 
 


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5.2 
Study Visits 
A written, signed informed consent form (ICF) must be obtained from each subject prior to 
performing any study related procedures and/or evaluations. 
 
For Visits 3 and 4 subjects should not apply the study medication within 18 hours prior to a study 
visit.  
 
Prior to Visit 5 subjects must be instructed to perform the study medication application 24 
(±6) hours prior to Visit 5. 
  
5.2.1 Visit 1/Day -28 to 0 (Screening) 
At this visit, the investigator or designee will: 
1. Review and explain the nature of the study to the subject, obtain the subject’s signature on 
the appropriate approved ICF and Health Insurance Portability and Accountability Act 
(HIPAA) authorization and provide a signed and dated copy to the subject 
2. Assign a Subject Identifier to the subject 
3. Confirm the subject meets all inclusion criteria and no exclusion criteria 
4. Collect demographic and medical history information 
5. Report concomitant therapies information 
6. Conduct a physical examination 
7. Measure vital signs 
8. Perform an ECG 
9. Collect samples for clinical laboratory tests 
10. Perform a urine pregnancy test for women of childbearing potential (WOCBP) 
11. Identify 6 Study cNF Tumors (i.e., 5 Target cNF Tumors and 1 Untreated cNF Tumor) 
12. Measure the dimensions of each of the 6 Study cNF Tumor 
13. Take standardized color photographs of each of the 6 Study cNF Tumor 
14. Review the study instructions with the subject and dispense a Subject Instruction Sheet 
15. Schedule Visit 2 (Day 1) within 28 days. 
 
5.2.2 Visit 2/Day 1 (Randomization; start of QD treatment) 
This visit must occur within 28 days after Visit 1. 
 
Subsequent study visit dates must be scheduled based on the date of this visit. 
 
This visit may not occur until the investigator reviews the subject’s Visit 1 clinical laboratory 
test results and ECG results.  
 


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At this visit, the investigator or designee will perform the following procedures PRIOR TO 
RANDOMIZATION: 
1. Query the subject in a non-directive manner about any changes in her/his health since the 
previous visit and report any changes as medical history or report as an AE as appropriate 
2. Query the subject about any changes in her/his concomitant therapies since the previous 
visit and report changes as appropriate 
3. Confirm the subject continues to fulfill all the inclusion criteria and none of the exclusion 
criteria  
4. Confirm the subject has followed all study instructions 
5. Perform a urine pregnancy test for WOCBP 
6. Confirm the location of each Target cNF Tumor 
7. Measure the dimensions of each Target cNF Tumor 
8. Confirm subject is eligible for randomization, discharge subjects who are not eligible from 
the study. 
 
For subjects eligible for randomization, the investigator or designee will perform the following 
procedures: ` 
1. Have the subject perform a pre-application Local Tolerability Assessment (LTA) of the 
symptoms for each Target cNF Tumor 
2. Have the subject perform a Subject’s Self-Assessment (SSA) for each Target cNF Tumor 
3. The investigator will perform a pre-application LTA of the signs for each Target cNF 
Tumor 
4. Perform a Physician’s Tumor Assessment (PTA) for each Target cNF Tumor 
5. Take standardized color photographs of each Target cNF Tumor 
6. At select sites only: Perform an ultrasound of each Target cNF Tumor 
7. Measure vital signs 
8. Perform an ECG 
9. Collect samples for clinical laboratory tests 
10. Randomize eligible subjects 
11. Weigh and dispense study medication 
12. At select sites only: Collect a blood sample for PK analysis prior to the first study 
medication application 
13. An investigational center staff member must:  
 Instruct the subject on the proper study medication application technique 
 Observe the subject’s first study medication application to each Target cNF Tumor and 
record the Application Completion Time 
 Monitor the subject for at least 20 minutes after the Application Completion Time 
14. Have the subject perform a post-application LTA of the symptoms for each Target cNF 
Tumor 10 (±4) minutes after the Application Completion Time 
15. The investigator will perform a post-application LTA of the signs for each Target cNF 
Tumor 20 (±4) minutes after the Application Completion Time 
16. Review the study instructions with the subject 
17. Schedule Visit 3. 
 


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5.2.3 Visits 3 and 4/Days 8 and 15 (QD Treatment) 
These visits must occur within the following visit windows: 
 Visit 3/Day 8: 7 days (±4 days) after Visit 2 
 Visit 4/Day 15: 14 days (±4 days) after Visit 2. 
 
Subjects should not apply the study medication within 18 hours prior to these study visits. 
 
At these visits, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health since the 
previous visit and report all AEs as appropriate 
2. Query the subject about any changes in her/his concomitant therapies since the previous 
visit and report changes as appropriate 
3. Confirm the subject has followed all study instructions 
4. Confirm the location of each Target cNF Tumor 
5. Have the subject perform an LTA of the symptoms for each Target cNF Tumor 
6. The investigator will perform an LTA of the signs for each Target cNF Tumor 
7. Collect and weigh study medication 
8. Weigh and dispense study medication 
9. Review the study instructions with the subject 
10. Schedule the next study visit. 
 
5.2.4 Visit 5/Day 29 (End of Treatment; start of no treatment follow-up) 
This visit must occur 28 days (±4 days) after Visit 2. 
 
At selects sites performing PK sample collection at this visit:  
 Subjects will be confined at the investigational center for approximately 6 hours for the 
collection of PK blood samples and for excision of the 6 Study cNF Tumors 
 This visit must be scheduled so that the previous study medication application was 
completed 24 (±6) hours prior to the 0-hour PK blood sample. 
 
At sites NOT performing PK sample collection at this visit:  
subjects will be confined at the investigational center for approximately 6 hours for excision of 
the 6 Study cNF Tumors. 
 
 


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At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health since the 
previous visit and report all AEs as appropriate 
2. Query the subject about any changes in her/his concomitant therapies since the previous 
visit and report changes as appropriate 
3. Confirm the subject has followed all study instructions including, at select sites, 
appropriate timing of the previous study medication application for PK blood sampling 
4. Measure vital signs 
5. Perform a urine pregnancy test for WOCBP 
6. Confirm the location of the 6 Study cNF Tumors (5 Target cNF Tumors and 1 Untreated 
cNF Tumor) 
7. Measure the dimensions of each Target cNF Tumor 
8. Have the subject perform an SSA for each Target cNF Tumor 
9. Have the subject perform an LTA of the symptoms for each Target cNF Tumor 
10. Perform a PTA for each Target cNF Tumor 
11. The investigator will perform an LTA of the signs for each Target cNF Tumor 
12. At select sites: Perform an ultrasound of each Target cNF Tumor 
13. Take standardized color photographs of each Target cNF Tumor 
14. Perform an ECG 
15. Collect samples for clinical laboratory tests then conduct the appropriate activities as 
indicated below. 
 
At select sites performing PK sample collection at this visit:  
16. Collect 0-hour blood sample for PK analysis 24 (±6) hours after the previous study 
medication application and prior to the Visit 5 study medication application 
17. Have the subject perform the last study medication application and record the Application 
Completion Time  
18. Have the subject perform a post-application LTA of the symptoms for each Target cNF 
Tumor 10 (±4) minutes after the Application Completion Time 
19. The investigator will perform a post-application LTA of the signs for each Target cNF 
Tumor 20 (±4) minutes after the Application Completion Time 
20. Collect post-application blood samples for PK analysis  
21. 4 (±1) hours after the Application Completion Time excise the 6 Study cNF Tumors (5 
Target cNF Tumors and 1 Untreated cNF Tumor) 
22. Collect and weigh study medication 
23. Review the study instructions with the subject 
24. Schedule Visit 6. 
 
At sites NOT performing PK sample collection at this visit:  
16. Have the subject perform the last study medication application  
17. Have the subject perform a post-application LTA of the symptoms for each Target cNF 
Tumor 10 (±4) minutes after the Application Completion Time 
18. The investigator will perform a post-application LTA of the signs for each Target cNF 
Tumor 20 (±4) minutes after the Application Completion Time 
19. 4 (±1) hours after the Application Completion Time excise the 6 Study cNF Tumors (5 
Target cNF Tumors and 1 Untreated cNF Tumor) 


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20. Collect and weigh study medication 
21. Review the study instructions with the subject 
22. Schedule Visit 6. 
 
5.2.5 Visit 6/Day ≥36 to ≤50 (Excision wound care) 
This visit must occur 7 (±4) days after Visit 5 and 7 (±4) days prior to Visit 7. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health since the 
previous visit and report any changes as medical history or report as an AE as appropriate 
2. Query the subject about any changes in her/his concomitant therapies since the previous 
visit and report changes as appropriate 
3. Confirm the subject has followed all study instructions 
4. The investigator will manage the excision wounds per her/his standard of care 
5. Review the study instructions with the subject  
6. Schedule Visit 7. 
 
5.2.6 Visit 7/Day 57 (End of study, early termination) 
This visit must occur 56 days (±4 days) after Visit 2 and 7 (±4) days after Visit 6. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject in a non-directive manner about any changes in her/his health since the 
previous visit and report all AEs as appropriate 
2. Query the subject about any changes in her/his concomitant therapies since the previous 
visit and report changes as appropriate 
3. Confirm the subject has followed all study instructions 
4. Measure vital signs 
5. Discharge the subject from the study. 
 
5.3 
Study cNF tumor identification 
At Visit 1 the investigator will identify 6 Study cNF Tumors: 
 5 Target cNF Tumors with 1 tumor on the face and 4 tumors on the anterior trunk or 
upper extremities 
  1 Untreated cNF Tumor on the anterior trunk or upper extremities 
 
The Untreated cNF Tumor should be located as far as possible from the nearest Target 
cNF Tumor. The Untreated cNF Tumor will NOT receive any study medication 
applications. 
 


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For this study the anterior trunk, upper extremities and face are defined as follows: 
 Anterior trunk: 
o The front of the torso, excluding the neck, down to the beltline 
 Upper extremities: 
o Arms from the shoulders to the tips of the fingers, including the back of the 
hands but excluding the palms 
 Face (Target cNF Tumor #5 must be on the face): 
o Vertically from the mandibular ridge to the hairline (for subjects with a 
receding hair the hairline is defined by a vertical lie drawn coronally from 
tragus to tragus) 
o Horizontally from tragus to tragus, excluding the eyelids and areas within 5mm 
of the orbital rim. 
 
At Visit 1 each of the 6 Study cNF Tumors must meet the following criteria for the subject to be 
enrolled and at Visit 2 the 5 Target cNF Tumors must meet to the following criteria for the 
subject to be randomized: 
 Has, in the investigator’s opinion, a clinically typical appearance 
 Is dome shaped 
 Is not pedunculated 
 Is a discrete tumor 
 Is not irritated 
 Is not in an area subject to repeated trauma (e.g., area that is shaved, on the 
beltline, under a bra strap, etc.) 
 Does not have an active cutaneous infection 
 Has a diameter that is ≥5mm and ≤10mm 
 Has a height of ≥2mm 
 Is, when centered in the center of the provided template, the only cNF tumor 
visible 
 Is not within 5mm of the orbital rim. 
 
At Visits 1, the investigator and an investigational center staff member will identify the 6 Study 
cNF Tumors using the provided template.  
 
 
 


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Number the Target cNF Tumors starting with 1 proceeding up to 5 with no number omitted or 
reused. Identify the Untreated cNF Tumor with the designation “UT”. For identification in the 
study photographs place 2 appropriately colored Identification (ID) Stickers in the small template 
cutouts approximately 180 degrees opposite each other with the Study cNF Tumor centered in 
large circular template cutout (diagram not to scale):                                        
 
                                                                      ID Sticker 
 
                                                   
 
 
 
                                                                                                           20mm diameter cutout  
                               Study cNF Tumor                                                            
 
 
 
 
 
 
                                                                       
 
 
 
 
 
 
 
                                                                        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ID Sticker 
 
Write the Study cNF Tumor Identifier on one of the ID stickers. 
 
The Study cNF Tumor Identifier/ID sticker color relationships are: 
 Target cNF Tumor #1/white ID stickers 
 Target cNF Tumor #2/red ID stickers 
 Target cNF Tumor #3/yellow ID stickers 
 Target cNF Tumor #4/blue ID stickers  
 Target cNF Tumor #5/green ID stickers (Target cNF Tumor #5 must be on the face) 
 Untreated cNF Tumor “UT”/pink ID stickers. 
 
Both ID stickers must be visible in the Study cNF Tumor photographs. 
 
