Clinical trial NCT02908620
Conditions: Anesthesia
Sponsor: Cetylite Industries
Start date: 2016-12-07; Completion date: 2017-06-07
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine if the topical application to cheek tissue of the combination of benzocaine and tetracaine has a longer duration of local anesthetic activity than benzocaine alone.

Detailed description:
In a blinded study, either benzocaine alone of the combination of benzocaine and tetracaine will be sprayed onto the cheek mucosal tissue. Onset and duration of local anesthesia will be evaluated over a one hour period using pin prick and QST heat stimulation. Subjects will receive both treatments in a cross-over design with each session separated by 5-7 days. A total of 76 subjects (normal volunteers) will be evaluated.

Arms: arm 1: A single spray of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) tested over a 60 minute session. arm 2: Two sprays of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) and a single spray of vehicle control (CTY-5339-P) (sprayed outside the circumscribed area to avoid dilution of active drug) tested over a 60 minute session. arm 3: A single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session. arm 4: A single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) and a single spray of vehicle control (CTY-5339-P) (sprayed outside the circumscribed area to avoid dilution of active drug) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a two sprays of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session.
Interventions: intervention 1: One spray CTY-5339-A intervention 2: One spray CTY-5339-CB intervention 3: Two sprays CTY-5339-A intervention 4: One spray CTY-5339-CB in combination with one spray CTY-5339-P (vehicle control: placebo)
Intervention descriptions: intervention 1: Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 28 mg) and 2.0% Tetracaine Hydrochloride (USP = 4 mg). Administered in a single anesthetic spray. intervention 2: Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredient: 14.0% Benzocaine (USP = 28 mg). Administered in a single anesthetic spray. intervention 3: Metered spray bottle with ≈400 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 56 mg total) and 2.0% Tetracaine Hydrochloride (USP = 8 mg total). Administered in two anesthetic sprays. intervention 4: A single spray of CTY-5339-CB in a metered spray bottle with ≈200 uL total spray volume, containing the active ingredient: 14.0% Benzocaine (USP = 28 mg). This was administered in combination with a single spray of CTY-5339-P (acting as vehicle control placebo with no active ingredient) in a metered spray bottle with ≈200 uL total spray volume. This combination was used to maintain double-blind conditions. The vehicle control was sprayed outside the circumscribed area to avoid dilution of active drug.

Protocol documents:
Prot_SAP_000.pdf: 
Cetylite Industries, Inc.                    
CONFIDENTIAL 
Amended (#3) Protocol C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
 
November 10, 2016 
Page 1 of 48 
Protocol v10.4 
 
 
Cetylite Industries, Inc. 
1. 
STUDY PROTOCOL 
Title: 
A double-blind, partial cross-over, incomplete factorial study to 
assess the local anesthetic efficacy and safety of CTY-5339 
Anesthetic Spray (CTY-5339-A) when applied to the cheek 
mucosal tissue in normal volunteers 
Test Drugs: 
CTY-5339-A (14.0% benzocaine, USP, 2.0% tetracaine HCL, USP)  
CTY-5339-CB (14.0% benzocaine, USP) 
CTY-5339-P (Vehicle Spray) 
(1 metered spray will deliver ≈200 µL containing either benzocaine 28 
mg + tetracaine HCl 4 mg or benzocaine alone 28 mg or vehicle.) 
Methods: 
Single-center, randomized, double-blind, partial cross-over, 
incomplete factorial design.  Pin Prick and QST Heat (QST) will 
be utilized to assess efficacy.  Assessment of ECGs, pulse 
oximetry, and methemoglobinemia (blood co-oximetry) will be 
utilized to assess safety.  ECGs and blood sampling will be 
performed at Baseline and after 1 hour of treatment. Pulse 
oximetry will be performed at Baseline and every 10 minutes 
through 1 hour after treatment. 
Sponsor Name and 
Address: 
Cetylite Industries, Inc. 
9051 River Road 
Pennsauken, NJ 08110 
Protocol Identification: 
C-002 
Development Phase IIb: Proof-of-Concept Experimental Pain Model 
Company/Sponsor 
Representative: 
Stephen A. Cooper, D.M.D., Ph.D 
117 Dalena Way 
Palm Beach Gardens, FL  33418    
Phone:  973-710-6677 
Compliance Statement: 
The study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and 
with standards of current Good Clinical Practice, as defined by 


Cetylite Industries, Inc.                    
CONFIDENTIAL 
Amended (#3) Protocol C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
 
November 10, 2016 
Page 2 of 48 
Protocol v10.4 
 
 
the International Conference on Harmonization and all applicable 
FDA regulations. 
 