 
 


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At Visit 1 the investigator will use body charts and the photographs to document the 
location of each Study cNF Tumor. The investigator will record the location of each Study 
cNF Tumor on an appropriate body chart using the following process: 
 Make a circle identifying the location of each Study cNF Tumor 
 Write the Study cNF Tumor Identifier adjacent to the circle 
 Record at least the following information on each body chart: 
o Protocol number 
o Subject Identifier 
o Visit number. 
 
At Visit 1, the investigator or designee will dispense a photocopy of the body charts 
completed at the visit to the subject as part of the subject instructions. The investigator or 
designee will place the original Visit 1 body chart in the subject’s study file for use at Visit 
2. The investigator or designee must also mark the approximate location of each Study cNF 
Tumor identified at Visit 1 in the CRFs and include the Study cNF Tumor Identifier. 
 
At Visit 2, the investigator will use the Visit 1 body charts and photographs to identify the 
location of the 6 Study cNF Tumors. 
 
Between Visit 1 and Visit 2 the status of 1 or more Target cNF Tumor may change, therefore at 
Visit 2, the investigator will evaluate each subject to determine which of the following categories 
describe each Target cNF Tumor identified at Visit 1: 
 All 5 Target cNF Tumors meet the protocol requirements for the subject to be eligible for 
randomization 
 1 or more Target cNF Tumors do not meet the protocol requirements for the subject to be 
eligible for randomization, but the subject HAS sufficient additional cNF tumors that meet 
the requirements to provide 5 Target cNF Tumors for randomization (Note: 1 Target cNF 
Tumor must be on the face and 4 Target cNF Tumors must be on the anterior trunk or upper 
extremities) 
 1 or more Target cNF Tumor does not meet the protocol requirements for the subject to be 
eligible for randomization, and the subject DOES NOT HAVE sufficient additional cNF 
tumors that meet the requirements to provide 5 Target cNF Tumors for randomization. 
 
At Visit 2, the investigator will discharge subjects from the study who are in category 3. 
 
At Visit 2, for subjects who are in category 1 or 2 the investigator will follow the Visit 1 


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procedures to identify the 5 Target cNF Tumors to be treated and the 1 Untreated cNF Tumor. 
The investigator will use a new set of body charts to document the location of each Study cNF 
Tumor. The investigator will record the location of each Study cNF Tumor on an appropriate 
body chart using the following process: 
 Make a circle identifying the location of each Study cNF Tumor 
 Write the Study cNF Tumor Identifier adjacent to the circle 
 Record at least the following information on each body chart: 
o Protocol number 
o Subject Identifier  
o Visit number. 
 
At Visit 2, the investigator or designee will collect the body charts dispensed to the subject 
at Visit 1 and then dispense a copy of the body charts created at Visit 2 to the subject as 
part of the subject instruction review.  
 
Clearly identify the Untreated cNF Tumor on the body chart and to the subject to 
ensure the subject understands the Untreated cNF Tumor  
is not to be treated with the study medication. 
 
The investigator or designee will place the original Visit 2 body chart in the subject’s study 
file for use at subsequent visits.  
 
The investigator or designee must also mark the approximate location of each Study cNF 
Tumor (5 Target cNF Tumors and 1 Untreated cNF Tumor) in the CRFs and include the 
Study cNF Tumor Identifier.   
 
At Visit 2-5, prior to any Target cNF Tumor assessments, an investigational center staff 
member other than the evaluating investigator will use the appropriate body charts and study 
photographs to identify the location each Target cNF Tumor for the study evaluations. The staff 
member will use the tumor template and for each Target cNF Tumor center the tumor in the 
large circular cutout and place the 2 appropriately colored and numbered ID stickers on the 
subject’s skin.  
 


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At Visit 5 only, the staff member will mark the location of the Untreated cNF Tumor as 
described above to assist the investigator with excision. 
6 
STUDY ASSESSMENTS 
6.1 
Safety assessments 
6.1.1 Adverse Event Assessments 
Information regarding occurrence of AEs will be captured throughout the study. The study 
site visits are designed to ensure any untoward events in subjects are quickly identified by the 
investigator and can be treated promptly. Duration (start and stop dates), severity/grade, 
outcome, treatment and relationship to study medication will be recorded. 
 
6.1.2 Clinical Laboratory Evaluations 
Non-fasting samples for clinical laboratory analysis will be collected by a qualified 
investigational center staff member at Visits 1, 2 (prior to the randomization) and 5 (prior to the 
study medication application at the visit). The following tests, at a minimum, will be conducted: 
Chemistry Panel 
Complete Blood Count 
Albumin
Hematocrit
Alkaline phosphatase
Hemoglobin
Alanine aminotransferase (ALT)
Platelet count
Aspartate aminotransferase (AST)
Red blood cell morphology
Blood urea nitrogen (BUN)
Red blood cell count
Bicarbonate
White blood cell count
Calcium
White blood cell differential
Chloride
   % & absolute
Creatinine
   Basophils
Glucose
   Eosinophils
Lactate dehydrogenase (LDH)
   Lymphocytes
Phosphorus
   Monocytes
Potassium
   Neutrophils
Sodium
Total bilirubin
Urinalysis with Microscopic
Total protein
Uric acid
 
The results of the clinical laboratory tests will be reported on the laboratory’s standard reports. 
The investigator must note NCR or clinically relevant (CR) to define the clinical relevance of 
any result that is outside the normal range for the laboratory. The investigator must date and 
sign/initial every laboratory report.  


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The investigator must review each subject’s Visit 1 laboratory reports prior to Visit 2. The 
subject must not be randomized if any of the Visit 1 results are outside normal range for the 
laboratory AND, in the opinion of the investigator, CR. The investigator must review all 
laboratory reports in a timely manner. 
 
The investigator must report all laboratory results that are BOTH outside the normal range for 
the laboratory AND, in the opinion of the investigator, CR as medical history if found prior to 
the first study medication application or as an AE if found after the first study medication 
application begins. 
 
6.1.3 Local Tolerability Assessment 
At Visits 2-5, the investigator and the subject will assess the local tolerability on each Target 
cNF using the LTA. The LTA is the investigator’s and the subject’s assessment of the average 
overall severity of the signs and symptoms, respectively, associated with irritation on each Target 
cNF. The investigator and subject must NOT refer to any other evaluation to assist with these 
assessments. This is not a comparison with the assessment at any other time point.  
The investigator will assess the LTA for signs using the scales below: 
 
 
Erythema 
0 
None 
No erythema present 
1 
Mild 
Slight red coloration 
2 
Moderate 
Definite redness 
3 
Severe 
Marked erythema, bright red to dusky dark red in color 
 
Edema 
0 
None 
No edema 
1 
Mild 
Slight, but definite edema 
2 
Moderate 
Definite edema 
3 
Severe 
Marked edema 
 
 
 


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Scabbing/Crusting 
0 
None 
No scabbing/crusting 
1 
Mild 
Slight, but definite scabbing/crusting 
2 
Moderate 
Definite scabbing/crusting 
3 
Severe 
Marked scabbing/crusting 
 
Vesiculation 
0 
None 
No vesicles 
1 
Mild 
Small vesicles, no pustules 
2 
Moderate 
Vesicles with pustules, transudate may be present  
3 
Severe 
Pustules with transudate, vesicles may be present, may extend 
outside treatment area 
 
Erosion 
0 
None 
No erosions 
1 
Mild 
Slight erosion on treatment area 
2 
Moderate 
Obvious erosion(s) on the treatment area  
3 
Severe 
Marked erosion that may extend outside treatment area 
 
The subject will assess the LTA for symptoms using the scales below: 
 
Stinging 
0 
None 
No stinging 
1 
Mild 
Slight stinging that is not bothersome 
2 
Moderate 
Definite stinging that is somewhat bothersome 
3 
Severe 
Intense stinging that causes definite discomfort and may interrupt 
daily activities and/or sleep 
 
Burning 
0 
None 
No burning 
1 
Mild 
Slight burning that is not bothersome 
2 
Moderate 
Definite burning that is somewhat bothersome 
3 
Severe 
Hot burning that causes definite discomfort and may interrupt daily 
activities and/or sleep 
 


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Pruritus 
0 
None 
No pruritus 
1 
Mild 
Slight pruritus that is noticeable but not bothersome 
2 
Moderate 
Definite pruritus that is bothersome but does not disrupt activities 
and/or sleep 
3 
Severe 
Intense pruritus that is bothersome and may interrupt daily activities 
and/or sleep 
 
The investigator will assess the LTA for signs according to the following schedule: 
 At Visits 2 and 5, when a study medication application is performed at the investigational 
center, perform the LTA for each sign prior to the start of the study medication applications 
and 20 (±4) minutes after the Application Completion Time.  
 At Visits 3, and 4, when no study medication application is performed at the investigational 
center, perform the LTA for each sign anytime during the visit. 
 
The subject will assess the LTA for symptoms according to the following schedule: 
 At Visits 2 and 5, when a study medication application is performed at the investigational 
center, perform the LTA for each symptom just prior to the start of the study medication 
applications and 10 (±4) minutes after the Application Completion Time  
 At Visits 3 and 4, when no study medication application is performed at the investigational 
center, assess the LTA for each symptom over the previous 24 hours anytime during the 
visit. 
 
Both the subject and the investigational center staff member will initial and date the source 
document to indicate the subject performed the LTA as instructed. The subject will mark the 
LTA grade for each symptom on each Target cNF on the appropriate source document. The staff 
member assisting the subject with the LTA assessment must not influence the subject’s 
assessment. 
 
6.1.4 Medical history 
At Visit 1, the investigator or designee, for each subject will collect medical history including 
all medical conditions and disease states that: 
 Are ongoing 
 Require concomitant therapy 
 Are, in the investigator’s opinion, relevant to the subject’s study participation 
 
At Visit 2, prior to randomization, the investigator will update the subject’s medical history. 


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6.1.5 Physical Examination 
At Visit 1, the investigator or designee will perform a complete physical examination for the 
subject that will include, at a minimum, the following body systems and organs: 
 General appearance 
 Skin 
 Abdominal 
 Extremities 
 Cardiovascular 
 Gastrointestinal/hepatobiliary 
 Musculoskeletal 
 Head, eyes, ears, nose and throat 
 Lymphatic 
 Neurological 
 Respiratory system. 
 
6.1.6 Vital Signs 
A qualified investigational center staff member will measure the following vital signs for each 
subject at the Visits 1, 2 (randomization), 5 and 7.  
 
At Visit 2, the vital signs must be measured prior to randomization: 
 Body temperature 
 Pulse rate 
 Respiration rate 
 Blood pressure (systolic and diastolic) after the subject sits quietly for at least 5 minutes 
 Height (at Visit 1 only) 
 Weight (at Visit 1 only). 
 
Any measure that is, in the opinion of the investigator, abnormal AND CR must be recorded as 
history if found prior to the start of the first study medication application at or as an AE if found 
after the first study medication application begins. 
  
A systolic blood pressure >140mm Hg or a diastolic blood pressure >100mm Hg is considered 
abnormal and therefore must be defined as CR or NCR in the CRF.  
 
A weight >300 lbs. is considered abnormal and therefore must be defined as CR or NCR in the 
CRF.  


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6.1.7 Urine pregnancy tests 
At Visits 1, 2 (prior to randomization) and 5, the investigator or designee will perform a urine 
pregnancy test for subjects who are WOCBP. The urine pregnancy test kits used must have a 
minimum sensitivity of 25-mIU ß-HCG/milliliter (mL) of urine.  
 
Subjects who are WOCBP must have a negative pregnancy test result at the Visit 1 to be enrolled 
in the study and at Visit 2 to be randomized. 
 
If the result of any post-treatment urine pregnancy test is positive, the subject will be withdrawn 
from the study and the subject’s pregnancy documented and followed. 
 
6.1.8 Electrocardiogram 
A 12-lead ECG will be performed by a qualified investigational center staff member at the Visits 
1, 2 (prior to randomization) and 5.  
 
The ECGs must be obtained using a 12-lead ECG with a 10mm/mV amplitude, at 25mm/sec and 
5-10 second duration. To ensure a steady heart rate the subject must rest quietly in the supine 
position for at least 5 minutes prior to performing the ECG.  
 
The following parameter, at a minimum, will be determined: 
 Heart rate 
 RR interval 
 PR interval 
 QRS interval 
 QT and QTc. 
 