 
Date 
Version 
Comment(s) 
Author 
April 20, 2016  
2.0 
Draft 
S. Cooper 
April 27, 2016 
3.0 
Draft- (Hersh, Weisman, Doyle) 
S. Cooper 
May 2, 2016 
3.1 
Draft- (Hersh, Weisman, Doyle)
S. Cooper 
May 7, 2016 
4.0 
Draft- (Hersh, Weisman, Doyle, Riley, Phelps)
S. Cooper 
May 7, 2016 
4.1 
Draft- (Hersh, Weisman, Doyle, Riley, Phelps)
S. Cooper 
May 7, 2016 
4.2 
Draft- (Hersh, Weisman, Doyle, Riley, Phelps)
S. Cooper 
May 10, 2016 
4.3 
Draft- (Hersh, Weisman, Doyle, Riley, Phelps)
S. Cooper 
May 16, 2016 
4.4 
Draft- (Hersh, Weisman, Doyle, Riley, Phelps)
S. Cooper 
May 18, 2016 
4.5 
Draft- (Hersh, Weisman, Doyle, Riley, Phelps)
S. Cooper 
May 25, 2016 
4.6 
Draft- Doyle Edits 
S. Cooper 
June 9, 2016 
4.7 
Minor Edits Prior to sign-off  Final Version 
S. Cooper/G.Doyle 
August 8, 2016 
5.0 
Incorporation of Amendment 1 Changes/Edits 
G. Doyle 
October 17, 2016 
6.0 
Incorporation of Pulse Oximetry and Stopping Rules 
S. Cooper/G. Doyle 
October 18, 2016 
7.0 
Correct version with latest edits & Pulse Oximetry 
S. Cooper/G. Doyle 
October 19, 2016 
8.0 
Added FDA comment & IND Number 
S. Cooper 
October 19, 2016 
9.0 
Added Tegra comments 
S. Cooper 
November 3, 2016 
10.0 
Refinements to QST Assessment, other minor edits/corrections 
S. Cooper/G. Doyle 
November 4, 2016 
10.1 
Refinements to QST Assessment, other minor edits/corrections 
S. Cooper/G. Doyle 
November 8, 2016 
10.2 
Refinements to Baseline/Screening PPT and QST Assessments 
S. Cooper/G. Doyle 
November 9, 2016 
10.3 
Refinements to Baseline/Screening PPT and QST Assessments 
S. Cooper/G. Doyle 
November 10, 2016 
10.4 
Corrected Minor Inconsistencies 
G. Doyle 
 
Confidential Information 
The information contained within this report is confidential and may not be used, 
divulged, published, or otherwise disclosed without the prior written consent of 
Cetylite Industries, Inc. 


Cetylite Industries, 
CONFIDENTIAL 
Amended (#3) Protocol C-002 IND# 117147
CTY-5339 Anesthetic Spray (CTY-5339-A) 
Signature Page 
Investigator Signature 
The signatures of the Principal Investigator (Pl) and representatives of Cetylite Industries,
Inc. (Cctylitc) below constitute their approval of this protocol and pnwidc the necessary
assurances Lhal this study will be conducted according lo all stipulations, dinically and
administratively, as detailed in the protocol, including all statements as to confidentiality.
It is agreed that the conduct and results of this study will be kept confidential and that the
CRFs and other pertinent data will become the property of Cetylite. 
It is agreed that the protocol contains all necessary infrmnation required to conduct the
study as outlined in the protocol, and that the study will not be initiated without the
approval of an appropriate Institutional Review Board or Independent Ethics Committee. 
It is agreed that all participants in this study will provide written informed consent in
accordance with the requirements specified in the FD/\ Regulations and the Current
International Conference on Harmonization Good Clinical Practice Guidelines. 
Ail
participants will also be informed that their medical records will be kept confidential
except for review by representatives of Cetytite, Institutional Review Board or other
University Offices, and the FDA and/or international regulatory authority. 
The following have reviewed and approved this protocol: 
Principal Investigator's Name : Elliot llcrsh, D.M.D., Ph.D. 
Medical Monitor's Signature: 
Medical Monitor's Name: Stephen A. Cooper, D.M.D., Ph.D. 
Sponsor Representative· s or President· s Signature: 
Sponsor Representative's Name: Gary L. Wachman, President 
November 10, 2016 
Page 3 of 48 
Date 
I 
Date 
Date 
Protocol vl0.4 


'••··f-
Cetylite Industries, Inc. 
-.CONFIDENTIAL 
Amended (#3) Protocol C-002 IND # 117147 
. CTY-5339 Anesthetic Spray (CTY-5339-A)
Signature Page 
Investigator Signature 
The signatures of the Principal Investigator (PI) and representatives of Cetylite Industries, 
Inc. (Cetylite) below constitute their approval of this protocol and provide the necessary 
assurances that this study will be conducted according to all stipulations, clinically and 
administratively, as detailed in the protocol, including all statements as to confidentiality. 
It is agreed that the conduct and results of this study will be kept confidential and that the 
CRFs and other pertinent data will become the property of Cetylite. 
It is agreed that the protocol contains all necessary information required to conduct the 
study as outlined in the protocol, and that the study will not be initiated without the 
approval of an appropriate Institutional Review Board or Independent Ethics Committee. 
It is agreed that all participants in this study will provide written informed consent in 
accordance with the requirements specified in the FDA Regulations and the Current 
International Conference on Harmonimtion Good Clinical Practice Guidelines. All 
participants will also be informed that their medical records will be kept confidential 
except for review by representatives of Cetylite, Institutional Review Board or other 
University Offices, and the FDA and/or international regulatory authority. 
The following have reviewed and approved this protocol: 
Principal Investigator's Signature: 
Date 
Principal Investigator's Name : Elliot Hersh, D.M.D., Ph.D. 
Sponsor Representative's or President's Signature: 
Date 
Sponsor Representative's Name: Gary L. Wachman, President 
November 10, 2016 
Page 3 of 48 
Protocol vl0.4 


Cetylite Industries, Inc. 
f 
Amended (#3) Protocol C-002 IND# 117147 
CTY-5339 Anesthetic Spray (CTY-5339-A) 
lnvcsti0ator Siunaturc 
le, 
"' 
Signature Page 
The signatures of the Principal Investigator (Pl) and representatives of Cetylite Industries, 
Inc. (Cetylite) below constitute their approval of this protocol and provide the necessary 
assurances that this study will be conducted according to all stipulations, clinically and 
administratively, as detailed in the protocol, including all statements as to confidentiality. 
It is agreed that the conduct and results of this study will be kept confidential and that the 
CRF s and other pertinent data will become the prope1iy of Cetylite. 
It is agreed that the protocol contains all necessary information required to conduct the 
study as outlined in the protocol, and that the study will not be initiated without the 
approval ofan appropriate Institutional Review Board or Independent Ethics Committee. 
It is agreed that all participants in this study \Vill provide ,vritten info1111ed consent in 
accordance with the requirements specified in the FDA Regulations and the Current 
International Conference on Harmonization Good Clinical Practice Guidelines. 
All 
participants will also be infonned that their medical records will be kept confidential 
except for review by representatives of Cetylite. Institutional Reviev,, Board or other 
University Offices. ,:md the FDA and/or international regulatory authority. 
L 
-------------·--------· 
Principal Investigator's Name: Elliot Hersh, D.M.D., Ph.D. 
Medical Monitor's Signature: 
Medical Monitor's Name: Stephen A. Cooper, D.M.D., Ph.D. 
Sponsor Representative's or President's Signature: 
Sponsor Representative·s Name: Gary L. \\/achman, President 
Date 
Date 
Date 
------------------------------ -·--·------·-
November 10, 2016 
Page 3 of 3 
Protocol v 10.4 