A normal ECG is defined as:  
 QTc 450msec for males and 460msec for females (use of the ECG algorithm is 
acceptable for this purpose) 
 Heart rate that is ≥50 and ≤100 beats/minutes 
 The tracing must not show any: 
o Rhythm disturbance other than a benign sinus dysrhythmia 
o Conduction disturbance including First Degree A-V Block (PR >200msec) and pre-
excitation (PR <120msec) 
o Acute or chronic signs of ischemia.   
 


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Variations such as minor ST changes (i.e., <0.5mm depression) and early re-polarization are 
considered normal.  
 
The ECG results must be interpreted by a qualified health professional, the evaluator, and the 
interpretation reported either directly on the tracing or in a separate report. The evaluator and the 
investigator or designee may be the same person. 
 
The investigator or a designee must review the ECG reports in a timely manner and in all cases 
prior to the next study visit. If an ECG result is defined as abnormal by the evaluator the 
investigator or designee should define the abnormality as CR or NCR. The investigator will 
record this information directly on the ECG tracing/report and date and initial the tracing/report. 
 
The subject must not be randomized if the Visit 1 ECG is, in the evaluator’s opinion, abnormal, 
regardless of the clinical relevance.   
 
The investigator must report ECG results that are BOTH abnormal AND CR as medical history 
if found prior to the first study medication application or as an AE if found after the first study 
medication application begins.  
 
6.2 
Efficacy Assessments 
The following efficacy assessments will be conducted by the appropriate investigational 
center staff and according to the noted schedules. 
 
6.2.1 Target cNF dimensions 
At Visits 1, 2 and 5, the investigator will measure the diameter and the height (thickness) 
above surrounding skin, in millimeters (mm), of each subject’s 5 Target cNF Tumors to the 
nearest 0.1mm using the provided ruler or equivalent. The diameter is the length of the 
longest dimension of the Target cNF Tumor parallel to the surrounding skin. The height is the 
maximum height of the tumor above the surrounding skin. 
 
At Visit 1, to be enrolled in the study, and at Visit 2, to be randomized, each subject must 
have 5 Target cNF Tumors with a diameter ≥5mm and ≤10mm and a height ≥2mm.  


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At Visit 1 only, the Untreated cNF Tumor must be measured to confirm a diameter ≥5mm and 
≤10mm and a height ≥2mm. 
 
6.2.2 Target cNF ultrasounds 
At select sites at Visits 2 (randomization) and 5, an investigational center staff member other 
than the investigator will perform a high frequency ultrasound (HFUS) imaging on each 
Target cNF. The HFUS must be taken prior to the study medication application at the visit.  
 
The HFUS results will be used to determine the volume of the Target cNF. 
HFUS imaging will be performed using an appropriate HFUS system (e.g., Vevo3100, GE Logiq E, 
etc.).  
 
The HFUS operator will be trained by the investigator or a subinvestigator in the proper device 
calibration and operation. This training will be documented in the study file. Equipment, 
supplies, training and detailed instructions for obtaining and managing the ultrasound images 
will be provided to the investigational center prior to the initiation of subject enrollment.  
 
6.2.3 Subject’s Self-Assessment (SSA) 
The SSA is the subject’s assessment of the average overall severity of each Target cNF at a 
particular time point and is not a comparison with the SSA at any other time point. The subject 
should NOT refer to any other evaluation to assist with these assessments.  
 
At Visits 2 and 5, each subject will assess each Target cNF Tumor using the scale below and report 
the one integer that best describes the average overall severity of the Target cNF Tumor. The 
subject must complete the SSA prior to the study medication application and prior to the PTA 
assessment at the visit. 
 
An investigational center staff member other than the investigator must educate the subject on the 
SSA scale before each evaluation. 
 
To perform the SSA an investigational center staff member other than the investigator will identify 
the Target cNF Tumor being assessed to the subject and direct the subject to assess the tumor. The  


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staff member must not influence the subject’s assessment. The study staff member will report the 
SSA grade the subject indicates for the Target cNF Tumor in the source document.  
 
This process will be repeated until the subject has assessed all 5 Target cNF Tumors. 
 
Both the subject and the study staff member must sign/initial the source document to indicate the 
subject performed the SSA as instructed. 
 
The subject and the investigator must not discuss the subject’s SSA grade and the subject must 
complete the assessment before the investigator performs the PTA at the visit. 
 
Subject’s Self-Assessment 
Grade 
Descriptor 
0 
Clear: no visible cNF tumor
1 
Almost Clear: a barely visible cNF tumor that is not noticeable (or do you think 
“bothersome” is better here)
2 
Mild: a slightly visible cNF tumor that is somewhat noticeable 
3 
Moderate: an obviously visible cNF tumor that is more noticeable than I prefer
4 
Severe: a prominently visible cNF tumor that is completely unacceptably 
noticeable 
 
6.2.4 Physician’ Tumor Assessment (PTA) 
The PTA is the investigator’s assessment of the average overall severity of each Target cNF Tumor 
at a particular time point. The investigator should NOT refer to any other assessments to assist with 
these assessments.  
 
At Visits 2 and 5, the investigator will conduct the PTA for each Target cNF Tumor using the scale 
below and report the one integer that best describes the average overall severity of each Target cNF 
Tumor. The investigator must complete the PTA prior to the study medication application and after 
the subject completes the SSA at the visit. 
 
 


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Physician’s Tumor Assessment 
Grade 
Descriptor 
0 
Clear/None: no visible cNF tumor (barely perceptible pigmentary changes may be 
present) 
1 
Almost Clear: a visible, macular (not raised above the surrounding skin), cNF 
tumor 
2 
Mild: a cNF tumor that is raised above the surrounding skin, tumor height that is 
less than half the diameter, tumor is soft and easily compressible 
3 
Moderate: a raised dome shaped cNF tumor, tumor height is greater than half the 
diameter, tumor is moderately firm and somewhat compressible 
4 
Severe: a raised dome shaped cNF tumor, tumor height is greater than half the 
diameter, tumor is very firm and only minimally compressible 
 
6.3 
Other Assessments 
6.3.1 Demographics 
At Visit 1, the investigator or designee, will collect demographic information for the subject 
including date of birth, race, ethnic group and sex at birth according to local regulations. For 
countries where local regulatory guidelines prohibit capture of full date of birth, partial date 
will be recorded in line with local regulations. In addition, medical and surgical history, NF1 
history, and concomitant illness(es) will be recorded. 
 
6.3.2 Pharmacokinetic blood samples 
At select sites at Visits 2 and 5, blood samples for Pharmacokinetic (PK) analysis of NFX-179 
and p-ERK levels will be collected by a qualified investigational center staff member.  
 
At select sites at Visit 2, a blood sample for PK analysis will be collected at just prior to the first 
study medication application. 
 
At select sites at Visit 5, blood samples for PK analysis will be collected at: 
 0-hour; taken 24 (±6) hours after the previous study medication application and just prior 
to the last study medication application 
 30 minutes (±2 minutes) after the Application Completion Time  
 1 hour (±4 minutes) after the Application Completion Time  
 2 hours (±4 minutes) after the Application Completion Time 
 4 hours (±4 minutes) after the Application Completion Time. 
 
 
 


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Detailed instructions for the collection, labeling, handling, processing, storage and shipment of 
the PK blood samples will be provided to the select investigational center prior to the initiation 
of subject enrollment.   
 
6.3.2.1 Study nourishment 
At Visit 5, subjects will be confined at the investigational center: 
 For PK blood sampling at select sites 
 For excision samples at all sites 
 
The investigator will provide subjects with meals, snacks and beverages as appropriate, at times 
that do not conflict with other study-related activities. Subjects may consume water on an ad 
libitum basis throughout these visits.  
 
6.3.3 Study cNF Tumor excision for p-ERK levels 
At Visit 5, 4 (±1) hours after the Application Completion Time for the last study 
medication application, the investigator will excise all 6 Study cNF Tumors (5 Target cNF 
Tumors and 1 Untreated cNF Tumor) to provide tissue samples to assess for p-ERK levels. 
 
For each of the 6 Study cNF Tumors the investigator will shave excise the entire tumor and 
cut the tissue into 2 halves vertically ensuring that each half contains epidermis and dermis. 
Half the tissue sample will be immediately frozen, and half will be preserved in formalin 
following the instructions below:  
 Frozen sample: 
o Immediately freeze half the tissue in liquid nitrogen using forceps to immerse 
tissue in liquid nitrogen for ~10 seconds 
o Place the frozen tissue in a 2mL screw cap cryovial 
o Immediately freeze on dry ice 
o Store the sample at -80ºC until shipment. 
 
 
 


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 Formalin preserved sample: 
o Within 30 minutes transfer half the tissue to a container prefilled with 10% 
neutral-buffered formalin 
o Store at room temperature until shipment. 
 
The tissue forceps, cryovials and prefilled containers of formalin will be supplied to each 
investigational center. 
 
Each sample will be shipped to a NFlection selected laboratory for evaluation of p-ERK 
levels. Detailed instructions for labeling, storing and shipping the tissue samples will be 
provided to each investigational center prior to the initiation of subject enrollment.  
The investigator will manage the excision wounds following her/his standard of care. All 
therapies associated with the care for the excision wounds (e.g., local anesthesia, topical 
antibiotics, etc.) must be reported as Concomitant Therapies but their use does not need to be 
reported as an AE. If an unexpected event that is not normally associated with the excision 
procedure occurs (e.g., infection, an event that is out of the ordinary in severity or duration) it 
must be reported as an AE, and any associated therapy must be reported as a Concomitant 
Therapy.  
 
At Visit 6, the investigator will see the subject for follow-up on the excision wound care. 
 
6.3.4 Standardized photography 
At Visits 1 (Screening), 2 (Baseline/Randomization) and 5, an appropriately trained investigational 
center staff member other than the evaluating investigator will take standardized 3-dimensional 
(3D) photographs of the Study cNF Tumors. The subject’s identity will not be revealed in the study 
photographs.  
 
The Visit 1 and Visit 2 study images are to document the location of the Study cNF Tumors at to 
assist with locating the tumors at subsequent visits.  
 


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At Visits 2 and 5 the photographs must be taken prior to the study medication application at the 
visit. These images will be used to assess the volume of the Target cNF Tumors above the 
surrounding skin. 
 
The investigator must not be allowed to use the study photographs to assist with any Target cNF 
Tumor evaluations. 
Care must be taken to ensure similar lighting, background, subject positioning relative to the 
camera and camera settings are used for each photograph.  
 
Equipment, supplies, training and detailed instructions for obtaining and managing the 
photographs will be provided to the investigational center prior to the initiation of subject 
enrollment.  
 
6.4 
Total Blood Volume 
The total number of venipunctures and the total volume of blood collected during the study 
will be limited to that need for the safety monitoring and the pharmacokinetic assessments. 
Refer to the laboratory manual(s) for the collection procedures and the total volume of blood 
collected. The total blood volume collected for each subject for the entire study will be 
compliant with World Health Organization guidelines. Safety laboratory tests will be 
prioritized if not all laboratory samples can be collected in compliance with the blood volume 
guidelines. 
 
7 
ADVERSE EVENTS 
All subjects who apply study medication will be assessed for safety. 
The investigator is responsible for monitoring the safety of the subjects who are enrolled in 
this study and for alerting NFlection regarding any event that seems unusual, even if this 
event may be considered an unanticipated benefit to the subject. The investigator is 
responsible for appropriate medical care of subjects during the study. 
 
 
 


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7.1 
Definitions 
7.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign or symptom 
associated with the use of an investigational product (including an abnormal laboratory finding), 
whether or not related to the investigational product.  
 
Thus, any new, CR worsening of an existing sign, symptom or disease, should be considered an 
AE.  
 
Worsening of the any Target cNF assessment should be reported as an AE only if the use of 
the study medication is interrupted or discontinued or other therapy is required to manage 
the event. 
 
Every new episode or clinically relevant worsening of a chronic condition (e.g., headaches, 
allergies, depression, and hypertension) should be reported as a separate AE, even if the 
condition is reported in the subject’s medical history. 
 
The investigator should, when certain, report a diagnosis rather than the signs, symptoms or 
clinically relevant abnormal laboratory values associated with the AE. Otherwise, signs, 
symptoms or abnormal laboratory values may be used to describe the AE. 
 
An abnormality discovered (e.g., clinically relevant laboratory abnormalities), prior to the first 
study medication application, should be reported as medical history, not as an AE. 
 


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7.1.2 Serious Adverse Event (SAE) 
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
 
The term “life threatening” refers to an event in which the subject was at risk of death at the time 
of event; it does not refer to an event that hypothetically might have caused death if it was more 
severe. 
 
Inpatient hospitalization is considered to have occurred if the subject is admitted to the hospital 
on an in-patient basis even if released the same day. Prolongation of hospitalization is defined as 
an additional night stay in the hospital. Hospitalization for a diagnostic test (even if related to an 
AE) or elective hospitalization that was planned before study enrollment are not themselves 
reasons for an event to be defined as a SAE. 
 
Important medical events are those that may not be immediately life threatening, result in death, 
hospitalization but are clearly of major clinical significance and may jeopardize the subject or 
require intervention to prevent one of the outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasia or convulsions that do 
not result in hospitalization. 
 
7.1.3 Unexpected Adverse Event 
An unexpected AE is any AE that the investigator defines as related to a study medication, the 
nature of which is not consistent with the Investigator’s Brochure or package insert. 
 
 
 


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7.1.4 Adverse Events of Special Interest 
The following are considered AEs of special interest, based on the route of administration, 
toxicology profile for NFX-179: adverse events related to kidneys, liver, coagulation, and the 
immune system. Reference is made to the IB for further details. 
 
7.2 
Reporting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the 
subject’s medical record, AE CRF, and SAE form (if applicable), and reported to NFlection. 
The AE CRF can be used to report both AEs and SAEs. If necessary (e.g., in case of failure of 
the Electronic Data Capture, system or for logistical reasons), a paper SAE form may be used 
instead. 
 
7.2.1 Adverse event reporting period 
The investigator must start reporting non-serious AEs from the time of the subject’s first study 
medication application until 30 days after the last study medication application. Reporting for 
SAEs must start when the subject signs the ICF and continue until 30 days past the subject’s last 
study medication application, whether or not they are related to the study. 
7.3 
Assessment of Adverse Events 
The investigator is responsible for assessing the severity, seriousness and causality of AEs. 
 
7.3.1 Severity of Adverse Events 
The investigator is to define the severity of each AE using the following definitions as a 
guideline. The investigator will consider the range of the possible severity of the event and 
identify the severity that is the most appropriate according to her/his medical judgment: 
 
Mild – Awareness of signs or symptom, but easily tolerated 
Moderate – Discomfort, enough to cause interference with usual activity 
Severe – Incapacitating with inability to perform usual activity 
 
 
 


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7.3.2 Relationship to Study Medication 
The investigator will determine if there is a reasonable causal relationship between the study 
medication and an AE or not. The investigator will use her/his best medical judgment and 
consider all relevant factors (e.g., temporal relationship, location of the event, the subject’s 
relevant medical history, concomitant therapies and concurrent conditions) to determine the 
relationship of the AE to the study medication. The investigator will define the relationship of an 
AE to the study medication by selecting one of the following categories: 
Related – There is a reasonable causal relationship between the study medication and the 
AE. 
Not Related – There is not a reasonable causal relationship between the study medication 
and the AE. 
 
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
(evidence) or arguments to suggest a causal relationship. 
 
7.4 
Procedures for reporting non-serious adverse events 
At each post-enrollment visit, the investigator will question the subject to elicit AEs using a non-
directive question such as “Has there been any change in your health since the previous study 
visit?”  If appropriate, based on the subject’s response to non-directed questioning to elicit AEs, 
the investigator will follow-up with directed questions and appropriate evaluations.  
Any AE noted during the reporting period must be reported in the source documents and on the 
appropriate AE CRF. AEs that are defined as “Not Related” to the study medications will be 
followed until they are resolved or until the subject’s last study visit. AEs that are defined as 
“Related” to the study medications will be followed until they are resolved or, if not resolved 
after the subject’s last study visit, until in the opinion of the investigator, the AE reaches a 
clinically stable outcome with or without sequelae. 
 
 
 


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7.5 
Procedures for reporting serious adverse events 
 
NFlection Medical Monitor 
Email: nflectionsae@nflectionrx.com 
24-hour telephone: (302) 559-8684 
Upon becoming aware of a SAE occurring during the AE reporting period, whether or not related 
to the study medications, the investigator must: 
1. Take the appropriate medical action to ensure the subject’s safety. 
2. Immediately inform the Medical Monitor of the SAE by email, ensuring that the subject 
information is deidentified (only subject initials and subject identifier) 
3. Print a copy of the email and place in the study file. 
4. Within 24-hours complete, as fully as possible, an AE CRF and an SAE form; e-mail the 
forms and any other relevant documentation (e.g., concomitant medication CRF, medical 
history CRF, laboratory test results, etc.) to the Medical Monitor. 
5. Monitor and document the progress of the SAE until it resolves or, if not resolved after 
the subject’s last study visit, until in the opinion of the investigator the SAE reaches a 
clinically stable outcome with or without sequelae AND the investigator and NFlection 
Medical Monitor agree that the SAE is satisfactorily resolved. 
6. Inform the NFlection Medical Monitor of SAE updates, via telephone, followed by an 
SAE form update sent by e-mail. 
7. Comply with the appropriate regulatory requirements and NFlection instructions 
regarding reporting of the SAE to the responsible Institutional Review Board (IRB) or 
Ethics Committee (EC). 
 
The investigator will define the severity of every AE as Mild, Moderate, or Severe using the 
following intensity grades definitions: 
Mild – Awareness of signs or symptom, but easily tolerated 
Moderate – Discomfort, enough to cause interference with usual activity 
Severe – Incapacitating with inability to perform usual activity 
 
Note the distinction between an AE with an intensity of “severe” and a “serious” AE, a severe 
event is not necessarily a serious event. For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the SAE criteria. 
 


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7.6 
Pregnancy 
If a female subject becomes pregnant during the treatment period or within 6 months after the 
last study medication application, a Pregnancy Report form should be completed and 
submitted to NFlection within 24 hours of learning of the pregnancy: 
NFlection Medical Monitor 
Email: nflectionsae@nfflectionrx.com 
24-hour telephone: (302) 559-8684 
Abortion, whether therapeutic or spontaneous, will also be reported on a Pregnancy Report 
form and sent to NFlection. If the abortion meets seriousness criteria, this information will be 
captured on the AE CRF and SAE form. 
 
Any congenital anomaly/birth defect in a child born to a female subject should be recorded 
and reported as an SAE. 
 
7.6.1 Woman of Childbearing Potential (WOCBP) 
WOCBP includes any female who has experienced menarche and who has not undergone 
successful surgical sterilization (e.g., hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal. Postmenopausal is defined as ≥12 months with no 
menses without an alternative medical cause.  WOCBP must have a negative UPT at Visit 1 to 
be enrolled in the study and at Visit 2 to be randomized to study medication. 
 
7.6.2 Protocol approved methods of birth control 
The investigator will discuss the potential risk factors associated with pregnancy and the 
importance of maintaining a highly effective method of birth control with all WOCBP. All 
WOCBP must use a protocol approved method of birth control throughout the duration of the 
study and for 30 days after the last study medication application.   
 
 
 


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For this study protocol approved methods of birth control include: 
 Women who are abstinent from reproductive sex as a matter of lifestyle (i.e., women 
having sex with women); or who are abstinent are acceptable methods of contraception 
(as these methods, if followed consistently, are at least as effective as hormonal birth 
control pills) 
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o Oral 
o Transdermal 
o Intravaginal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Implantable  
o Injectable 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system 
 
WOCBP must be on at least 1 protocol approved method of birth control for the following time 
periods prior to Visit 1:  
 Abstinence (≥30 days) 
 Implants (on a stable dose for ≥30 days) 
 Injectables (on a stable dose for ≥30 days) 
 Patches (on a stable dose for ≥30 days) 
 Combined oral contraceptives (on a stable dose for ≥30 days) 
 Intrauterine devices (inserted for ≥30 days). 
 
Prior to trial enrollment the investigator must discuss with all WOCBP the potential risk factors 
associated with a pregnancy during the study and the importance of avoiding pregnancy during 
study participation. The subject must sign an informed consent form documenting this 
discussion.  During the trial, all WOCBP will be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual period). 
If a subject or investigator suspects that the subject may be pregnant prior to study medication 
administration, the study medication must be withheld until the results of a pregnancy test are 
available.  If pregnancy is confirmed, the subject must not receive study medication and must be 
discharged from the study.  
 
If, following the first study medication application it is determined that the subject may have 
been or was pregnant at the time of study medication exposure (including 30 days after the last 


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study medication application) the investigator must immediately notify the NFlection Medical 
Monitor and record the pregnancy on a pregnancy surveillance form. While not an AE or SAE, 
the investigator must report every pregnancy using a pregnancy surveillance form and follow the 
same reporting procedures as described for reporting an SAE. 
 
Protocol-required procedures for trial discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. In addition, the investigator must report 
follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome on the pregnancy surveillance form. Infants should be followed for a minimum of six 
weeks. 
  
8 
STATISTICAL METHODOLOGY 
8.1 
Sample Size Determination 
This is a Phase 2a safety study designed to evaluate the safety, proof of mechanism, 
preliminary efficacy and systemic exposure of NFX-179. A maximum of approximately 48 
subjects with confirmed EN are planned to be randomized in the study. The sample size is 
based on practical considerations. The proposed number of subjects takes into account the 
rarity of the condition and the exploratory nature of the study and is considered adequate to 
fulfill the objectives of the study. 
 
8.2 
Randomization 
Subjects will be randomized with a treatment allocation ratio of 1:1:1:1 (NFX-179 Gel 0.05% 
to NFX-179 Gel 0.15% to NFX-179 Gel 0.50% to Vehicle Gel) for cNF. 
 
8.3 
Statistical Analyses 
8.3.1 General Approach 
All randomized and treated subjects will be assessed in terms of safety and exploratory 
efficacy. 
 
 
 


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Descriptive statistics will be produced on relevant screening and baseline data and on 
demographic characteristics. Safety and exploratory efficacy endpoints will be summarized 
descriptively by treatment (when applicable) and for all subjects combined and may be 
analyzed using appropriate parametric or nonparametric inference tests. The primary outcome 
measure by suppression of p-ERK levels in defined cNF in treatment groups as compared to 
vehicle group after 4 weeks of treatment will be assessed. A comparison between NFX-179 
treated tumors and vehicle treated tumors will also be performed. Summaries and analyses 
will be based primarily on non-missing data. Extent of exposure using serum levels of NFX-
179 will be evaluated. 
 
Details of the proposed statistical analysis will be documented in the Statistical Analysis Plan 
(SAP), which will be written following finalization of the protocol and prior to any unblinding 
of data. 
 
As this is an early phase clinical study, additional exploratory analyses not necessarily 
identified in the SAP may also be performed to support the clinical development program. 
Any post-hoc, or unplanned, analyses not identified in the SAP will be clearly identified in the 
Clinical Study Report in accordance with ICH E3. 
 
8.3.2 Baseline Assessment 
Descriptive statistics will be performed on relevant Visit 1 and Visit 2 data (i.e., data collected 
prior to the treatment administration) and on demographic characteristics. There will be no 
formal comparison of baseline data, that is, no statistical hypothesis testing. 
 
The number and percentage of subjects enrolled in each study site will be presented by 
diseases classification (e.g., cNF generalized severe, cNF, generalized intermediate). 
 
8.3.3 Efficacy Analyses 
The first primary objective is to determine the pharmacodynamic activity of NFX-179 Gel as 
defined by suppression of p-ERK levels in the Target cNF Tumors in the NFX-179 Gel treatment 
groups as compared to Vehicle Gel group after 28 days of QD treatment. This will be assessed 


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by analyzing p-ERK levels at Visit 5 (Week 4). ANOVA models at the subject level will be used 
to compare mean p-ERK level between each active treatment group and the vehicle treatment 
group, with treatment as the independent factor. Within each subject, both the mean and the 
median p-ERK levels will first be calculated across all 5 tumors. The within-subject mean levels 
will be analyzed in the primary ANOVA model. The within-subject median levels will also be 
analyzed in a second ANOVA model to assess whether individual tumor outlier values may have 
an influence on the analysis. Mixed-model repeated measures ANOVA models will also be used 
to analyze p-ERK data at the tumor level. In addition, p-ERK levels from the untreated tumor for 
each subject will be used in exploratory analyses to determine whether the inclusion of this 
reference level in analysis models may increase sensitivity. 
 