Cetylite Industries, Inc.     
CONFIDENTIAL 
Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 4 of 48 
Protocol v10.4 
2. 
   TABLE OF CONTENTS 
1.  STUDY PROTOCOL .................................................................................................1 
2.  TABLE OF CONTENTS ...........................................................................................4 
3.  CLINICAL PROTOCOL SYNOPSIS ......................................................................7 
4.  STUDY FLOW CHART ..........................................................................................16 
5.  LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................19 
6.  ETHICS .....................................................................................................................20 
6.1 
Independent Ethics Committee or Institutional Review Board ......................20 
6.2 
Declaration of Helsinki ...................................................................................20 
6.3 
Subject Information and Consent ...................................................................20 
7.  INTRODUCTION.....................................................................................................21 
8.  RATIONALE, OBJECTIVES, OUTCOMES, AND HYPOTHESIS ..................23 
8.1 
Rationale .........................................................................................................23 
8.2 
Objectives .......................................................................................................23 
8.3 
Outcomes ........................................................................................................23 
8.3.1  Primary Outcome Measures ...............................................................23 
8.3.2  Secondary Outcome Measures ...........................................................24 
8.4 
Hypothesis ......................................................................................................24 
9.  SUMMARY OF STUDY DESIGN ..........................................................................25 
9.1 
Number of Subjects ........................................................................................26 
9.2 
Inclusion Criteria ............................................................................................27 
9.3 
Exclusion Criteria ...........................................................................................27 
10.  CLINICAL SUPPLIES ............................................................................................28 
10.1 
Study Medication and Dosage ........................................................................28 
10.2 
Packaging and Labeling .................................................................................29 
10.3 
Assignment of Study Medication ...................................................................30 
10.4 
Administration of Study Medication and Duration of Evaluation .................30 
10.5 
Study Medication Accountability ...................................................................30 
10.5.1  Storage ..............................................................................................30 
10.5.2  Study Medication Inventory .............................................................30 
10.5.3  Return of Study Supplies ..................................................................31 
11.  STUDY PROCEDURES ..........................................................................................31 
11.1 
Study Conditions ............................................................................................31 


Cetylite Industries, Inc.     
CONFIDENTIAL 
Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 5 of 48 
Protocol v10.4 
11.2 
Schedule of Assessments ................................................................................31 
11.2.1  Screening Assessments .....................................................................31 
11.2.2  Baseline Assessments .......................................................................32 
11.2.3  Post-Baseline Assessments ...............................................................32 
11.3 
Efficacy Assessments .....................................................................................33 
11.3.1  Pin Prick Test (PPT) .........................................................................33 
11.3.2  Heat Sensation Tolerance .................................................................33 
11.4 
Safety Assessments ........................................................................................33 
11.5 
Blood Sampling, ECG and Pulse Oximetry ...................................................34 
11.6 
Concomitant Medication ................................................................................34 
11.7 
Study Participant Discontinuation ..................................................................34 
12.  SAFETY ....................................................................................................................35 
12.1 
Subject Examinations .....................................................................................35 
12.2 
Subject Safety Information .............................................................................35 
12.3 
Availability of Investigator .............................................................................35 
12.4 
Adverse Events ...............................................................................................35 
12.4.1  Definitions ........................................................................................35 
12.4.2  Reporting Adverse Events ................................................................37 
12.4.3  Other Reportable Events ...................................................................38 
12.4.4  Adverse Event Recording and Reporting .........................................38 
12.4.5  Breaking the Blind ............................................................................39 
12.4.6  Discontinuation of Study due to an SAE ..........................................39 
13.  STATISTICAL METHODS AND DATA HANDLING .......................................39 
13.1 
Sample Size Determination ............................................................................39 
13.2 
Analysis Populations ......................................................................................40 
13.3 
Demographic Data and Baseline Comparability ............................................40 
13.4 
Data Adjustments and Derived Endpoints .....................................................40 
13.4.1  Time Windows .................................................................................40 
13.5 
Statistical Methods for Efficacy Evaluations .................................................41 
13.6 
Multiple End Points and Multiple Comparisons ............................................41 
13.7 
Safety Analysis ...............................................................................................42 
14.  STUDY ADMINISTRATION .................................................................................42 
14.1 
Investigator Study Binder ...............................................................................42 
14.2 
Subject Identification ......................................................................................42 
14.3 
Case Report Forms .........................................................................................43 