The second primary objective is to determine the safety and tolerability of treatment with NFX-
179 Gel (0.05%, 0.15% and 0.50%) or Vehicle Gel applied QD for 28 days of treatment. The 
frequency of dermal safety and tolerability assessments including pain/burning, pruritus, 
erythema, edema, scabbing/crusting, and vesiculation/erosion will be summarized by treatment 
group and visit. All data will be listed. The third primary objective of evaluating adverse events 
will be based on summaries and listings of adverse events by treatment group, as described 
below under Safety Analyses. 
 
The first secondary objective is to determine the clinical efficacy of NFX-179 Gel defined as the 
percent change in neurofibroma volume after 28 days of treatment based on tumor size derived 
from high frequency ultrasound measurements and 3D photographs. This will be analyzed 
analogously to the first primary endpoint. Analyses will be conducted both on the tumor level 
and the subject level, as planned for the first primary endpoint. 
 
The second secondary objective is to measure systemic exposure of NFX-179 gel during the 
clinical study. Plasma concentrations of NFX-179 will be summarized at Visit 5 (Weeks 4) by 
treatment group.  
 
The third and fourth secondary objectives are to determine the clinical efficacy of NFX-179 Gel 
defined as the change from baseline in the Subject’s Self-Assessment grade and Physician’s 


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Tumor Assessment grade, separately, after 28 days of treatment. Appropriate mixed-model 
ANCOVAs will be used to compare, for each treated tumor, change from baseline grade between 
treatment groups, with treatment as the independent factor, baseline value as the covariate, and 
subject as the repeated factor. ANCOVA models will also be performed on the subject level after 
first calculating the within-subject mean values across treated tumors. In addition, for each 
assessment dichotomized analyses will be conducted on the proportion of tumors achieving a 
grade of Clear, and also the proportion of tumors achieving a grade of either Clear or Almost 
Clear, after 28 days of treatment. Treatment groups will be compared to vehicle using 
appropriate mixed-model logistic regression, as well as a Chi-square analysis of within-subject 
averaged results across tumors. 
 
8.3.4 Safety Analyses 
Safety and tolerability will be assessed versus baseline conditions and differences between 
treated tumors. Descriptive statistics will be produced, where applicable. Safety assessments 
will be summarized across all subjects. Summaries will be provided by treatment for tumor 
specific safety assessments. 
 
Extent of exposure using serum levels of NFX-179 will be evaluated. 
Adverse events noted during the study will be coded to system organ classes (SOCs) and 
preferred terms (PTs) using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. The number and percentage of subjects with pre-treatment and treatment emergent 
AEs (TEAEs) will be summarized by SOC and PT. TEAEs will also be presented as on- 
treatment and post-treatment. All AE details will be listed. As the risk profile of NFX-179 in 
humans is unknown and this is a first in human study, all AEs will be considered in 
determining the safety profile of NFX-179 unless obviously unrelated. 
 
Descriptive summaries of laboratory assessments will be presented for each time point, for 
actual values and changes from baseline. 
 
Other safety assessments, such as physical examination will also be summarized. 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) drug dictionary. Prior and concomitant medications will be listed and summarized by 


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preferred drug name. 
 
8.4 
Missing Data 
Summaries and analyses will be based primarily on non-missing data, with the number of 
non-missing observations included in the summary. Any additional methods to handle 
missing data will be provided in the SAP. 
 
8.5 
Sub-Group Analyses 
Exploratory investigations may be carried out based on country, age, cNF classification and 
other factors identified in the SAP. 


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9. 
TRAINING, DATA HANDLING AND RECORD KEEPING 
9.1. 
Training 
For each investigational center, participants will be trained to the protocol, study specific 
procedures, and the CRFs. Those unable to attend the training must receive on-site training from 
an appropriately trained individual prior to participating in any of the procedures and evaluations 
in this study.  
Clinical Research Associates (CRAs) and other applicable personnel will be trained prior to 
study initiation to familiarize CRAs with the disease, the Standard Operating Procedures (SOPs), 
the protocol and other study specific items.  Team organization, communication and operational 
issues will also be discussed. 
NFlection will provide an investigational center file to each center. 
 
9.2. 
Data Collection 
The investigator must maintain required records for all study subjects.  Data for this study will be 
recorded in the subject's source document and on the eCRFs.  All data on these CRFs should be 
recorded completely and promptly.  A copy of the completed eCRFs for each subject will be 
retained by the investigational center. 
 
Records of the subject’s participation in this study will be held confidential except as disclosure 
is required by law. The study doctor, NFlection, persons working on behalf of NFlection, and 
under certain circumstances, the United States Food and Drug Administration and the 
Institutional Review Board will be able to inspect and copy confidential study-related records 
that identify subjects by name. Therefore, absolute subject confidentiality cannot be guaranteed. 
If the results of this study are published or presented at meetings, the subject’s identity will not 
be revealed. 
 
9.3. 
Data Management 
Data Management activities of this study will be subcontracted.  Edit checks and review 
processes will be performed by the sub-contractor until all data clarifications are resolved. The 
data will be exported to be stored in SAS datasets (or equivalent) by the sub-contractor. After all 


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data clarifications are resolved and subject’s evaluability is determined, the database will be 
locked. 
9.4. 
Study Monitoring 
Before an investigational center can enter a patient into the study, a representative of NFlection 
will visit the investigational study site to: 
 Determine the adequacy of the facilities 
 Discuss with the investigator(s) and other personnel their responsibilities regarding 
protocol adherence, and the responsibilities of NFlection or its representatives.  This will 
be documented in a Clinical Study Agreement between NFlection and the investigator. 
 
During the study, a monitor from NFlection or representative will have regular contacts with the 
investigational center, for the following: 
 Provide information and support to the investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational center staff is adhering to the protocol, that data are 
being accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
 Perform source data verification.  This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each patient (e.g., clinic charts). 
 Record and report any protocol deviations not previously sent to NFlection 
 Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to NFlection and those SAEs that met criteria for reporting have 
been forwarded to the IRB 
 
The monitor will be available between visits if the investigator(s) or other investigational 
center staff needs information or advice. 
 
9.5. 
Source Documentation 
Investigators must keep accurate separate records (other than the CRFs) of all subjects' visits that 
include all pertinent study related information.  A statement should be made indicating that the 
subjects have been enrolled in this clinical study and have provided written informed consent.  
Any AEs must be completely documented. Source documentation includes results of any 
diagnostic tests conducted during the study.   


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9.6. 
Inspection of Records 
 
NFlection individual or designee will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The investigator agrees to allow 
the monitor to inspect the drug storage area, study medication stocks, drug accountability 
records, subject charts and study source documents, and other records relative to study conduct. 
 
9.7. 
Retention of Records 
The investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for NFlection or the 
Regulatory Authority to review any documentation relating to the study, the investigator must 
permit access to such records. 


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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study is conducted under the sponsorship of NFlection in compliance with the applicable 
regulatory requirements as well as applicable ICH guidelines, Declaration of Helsinki, and in 
respect of the sponsor and/or sub-contractor SOPs for study conduct and monitoring. 
Audits may be carried out by NFlection or designee, and inspections may be performed by 
regulatory authorities or IRB/ECs before, during or after the study.  The investigator will provide 
the auditing/inspecting group direct access to all study records (e.g., eCRFs, subject medical 
records, study medication dispensing records) and the investigational center study facilities. The 
investigator and investigational center staff will be available and will assist the 
auditing/inspecting groups as appropriate. 


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11. 
ETHICS 
11.1. 
Ethics Review 
This protocol, informed consent form, any information provided to subjects, subject-recruiting 
advertisements, and any amendments to these items will receive IRB/EC approval prior to use. 
The IRB/EC must receive a copy of the Investigator’s Brochure, all protocol amendments, safety 
reports and other study related information as required by regulation or the IRB/EC procedures. 
 
11.2. 
Ethical Conduct of the Study 
The rights, safety and well-being of the subjects are the most important considerations in this 
study and take priority over the interests of society and science.  
 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, the current ICH E6 GCP guideline, local regulatory requirements and, at 
US investigational centers, in compliance with the HIPAA. The study will be conducted in 
compliance with the IRB/EC approved version of the protocol and any applicable amendments. 
 
11.3. 
Written Informed Consent 
The investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. The investigator(s) must maintain the original, signed Informed Consent Form.  A 
copy of the signed Informed Consent Form must be given to the subject. 
 
11.4. 
Study Conduct and Protocol Amendments 
With the exception of eliminating an immediate hazard to a subject, the investigator should not 
deviate from the protocol or implement any changes without prior written approval from the 


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sponsor representative or designee and prior review and documented approval from the IRB/EC. 
 
Changes that involve only logistical or administrative changes are allowed.  The investigator 
should document and explain any deviation from the protocol.  A protocol deviation is a non-
adherence to protocol-specific study procedures or schedules that does not increase the risk to a 
study subject and does not affect the scientific integrity of the study.   
 
A protocol violation is defined as any divergence from the protocol-specific study procedures or 
schedules that may results in an increased risk to a study subject or that affect the scientific 
integrity of the study.  All protocol violations must be reviewed by the sponsor Medical Monitor 
and reported to the IRB by the investigator, as directed by the IRB-specific procedures. 
 
11.5. 
Regulatory Documents 
The investigator must maintain a study file containing current and complete regulatory 
documentation in compliance with the current ICH E6 GCP guideline. This file will be reviewed 
as part of the routine monitoring for this study. 
 
11.6. 
Contractual Requirements 
A contractual agreement will be signed between NFlection and each investigator.  This document 
will contain supplemental information, including financial terms, confidentiality, study schedule, 
third party responsibility, and publication rights. 

Prot_003.pdf: 
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Protocol No. NFX-179-NF1-201; Amendment No. 3 
Date: 01-APR-2021 
 
 
Page 1 of 5 
 
 
Supersedes: NEW 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Phase 2a 
Study to Determine Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamic Activity of NFX-179 Gel in Subjects with Cutaneous 
Neurofibromas 
 
Protocol No. NFX-179-NF1-201 
Protocol/Amendment Date: 01-APR-2021 
Amendment No.: 3 
Supersedes: N/A 
Sponsor: NFlection Therapeutics  
714 Woodcrest Road,  
Wayne, PA 19087  
United States 
Medical Monitor: Guy Webster, M.D. Ph.D. 
24-hour telephone: (302) 559-8684 
Email: GWebster@Nflectionrx.com 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains proprietary and confidential information of NFlection Therapeutics. Acceptance of this 
document constitutes agreement by the recipient that no previously unpublished information contained herein 
will be published or disclosed without the prior written approval of NFlection Therapeutics with the exception 
that this document may be disclosed to study staff under your supervision who need to know the contents for 
conducting the study and to appropriate Institutional Review Boards /Ethics Committees under the condition that 
the staff have agreed to keep this information confidential. The foregoing shall not apply to disclosure required 
by governmental regulations or laws, however, NFlection Therapeutics shall be promptly notified of any such 
disclosure.
 
 
 


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Supersedes: NEW 
PROTOCOL AMENDMENT INVESTIGATOR SIGNATURE PAGE 
Protocol Number: NFX-179-NF1-201 
Amendment Number: 3 
 
INVESTIGATOR COMMITMENT: 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by NFlection to the investigational center staff under my supervision. I 
will discuss this material with them to ensure that they are fully informed about the 
Investigational Medicinal Product and the study protocol. 
I agree to conduct this clinical study according to the attached protocol, except when mutually 
agreed to with NFlection in writing. I also agree to conduct this study in compliance with all 
local regulatory requirements, Good Clinical Practices, as well as with the requirements of the 
appropriate Institutional Review Board(s) /Ethics Committee(s) and any other Institutional 
requirements. 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
 
 


PROTOCOL AMENDMENT APPROVAL PAGE
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TABLE OF CONTENTS 
 
PROTOCOL AMENDMENT INVESTIGATOR SIGNATURE PAGE .............................. 2 
PROTOCOL Amendment APPROVAL PAGE ...................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 4 
1 
AMENDMENT HISTORY ............................................................................................ 5 
2 
AMENDMENT SUMMARY ......................................................................................... 5 
3 
AMENDMENT RATIONALE ...................................................................................... 5 
4 
PROTOCOL CHANGES............................................................................................... 5 
 
 
 
 
 
 
 
 
 
 
 


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1 
AMENDMENT HISTORY 
Revised protocol 1 footer date: 24-JUL-2020 
Previous amendments: Amendment 2, footer date 25-MAR-2021 
 
2 
AMENDMENT SUMMARY 
The following section of the NFX-179-NF1-201 revised protocol (footer date 24-JUL-2020) as 
modified by amendment 2 (footer date 25-MAR-2021) and with a final NFlection Therapeutics 
approval signature date of 27-JUL-2020 is amended: 
 Section 8.3.3 Efficacy analyses. 
 
3 
AMENDMENT RATIONALE 
This protocol change is made to allow for Target cNF Tumors that are found not to be qualifying 
neurofibromas to be excluded from sensitivity analyses of efficacy results. 
 
4 
PROTOCOL CHANGES 
Section 8.3.3 Efficacy analyses: 
Previous paragraph 1: 
“…Tumor volume is the primary measurement of interest; however, the ruler measurements of 
tumor length and height will also be analyzed as described below.” 
 
Changed paragraph 1: 
“…Tumor volume is the primary measurement of interest; however, the ruler measurements of 
tumor length and height will also be analyzed as described below. Any Target cNF Tumors 
confirmed not to be qualifying neurofibromas based on histological evaluation of the excised 
tissue may be excluded from sensitivity analyses of efficacy results.” 
 
 

Prot_002.pdf: 





























Prot_001.pdf: 
Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Amendment No. 1 
Date: 20-JUL-2020 
 
 
Page 1 of 7 
 
 
Supersedes: 17-JUL-2020 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Phase 2a 
Study to Determine Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamic Activity of NFX-179 Gel in Subjects with Cutaneous 
Neurofibromas 
 
Protocol No. NFX-179-NF1-201 
Protocol/Amendment Date: 20-JUL-2020 
Amendment No.: 1 
Supersedes: N/A 
Sponsor: NFlection Therapeutics  
714 Woodcrest Road,  
Wayne, PA 19087  
United States 
Medical Monitor: Guy Webster, M.D. Ph.D. 
24-hour telephone: (302) 559-8684 
Email: GWebster@Nflectionrx.com 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains proprietary and confidential information of NFlection Therapeutics. Acceptance of this 
document constitutes agreement by the recipient that no previously unpublished information contained herein 
will be published or disclosed without the prior written approval of NFlection Therapeutics with the exception 
that this document may be disclosed to study staff under your supervision who need to know the contents for 
conducting the study and to appropriate Institutional Review Boards /Ethics Committees under the condition that 
the staff have agreed to keep this information confidential. The foregoing shall not apply to disclosure required 
by governmental regulations or laws, however, NFlection Therapeutics shall be promptly notified of any such 
disclosure.
 
 
 


Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Amendment No. 1 
Date: 20-JUL-2020 
 
 
Page 2 of 7 
 
 
Supersedes: 17-JUL-2020 
PROTOCOL AMENDMENT INVESTIGATOR SIGNATURE PAGE 
Protocol Number: NFX-179-NF1-201 
Amendment Number: 1 
 
INVESTIGATOR COMMITMENT: 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by NFlection to the investigational center staff under my supervision. I 
will discuss this material with them to ensure that they are fully informed about the 
Investigational Medicinal Product and the study protocol. 
I agree to conduct this clinical study according to the attached protocol, except when mutually 
agreed to with NFlection in writing. I also agree to conduct this study in compliance with all 
local regulatory requirements, Good Clinical Practices, as well as with the requirements of the 
appropriate Institutional Review Board(s) /Ethics Committee(s) and any other Institutional 
requirements. 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
 
 




Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Amendment No. 1 
Date: 20-JUL-2020 
 
 
Page 4 of 7 
 
 
Supersedes: 17-JUL-2020 
TABLE OF CONTENTS 
 
PROTOCOL AMENDMENT INVESTIGATOR SIGNATURE PAGE .............................. 2 
PROTOCOL Amendment APPROVAL PAGE ...................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 4 
1 
AMENDMENT HISTORY ............................................................................................ 5 
2 
AMENDMENT SUMMARY ......................................................................................... 5 
3 
AMENDMENT RATIONALE ...................................................................................... 5 
4 
PROTOCOL CHANGES............................................................................................... 6 
 
 
 
 
 
 
 
 
 
 
 


Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Amendment No. 1 
Date: 20-JUL-2020 
 
 
Page 5 of 7 
 
 
Supersedes: 17-JUL-2020 
1 
AMENDMENT HISTORY 
Protocol footer date: 25-MAY-2020 
Previous amendments: None 
 
 
2 
AMENDMENT SUMMARY 
The following sections of the NFX-179-NF1-201 protocol with footer date 15-MAY-2020 and 
with a final NFlection Therapeutics approval signature date of 27-MAY-2020 are amended: 
 PROTOCOL APPROVAL PAGE (page 3 of 77) 
 Section 4.8 Subject discontinuation from the study 
 Section 5.2.3 Visits 3 and 4/Days 8 and 15 (QD treatment) 
 Section 5.3 Study cNF tumor identification 
 Section 6.2.2 Target cNF ultrasounds 
 Section 6.3.1 Demographics. 
 
 
3 
AMENDMENT RATIONALE 
These protocol changes are made to: 
 Correct a typographic error to the protocol number on the PROTOCOL APPROAL PAGE 
 Respond to recommendations from the Food and Drug Administration; changes to section 
4.8 
 Correct an error which instructs the investigator to take standardized photographs at Visits 
3 and 4; changes to protocol section 5.2.3 
 Add the requirement that for each subject Target cNF Tumor number 5 be on the face; 
changes to protocol section 5.3 
 Update the description of the high frequency ultrasound equipment that may be used; 
changes to section 6.2.2 
 Correct a typographic error; changes to section 6.3.1. 
 
 
 
 


Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Amendment No. 1 
Date: 20-JUL-2020 
 
 
Page 6 of 7 
 
 
Supersedes: 17-JUL-2020 
4 
PROTOCOL CHANGES 
PROTOCOL APPROVAL PAGE (page 3 of 77): 
Previous protocol number: 
NFX-179-NF-201. 
 
Changed protocol number: 
NFX-179-NF1-201. 
 
 
Section 4.8 Subject discontinuation from the study: 
Previous paragraph 2: 
The investigator may remove a subject from the study if, in the investigator's opinion, it is not in 
the best interest of the subject to continue the study. Examples of other reasons subjects may be 
discontinued from the study are a change in compliance with an inclusion or exclusion criterion, 
occurrence of AEs, occurrence of pregnancy or use of a prohibited therapy. Notification of 
discontinuation will immediately (within 24 hours) be made to the NFlection study monitor.  
 
Changed paragraph 2: 
The investigator will remove a subject from the study if, in the investigator's opinion, it is not in 
the best interest of the subject to continue the study. The investigator must remove a subject from 
the study if the subject experiences: 
 A Serious Adverse Event the investigator defines as related to the study medication, 
regardless of the intensity of the event 
 A non-serious adverse event the investigator defines as related to study medication that 
has a severity of severe and requires treatment to resolve.  
 
Examples of other reasons subjects may be discontinued from the study are a change in 
compliance with an inclusion or exclusion criterion, occurrence of AEs, occurrence of pregnancy 
or use of a prohibited therapy. Notification of discontinuation will immediately (within 24 hours) 
be made to the NFlection study monitor. 
 
 
Section 5.2.3 Visits 3 and 4/Days 8 and 15 (QD treatment): 
Previous procedure 7: 
Take standardized color photographs of each Target cNF Tumor. 
 
Changed procedure 7: 
Procedure 7 is deleted. 
 
 
 


Proprietary and Confidential 
Protocol No. NFX-179-NF1-201; Amendment No. 1 
Date: 20-JUL-2020 
 
 
Page 7 of 7 
 
 
Supersedes: 17-JUL-2020 
Section 5.3 Study cNF tumor identification: 
Previous paragraph 3 major bullet 3: 
 Face: 
o Vertically from the mandibular ridge to the hairline (for subjects with a receding 
hair the hairline is defined by a vertical lie drawn coronally from tragus to tragus) 
o Horizontally from tragus to tragus, excluding the eyelids and areas within 5mm of 
the orbital rim. 
Changed paragraph 3 major bullet 3: 
 Face (Target cNF Tumor #5 must be on the face): 
o Vertically from the mandibular ridge to the hairline (for subjects with a receding 
hair the hairline is defined by a vertical lie drawn coronally from tragus to tragus) 
o Horizontally from tragus to tragus, excluding the eyelids and areas within 5mm of 
the orbital rim. 
  
Previous paragraph 5 bullet 5: 
 Target cNF Tumor #5/green ID stickers 
  
Changed paragraph 5 bullet 5: 
 Target cNF Tumor #5/green ID stickers (Target cNF Tumor #5 must be on the face). 
 
 
Section 6.2.2 Target cNF ultrasounds: 
Previous paragraph 2: 
The HFUS results will be used to determine the volume of the Target cNF. HFUS imaging 
will be performed using the Vevo3100 System.  
 
Changed paragraph 2: 
The HFUS results will be used to determine the volume of the Target cNF. HFUS imaging 
will be performed using an appropriate HFUS system (e.g., Vevo3100, GE Logiq E, etc.).  
 
 
Section 6.3.1 Demographics: 
Previous paragraph 1 sentence 3: 
In addition, medical and surgical history, EN history, and concomitant illness(es) will be 
recorded.  
 
Changed paragraph 1 sentence 3: 
In addition, medical and surgical history, NF1 history, and concomitant illness(es) will be 
recorded. 

ICF_004.pdf: 
NFlection Therapeutics, Inc./ Protocol Number NFX-179-NF1-201 
Page 1 of 17   
 
«PiFullName» 
Version 03 June 2020 
Revised «PIApprovalDate» 
 
INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
NFlection Therapeutics, Inc. / “A Randomized, Double-
Blind, Vehicle-Controlled, Parallel Group Phase 2a 
Study to Determine Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamic Activity of 
NFX-179 Gel in Subjects with Cutaneous 
Neurofibromas ” 
 
Protocol Number: 
 
NFX-179-NF1-201 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
INTRODUCTION 
Before agreeing to participate in this research study, it is important that you read and 
understand the following explanation of the proposed research study. This consent 
document describes the purpose, procedures, benefits, risks, discomforts and 
precautions of the study. It also describes the alternative procedures that are available 
to you and your right to withdraw from the study at any time. No guarantees or 
assurances can be made as to your results in this study. 
 
If you are not completely truthful with your study doctor regarding your health history, 
you may harm yourself by participating in this study. 
 
The study is being conducted for NFlection Therapeutics. Your study doctor is being 
paid by NFlection Therapeutics (the Sponsor) to conduct this study.  
 
Advarra IRB Institutional Review Board (IRB) has approved the information in this 
consent document and has given approval for the study doctor to do the study. An IRB 
is an independent committee established to help protect the rights of research 
subjects. Although Advarra IRB has approved the information provided in this informed 
consent form and has granted approval for the study doctor to conduct the study, this 
does not mean the IRB has approved your participation in the study. You must think 
about the information in this consent document for yourself and then decide if you want 
to be in the study. 
 
Please read this form carefully. Take your time to ask the study doctor or study staff as 
many questions about the study as you would like. The study doctor or study staff can 
explain words or information that you do not understand. Reading this form and talking 


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Revised «PIApprovalDate» 
 
to the study doctor or study staff may help you decide whether to take part or not. If you 
decide to take part in this study, you must sign your name at the end of this form and 
date it. 
 
BACKGROUND AND PURPOSE  
You are being asked to participate in this research study because you are clinically 
diagnosed neurofibromatosis type 1 (NF1) with cutaneous neurofibromas (cNF) present 
on your skin.  
 
NF1 is caused by mutations in the NF1 gene, which can result in cNF anywhere on the 
body. A new topical (applied to the skin) investigational formulation, NFX-179 Gel, is 
being developed to treat cNF. An investigational formulation is a study drug that is not 
approved by the US Food and Drug Administration (FDA). This investigational 
formulation of NFX-179 may or may not reduce the size of cNF. 
 
The purpose of this study is to assess the safety, tolerability, pharmacokinetics (how 
much study drug is in your blood) and pharmacodynamic (what the study drug does to 
your body) properties of three strengths of NFX-179 Gel when applied to cNF compared 
to a matching Vehicle Gel. The Vehicle Gel is the same formulation as the NFX-179 Gel 
but does not contain any active drug. The skin’s response to the gels will be evaluated 
and information on any side effects that may occur will be collected and evaluated. In 
addition the amount of active ingredient that enters your blood stream 
(pharmacokinetics) will be determined. The gels will be referred to as the ‘study drugs’ 
in this document. 
 