Cetylite Industries, Inc.     
CONFIDENTIAL 
Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 6 of 48 
Protocol v10.4 
14.4 
Monitoring of Study .......................................................................................43 
14.5 
Protocol Modifications ...................................................................................43 
14.6 
Discontinuation of Study by Sponsor or PI ....................................................44 
14.7 
Disclosure of Data/Publications .....................................................................44 
14.8 
Informed Consent ...........................................................................................44 
14.9 
Institutional Review........................................................................................44 
14.10  Retention of Records ......................................................................................45 
14.11  Responsibilities of Principal Investigator .......................................................46 
14.12  Filing of Protocol with FDA...........................................................................47 
15.  TEXT REFERENCES .............................................................................................48 
 
 
List of Tables  
Table 1- List of formulation components; CTY-5339 and Placebo Spray………...22 
Table 2- Study Medications…………………………………………………………...28 
 
 
 
 
 


Cetylite Industries, Inc.     
CONFIDENTIAL 
Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 7 of 48 
Protocol v10.4 
3. 
CLINICAL PROTOCOL SYNOPSIS 
TITLE: 
A double-blind, partial cross-over, incomplete factorial study to assess 
the local anesthetic efficacy and safety of CTY-5339 Anesthetic Spray 
(CTY-5339-A) when applied to the cheek mucosal tissue in normal 
volunteers 
STUDY 
NUMBER: 
C-002 
PRINCIPAL 
INVESTIGATOR: 
Dr. Elliot V. Hersh, Director Clinical Pharmacology Research Unit, 
Dept. of Oral and Maxillofacial Surgery/Pharmacology, University of 
Pennsylvania, School of Dental Medicine 
SITE: 
University of Pennsylvania, School of Dental Medicine 
240 South 40th Street, Robert Schattner Center, Philadelphia, PA 
19104. 
STUDY 
OBJECTIVES: 
This study is designed to assess the efficacy and safety of locally 
applied CTY-5339 Anesthetic Spray compared to 14.0% benzocaine 
alone in normal volunteers using experimental sensation including 
pinprick with a needle (PPT) and heat sensation threshold (QST).  The 
objective of this study is to demonstrate that the combination of the two 
constituents in the CTY-5339 Anesthetic Spray (CTY-5339-A) 
provides longer acting local anesthesia than 14.0% benzocaine alone 
(CTY-5339-CB).  The primary objective is to demonstrate that the 
CTY-5339-A one-spray dose is superior to CTY-5339-CB.  The 
secondary objective is to demonstrate that the CTY-5339-A up to two 
sprays is a safe dosage. 
HYPOTHESIS: 
CTY-5339-A when locally applied to cheek mucosal tissue in the 
mouth will have an onset comparable to the fastest constituent, 
benzocaine, and a prolonged effect comparable to the longest acting 
constituent, tetracaine, of the combination product.  The study also is 
designed to demonstrate that both the CTY-5339-A one- and two-spray 
dosages are safe.  (The assumption being made is that benzocaine has a 
faster onset of action than tetracaine.) 
 