This is the first time NFX-179 Gel will be applied on humans. 
 
The study doctor will identify five cNF, called the Target cNF, that you will treat and the 
study doctor will evaluate during this study. One of the five Target cNF must be located 
on your face. 
 
Photographs of the Target cNF are required for you to participate in this research study. 
Your identity will not be revealed in these photographs or in any information included 
with them. The Sponsor is taking actions to ensure you will remain unidentifiable in the 
study photographs (for example, using a code and not your name to identify you) 
however there is still a possibility you could be identified. 
 
If you do not want photographs of your cNF taken you will not be allowed to 
participate in this study.   
 
The photographs taken during the study may be used for research purposes related to 
the study and for presentation at regulatory agencies, at scientific meetings and, for 
scientific publications. In addition the photographs may be used for general corporate 
purposes or for marketing purposes. 
 


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«PiFullName» 
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During Visit 3 you will be randomly assigned by chance (like the flip of a coin) to receive 
either NFX-179 Gel 0.05%, NFX-179 Gel 0.15%, NFX-179 Gel 0.50% or Vehicle Gel. 
You have an equal chance of being in any of the four groups. You will treat the Target 
cNF with the same study drug once-daily throughout the 4-week study treatment period. 
 
This is a double-blind study, which means neither you nor the study doctor will know 
which of the study drugs you are assigned to receive. In case of an emergency, 
however, the study doctor can get this information.  
 
NUMBER OF SUBJECTS / LENGTH OF PARTICIPATION  
About 48 subjects will participate in this study at approximately 6 study centers in the 
United States (US). Your participation in this study will last approximately 88 days and 
includes 7 study visits to the study center. 
 
You are being invited to participate in this research study because you are 18 years of 
age or older and have been diagnosed with cNF. Research subjects must meet certain 
criteria to participate in this study. 
 
Female subjects must not be pregnant or nursing and must either be of non-
childbearing potential. Women of non-childbearing potential must have undergone 
successful surgical sterilization (hysterectomy (removal of uterus), bilateral tubal ligation 
(having your tubes tied) or bilateral oophorectomy (removal of ovaries) or be 
postmenopausal (defined as having no menses for 12 consecutive months). If a woman 
is of childbearing potential, she must agree to use an effective active form of birth 
control for the duration of the study. Effective methods of birth control are listed in the 
Pregnancy/Birth Control section of this document. 
 
PROCEDURES 
Before any study-related tests or procedures are performed, you will be asked to read, 
sign and date this consent document. The following tests and procedures will be 
performed to determine if you qualify to take part in this study:   
• Visit 1 (Week -4 to 0); Screening: 
o The nature of the study will be reviewed with you 
o It will be determined if you meet all the inclusion and none of the exclusion 
criteria 
o Information about your age, race/ethnicity and medical history including 
any medicines you are using will be collected 
o The study doctor will perform a physical examination 
o An electrocardiogram (ECG, a tracing of your heart rhythm), to evaluate 
your heart’s electrical rhythm will be conducted 
o Blood samples will be collected for routine laboratory evaluation 
o A urine pregnancy test will be performed if you are a woman who can 
have a baby 
o The study doctor will identify and evaluate five cNF (Target cNF) that will 
be treated and evaluated during the study 
o The study doctor will evaluate and measure the Target cNF 


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o Photographs of the Target cNF will be taken 
o A member of the study staff will review the study instructions with you 
o You will be given a subject instruction sheet 
 
• Visit 2 (Week 0); randomization: 
o You will be asked about any changes in your health and the medications 
you are taking since the previous study visit 
o You will be asked if you followed the study instructions since the previous 
study visit 
o You will be asked to complete a Patient Reported Outcome Questionnaire 
(PRO) 
o It will be confirmed that you meet all the inclusion and none of the 
exclusion criteria 
o A urine pregnancy test will be performed if you are a woman who can 
have a baby 
o The study doctor will evaluate and measure the Target cNF 
o If you qualify you will be randomized to a study drug; if you do not qualify 
you will be discharged from the study 
o Photographs will be taken of the Target cNF 
o An electrocardiogram (ECG), to evaluate your heart’s electrical rhythm will 
be conducted 
o A high-frequency ultrasound (a painless test where sound waves are 
delivered through the skin) to evaluate cNF size will be conducted 
o Your vital signs will be measured 
o Blood samples will be collected for routine laboratory evaluation 
o Before the first study drug application a blood sample will be collected for 
evaluation of the study drug’s active ingredient in your blood 
o You will evaluate symptoms of irritation on the Target cNF before the first 
study drug application 
o You will be instructed on the proper technique for applying the study drug, 
then you will be supplied with study drug and make your first application 
while a study staff member watches 
o A study staff member will monitor you for at least 20 minutes to determine 
if you have any adverse events (side effects) to the first study drug 
application 
o After the study drug application, you will evaluate the target cNF for 
symptoms of irritation (such as redness, swelling, pain or itching) 
o Starting the day after this visit you will continue to apply the study drug 
once-daily to the Target cNF for 4 weeks 
o You must apply the study drug to the Target cNF 18-30 hours prior to your 
next study visit 
o A member of the study staff will review the study instructions with you and 
provide you with study drug  
 


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«PiFullName» 
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• Visits 3-4 (Weeks 2 and 3); study treatment period: 
o During this period you will apply the study drug once-daily to the Target 
cNF 
o You must apply the study drug to the Target cNF 18-30 hours prior to 
each study visit 
o You will be asked about any changes in your health and the medications 
you are taking since the previous study visit 
o You will be asked if you followed the study instructions since the previous 
study visit 
o The study doctor will evaluate and measure the Target cNF 
o You will evaluate symptoms of irritation on the Target cNF 
o Photographs will be taken of the Target cNF 
o A blood sample will be collected for evaluation of study drug in your blood  
o A member of the study staff will examine your study drug containers and 
collect and dispense study drug as needed  
o A member of the study staff will review the study instructions with you 
 
• Visit 5 (Week 4); end of the study treatment period: 
o You will be asked about any changes in your health and the medications 
you are taking since the previous study visit 
o You will be asked if you followed the study instructions since the previous 
study visit 
o You will be asked to complete a Patient Reported Outcome Questionnaire 
(PRO) 
o Your vital signs will be measured 
o A urine pregnancy test will be performed if you are a woman who can 
have a baby 
o An ECG, to evaluate your heart’s electrical rhythm will be conducted 
o A high-frequency ultrasound to evaluate cNF size will be conducted 
o Blood samples will be collected for routine laboratory evaluation 
o Before the study drug application at this visit a blood sample will be 
collected for evaluation of study drug in your blood 
o Photographs will be taken of the Target cNF 
o The study doctor will evaluate and measure the Target cNF 
o You will evaluate symptoms of irritation on the Target cNF before the 
study drug application 
o You will make your final study drug application 
o After the study drug application, you will evaluate symptoms of irritation 
the Target cNF 
o After the study drug application, the study doctor will evaluate signs of 
irritation on the Target cNF 
o 30 minutes, and 1, 2, and 4 hours after the study drug application blood 
samples will be collected for evaluation of study drug in your blood 
o The study doctor will remove each (5) Target cNF and one Non-Target 
cNF (not on the face) by excision (using a scalpel) 3-5 hours after the 
study drug application. Excision means that the doctor will cut out the 


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«PiFullName» 
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entire skin lesion using a scalpel (sharp surgical knife).  You will be given 
numbing medication either applied to the skin or injected under the skin 
before the procedure. You may need to have stitches put in following the 
excision. You should ask the doctor to explain this procedure further if you 
have questions. 
o A member of the study staff will collect all of your study drug containers  
o A member of the study staff will review the study instructions with you 
 
• Visit 6 (1-3 weeks after Visit 5) ; excision site care: 
o You will be asked about any changes in your health and the medications 
you are taking since the previous study visit 
o You will be asked if you followed the study instructions since the previous 
study visit 
o Your excision wounds will be managed following the study doctor’s routine 
standard of care 
o A member of the study staff will review the study instructions with you 
 
• Visit 7 (Week 8); end of the study: 
o You will be asked about any changes in your health and the medications 
you are taking since the previous study visit 
o You will be asked if you followed the study instructions since the previous 
study visit 
o You will be discharged from the study 
 
USE OF PHOTOGRAPHS 
Color photographs of your face will be taken throughout the study to document the 
status of the Target cNF. Your identity will not be revealed in these photographs or in 
any information included with them. 
 
If you do not permit the study staff to take photographs of you as described above, then 
you will not be able to participate in this study. If you withdraw from the study or 
withdraw your permission for the study staff to take photographs of your face, you may 
no longer participate in the study and your photographs will no longer be used, except 
to the extent that the photographs have already been published and appear in print, 
broadcast media, internet publications, presentations or journals.  
 
The study photographs may be used for research purposes related to the study and for 
presentation at the FDA, at scientific meetings and, for scientific publications. 
 
In addition, the photographs may be used for general corporate purposes or for 
marketing purposes. 
 
There will be no additional compensation for any photographs of your face.  
 
 
 


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EXPECTATIONS  
While you are in this study, you must: 
• Attend every study visit 
• Follow all the instructions you are given 
• Tell the study doctor about any changes in your health or the way you feel  
• Tell the study doctor if you want to stop being in the study at any time 
 
During the entire duration of the study you must:  
• Continue to use your routine cleansers and cosmetics, but do not start using any 
new ones during the study 
• Do not apply any non-study topical products to the Target cNF within 18 hours 
prior to a study visit 
• Avoid exposing the Target cNF to excessive natural (for example, sunlight) or 
artificial (for example. tanning beds) ultraviolet radiation and use your routine 
sunscreen if excessive exposure cannot be avoided. This is because the study 
drug may make your skin more sensitive to sunlight 
• Bring this instruction sheet to every visit 
 
During the 4-week study treatment period, you must also: 
• Apply the study drug to your Target cNF as directed, once daily, with at least 20 
hours between applications 
• Do not apply the study drug to any open wounds or obviously infected skin 
• On days prior to every study treatment period visit perform your study drug 
application 18 - 30 hours prior to the visit 
• Do not wash or submerge your Target cNF for at least 6 hours after a study drug 
application 
• Do not apply any topical products to your Target cNF for at least 6 hours after a 
study drug application 
• Do not allow anyone else to use your study drug 
• Keep the study drug away from children 
• Store the study drug at room temperature 
• Bring all study drug tubes to every visit 
• Bring this instruction sheet to every visit 
 
RISKS, SIDE EFFECTS AND/OR DISCOMFORTS 
 
Risks of NF-179 Gel: 
This is the first human study of the topical formulation of NFX-179 Gel.  
 
The active ingredient in NFX-179 Gel is a new compound that never been approved for 
marketing or tested in humans. Based on animal studies, where the drug was applied to 
the skin, side effects that might be seen include: 
• Crusting of the skin 
• Swelling 
• Redness 


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• Itching 
• Scaling 
• Scabbing 
 
There are similar drugs, like MEK inhibitors, that are approved as oral (taken by mouth) 
treatment of patients with certain types of metastatic melanoma, a serious type of skin 
cancer. 
 
Common adverse effects associated with the use of these oral study drugs in clinical 
trials include: 
• Skin rash 
• Acne like eruptions 
• Dry skin 
• Itching (pruritus) 
• Inflammation around the fingernails and toenails 
• Diarrhea 
• Tenderness and swelling in the mouth 
• Abdominal pain 
• Swelling of the lymph glands 
• High blood pressure (hypertension) 
• Bleeding of mucous membranes (such as the linings of the nose and mouth) 
• Blood chemistry abnormalities including increased liver enzyme levels (possible 
liver injury), anemia (low red blood cell count which may cause fatigue or 
shortness of breath) and reduce blood albumin levels (may cause swelling) 
 
Due to the anticipated minimal blood levels of NFX-179 associated with the topical 
formulation of NFX-179 it is anticipated that there will be a low frequency of these side 
effects and that if they occur, they will be mild. 
 
Risks of the Vehicle ( inactive part of the gel) 
• Vehicle Gel: The Vehicle Gel does not have any active ingredient. It looks like 
the NFX-179 Gel but is not designed to treat any disease or illness. It is designed 
to be compared with the NFX-179 Gel to learn if the NFX-179 Gel has any real 
effect. If you receive the Vehicle Gel your condition will not be treated with study 
drug and may become worse, stay the same or improve. 
 
Procedure Risks: 
You may feel discomfort during some of the protocol required tests and these tests may 
also have risks, such as: 
• Blood samples:  Possible side effects from blood drawing include faintness, 
inflammation of the vein, pain, bruising, or bleeding at the site of puncture. There 
is also a slight possibility of infection. 
• ECG: You may have mild irritation, slight redness, or itching at the sites on your 
skin where the recording patches are placed. 


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• Skin excisions (removal of cNF with a scalpel): Possible side effects from skin 
biopsies include pain, soreness, and/or tenderness at the excision site, bleeding, 
infection, skin discoloration, and permanent scarring. Removed lesions may grow 
back. Most side effects are temporary. 
 
UNFORESEEN RISKS 
Since NFX-179 Gel is an investigational product, there may be other risks that are 
unknown. All drugs have a potential risk of an allergic reaction, which if not treated 
promptly, could become life-threatening. 
 
RISKS TO THE UNBORN 
Pregnancy/Fetal Risks:  The effects of NFX-179 Gel on a pregnancy, embryo or an 
unborn child are unknown and may be hazardous.   
 
PREGNANCY / BIRTH CONTROL  
If you are pregnant, planning to become pregnant or are breastfeeding a child, you 
cannot participate in this study. 
 
If you are a woman who can have a baby, in order to reduce the risk of pregnancy, you 
must use an effective active method of birth control while you are participating in this 
study, and up to 30 days after the last application of study drug. If you are already using 
a method of birth control, the study doctor or study staff will discuss with you whether 
your current method of birth control is acceptable for use during this study.   
 
For the purposes of this study, the following methods of birth control are considered 
effective and acceptable to use during this study:  
• Combined (estrogen and progestogen containing) oral, transdermal or 
intravaginal hormonal contraception associated with inhibition of ovulation 
• Progestogen-only oral, implantable, injectable, intrauterine device (IUD) or 
hormonal contraception or intrauterine hormone-releasing system associated 
with inhibition of ovulation. 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
 
If you think that you have become pregnant during the study or within 30 days of 
stopping the study drug, it is important that you inform the study doctor immediately. If 
you become pregnant or think that you may be pregnant, you will be removed from the 
study and the study doctor will refer you to seek obstetric care, the cost of which will be 
your responsibility. The study doctor will request to track your pregnancy and will report 
the pregnancy to the Sponsor. 
 
ALTERNATIVE TREATMENT 
There is no approved drug therapy for the treatment of cNF. There are surgical 
treatments available to treat the signs and symptoms of cNF. You should feel free to 
discuss these alternative treatments and the associated risks and the potential benefits 


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for your cNF with the study doctor. You do not have to be in this study to receive these 
treatments for the signs and symptoms of your cNF. 
 
NEW FINDINGS 
Any new important information that is discovered during the study and which may 
influence your willingness to continue participation in the study will be made available to 
you. 
 
BENEFITS 
You may benefit because of your participation in this study. There is, however, no 
guarantee that you will benefit from your participation. Results from this study may 
benefit others in the future.  
 
COMPENSATION FOR PARTICIPATION  
«Compensation» 
 
You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the 
visits you complete according to the following schedule: 
• $xx.xx for Visits xxx.  
• $xx.xx for Visits xxx.  
• $xx.xx for Visits xxx.  
 
If you do not complete the study, for any reason, you will be paid for each study visit you 
do complete.  
 
You will be paid ___________ [“after each visit,” “annually,” “bi-weekly,” etc.] 
 
If you have any questions regarding your compensation for participation, please contact 
the study staff.   
 
[OR] 
 
You will not receive any monetary compensation for your participation in this study.  
 
If you have any questions regarding your compensation for participation, please contact 
the study doctor at the telephone number listed on page one of this consent document. 
 
CONFIDENTIALITY 
Records of your participation in this study will be held confidential except as disclosure 
is required by law or as described in this informed consent document (under 
"Confidentiality" or "Authorization to Use and Disclose Protected Health Information").   
 
The study doctor, the Sponsor or persons working on behalf of the Sponsor, and under 
certain circumstances, the FDA and the IRB will be able to inspect and copy confidential 
study-related records which identify you by name. Therefore, absolute confidentiality 


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cannot be guaranteed. If the results of this study are published or presented at 
meetings, you will not be identified. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
 
COMPENSATION FOR INJURY 
If, during the course of this study, any injury occurs to you as a direct result of the 
administration of the study drug or properly performed study procedures, the Sponsor 
agrees to pay all medical expenses necessary to treat such injury: 1) to the extent you 
are not otherwise reimbursed by medical, third party or government insurance; 2) 
provided you have followed the directions of the study doctor; 3) the study doctor and 
the study staff followed the protocol directions.  
 
You will not lose any of your legal rights or release the Sponsor, the study doctor, the 
study staff, or study site from liability for negligence or intentional misconduct by signing 
and dating this consent document. 
 
There are no plans to provide financial compensation for such things as lost wages, 
disability or discomfort due to injury. To pay medical expenses, the sponsor will need to 
know some information about you like your name, date of birth, and Medicare 
Beneficiary Identifier (MBI). This is because the sponsor has to check to see if you 
receive Medicare and if you do, report the payment it makes to Medicare. 
 
 
 
COSTS  
There will be no charge to you for your participation in this study. The study medication, 
study-related procedures, and study visits will be provided at no charge to you or your 
medical insurance company. 
 
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study, please contact the 
study doctor at the telephone number listed on the first page of this consent document. 
If you seek emergency care, or hospitalization is required, alert the treating physician 
that you are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research subjects. If you have any questions about your rights as a 
research subject, and/or concerns or complaints regarding this research study, contact: 


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• By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00043941. 
 
VOLUNTARY PARTICIPATION / WITHDRAWAL  
Your decision to participate in this study is voluntary. You may choose to not participate 
or you may withdraw from the study for any reason without penalty or loss of benefits to 
which you are otherwise entitled and without any effect on your future medical care. 
 
If you decide to withdraw from this study, please contact the study doctor to discuss any 
follow-up care that may be necessary. There is no increased risk of side effects due to 
your withdrawal from the study.  
 
The study doctor or the Sponsor can stop your participation at any time without your 
consent for the following reasons: 
• If it appears to be medically harmful to you; 
• If you fail to follow directions for participating in the study; 
• If it is discovered that you do not meet the study requirements; 
• If the study is canceled; or  
• For administrative reasons, including competitive enrollment (subject enrollment 
will be terminated when the target number of subjects has entered the study 
treatment phase). 
 
If you leave the study for any reason, the study doctor may ask you to have some end-
of-study tests for your safety.   
 
PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION 
Please check one line below to indicate whether you want us to notify your primary care 
physician or your specialist of your participation in this study. 
 
________ 
Yes, I want the study doctor to inform my primary care physician/specialist 
of my participation in this study. 
 
________ 
No, I do not want the study doctor to inform my primary care 
physician/specialist of my participation in this study. 
 
________ 
I do not have a primary care physician/specialist. 
 


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________ 
The study doctor is my primary care physician/specialist. 
 
Name and address of family 
doctor or primary health care 
provider: 
Name: 
Address: 
 
Telephone and Fax Number: 
Tel: 
Fax: 
 
CONSENT 
I have read and understand the information in this informed consent document. I have 
had an opportunity to ask questions and all my questions have been answered to my 
satisfaction. I voluntarily agree to participate in this study until I decide otherwise. I do 
not give up any of my legal rights by signing and dating this consent document. I will 
receive a copy of this signed and dated consent document. 
 
 
 
_______________________________ 
Subject’s Printed Name  
 
 
 
_______________________________  
 
 
_________ 
Subject’s Signature  
 
 
 
 
 
Date 
 
 
 
____________________________________ 
Printed Name of the Person Conducting the 
Consent Discussion 
 
 
 
_____________________________________  
 
__________ 
Signature of the Person Conducting the   
 
 
Date 
Consent Discussion 
 


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AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
During your participation in this research study, the study doctor and study 
staff will collect or create personal health information about you (for 
example, medical histories and results of any tests, examinations or 
procedures you undergo while in the study) and record it on study 
documents. The study doctor will keep this personal health information in 
your study-related records (that we will refer to as "your study records").  
 
If you have consented for the study staff to take and use your non-
identifiable photographs, the photographs will become part of your study 
records. In addition, the study doctor may obtain, and include in your study 
records, information regarding your past, present and/or future physical or 
mental health and/or condition. Your study doctor may ask you to sign a 
separate authorization to obtain some or all of your medical records from 
your regular doctor. Your study records may include other personal 
information (such as social security number, medical record numbers, date 
of birth, etc.), which could be used to identify you. Health information that 
could identify you is called "Protected Health Information" (or "PHI"). 
 
PHI that will be collected during this study include: 
• Your name 
• Address 
• Your birth date, sex, race and ethnicity  
• A history of your medical conditions 
• Study photographs; these photographs, and any information 
included with them, will not identify you and they may be used for 
scientific presentations, for general corporate purposes or for 
marketing purposes 
• A personal identification number such as your driver’s license 
number or your social security number 
• Results of medical test results such as laboratory tests of your 
blood, and other information from your study visits 
• If you are a woman who can have a baby, pregnancy tests results 
 


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Under federal law (the "Privacy Rule"), your PHI that is created or obtained 
during this research study cannot be "used" to conduct the research or 
"disclosed" (given to anyone) for research purposes without your 
permission. This permission is called an "Authorization." Therefore, you 
may not participate in this study unless you give your permission to use 
and disclose your PHI by signing this Authorization. By signing and dating, 
you are agreeing to allow the study doctor and study staff to use your PHI 
to conduct this study. The study doctor will not use your PHI for any other 
purposes. 
 
By signing and dating this Authorization, you also are agreeing to allow the 
study doctor to disclose PHI as described below: 
• Representatives of the Sponsor (NFlection Therapeutics, Inc.), and 
anyone working on behalf of the Sponsor to conduct this study. The 
Sponsor will analyze and evaluate the PHI and may use it to develop 
new tests, procedures and commercial products. The study staff will 
assign a code number and/or letters to your records, which means 
that you will not ordinarily be identified in the records sent to the 
Sponsor. The Sponsor may, however, look at your complete study 
records that identify you. In addition, the Sponsor may visit the study 
site to oversee the way the study is being conducted and may review 
your PHI during these visits to make sure the information is correct.   
• Representatives of Advarra IRB, (an Institutional Review Board that 
reviews this study) 
• The Food and Drug Administration (FDA) and other US federal and 
state agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, 
and STDs) must be reported. 
• Governmental agencies of other countries. 
• Outside individuals and companies, such as laboratories and data 
storage companies, that work with the researchers and sponsor and 
need to access your information to conduct this study. 
• Other research doctors and medical centers participating in this 
study, if applicable.  
• A data safety monitoring board which oversees this study 
 
Your health data will be used to conduct and oversee the research, 
including for instance: 
• To see if the study drug works and is safe. 


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• To compare the study drug to other drugs. 
• For other research activities related to the study drug. 
 
These disclosures also help ensure that the information related to the 
research is available to all parties who may need it for research purposes. 
 
Except for the disclosures described above, your PHI will not be shared 
with others unless required by law. If your PHI is given to the parties listed 
above and/or to others who are not required to comply with the federal law, 
your PHI will no longer be protected by this law and could possibly be used 
or disclosed in ways other than those listed here.  
 
You have a right to see and make copies of your PHI. You are agreeing, 
however, by signing this document, not to see or copy some or all your PHI 
until the Sponsor has completed all work related to this study. At that time, 
you may ask to see your records. 
 
This Authorization will expire 50 years from the date you sign and date it 
unless you revoke (cancel or withdraw) it sooner.   
 
You have a right to revoke your Authorization at any time. If you revoke it, 
your PHI will no longer be used for this study, except to the extent the 
parties to the research have already taken action based upon your 
Authorization or need the information to complete analysis and reports for 
this research. To revoke your Authorization, you must write to the study 
doctor, at the address listed on the first page of this consent form, stating 
that you are revoking your Authorization to Use and Disclose Protected 
Health Information. If you revoke this Authorization, you will not be allowed 
to continue to participate in this study.   
 


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You will receive a copy of this Authorization after you have signed and 
dated it. 
 
 
 
____________________________________  
__________ 
Signature of Subject 
 
 
 
 
 
Date 
 
 
 
____________________________________ 
Printed Name of Subject 
 
 
 
 
____________________________________  
__________ 
Signature of the Person Obtaining the 
 
 
Date 
Authorization 
 
 
 
_____________________________________ 
Printed Name of the Person Obtaining the  
Authorization