 


Cetylite Industries, Inc.     
CONFIDENTIAL 
Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 8 of 48 
Protocol v10.4 
STUDY 
DESIGN: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
This is a single-dose, partial cross-over, double-blind and single-center 
study with an active control treatment.  All subjects will remain at the 
study center for each of the two 60 minute test sessions.  The subjects 
will be tested at two different test sessions separated by 4-14 days. 
The study will include 76 subjects who will be evaluated for 60 
minutes at each test session. At each session, a circular area of 
approximately one inch in diameter will be isolated on one side of the 
inner cheek using an indelible oral pencil.  Each session will use a 
different side of the cheek.  The possible sequences of treatments with 
the metered spray at the two sessions are: 
Session 1 
Session 2 
Formulation 
Sprays 
Formulations 
Sprays 
CTY-5339-A 
1 
CTY-5339-CB 
1 
CTY-5339-A 
2 
CTY-5339-CB 
1 
CTY-5339-CB 
1 
CTY-5339-A 
1 
CTY-5339-CB 
1 
CTY-5339-A 
2 
To maintain double-blind conditions, the CTY-5339-CB subjects in the 
two spray sequences will also receive one spray with the vehicle 
control (CTY-5339-P).  A third party not involved with evaluating 
subjects will administer the drug.  The CTY-5339-P Vehicle will be 
sprayed outside the circumscribed area to avoid dilution of active drug.  
Efficacy evaluations will be done at 1-5 minute intervals beginning 
immediately after drug administration and will include: 
Pin Prick (PPT) & QST Heat Sensation Tests: 
For PPT, evaluations will be done at 1 minute intervals for the first 5 
minutes to capture onset of anesthesia.  Starting at 5 minutes after drug 
administration, both PPT and QST will be done at 5 minute intervals up 
to the one hour time point.  If there is no indication of anesthesia by 10 
minutes, the subject will be considered a treatment failure and the 
assessment of PPT and/or QST, as appropriate, will be discontinued.  In 
addition, once onset of anesthesia has occurred, if there is no longer 
any anesthesia at two consecutive evaluation time points from 10 
minutes onward, the assessment of PPT and/or QST, as appropriate, 
will be discontinued.   
Pin Prick Test (PPT): The PPT will be assessed, using a 90-mm, 26-


Cetylite Industries, Inc.     
CONFIDENTIAL 
Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 9 of 48 
Protocol v10.4 
DESIGN: (cont) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
DESIGN: (cont) 
gauge pencil-point spinal needle (Polymedic; Temena S.A., Bondy, 
France or equivalent).  At screening, 3 pin pricks will be performed on 
each cheek.  Pin pricks will be assessed using a 0 (no pain) to 10 
(severe pain) Numerical Rating Scale (NRS).  In order to be eligible for 
the study, for each cheek, subjects must have a minimum score of “3” 
for the last 2 pin pricks, and one of those scores has to be “4” or higher. 
During each treatment session, at Baseline and at each post-dosing time 
point, 3 pin pricks will be performed first on the non-treated cheek and 
then on the treated cheek.  At Baseline, pin pricks on both cheeks will 
be assessed using a 0 (no pain) to 10 (severe pain) NRS.  Post-Baseline, 
pin pricks on the non-treated cheek will also be assessed using the 0 to 
10 NRS, but on the treated cheek, the three repetitions will be 
compared to the non-treated cheek as “No pain”, “Less Pain” or 
“Similar/More Pain”.  For each cheek, the first pin prick will not be 
used for analysis.  Of the remaining 2 pin pricks, the one with the most 
severe pain rating will be used for analysis.  During each treatment 
session, in order for a subject to be eligible to continue in the study, for 
each cheek, both of the last 2 Baseline assessment pin pricks must have 
a minimum score of “3” for the last 2 pin pricks, and one of those 
scores has to be “4” or higher.  Post-Baseline, an assessment of “No 
Pain” or “Less Pain” at a drug application site will be recorded as 
presence of analgesia/anesthesia (“Responder”).     
Heat sensation threshold (QST-Heat): The heat stimuli are delivered 
in 3 repetitions, with inter-stimulus intervals of 30s. The basal 
thermode temperature is set at a comfortable 35ºC.  The rate at which 
the thermode heats up is set at 0.5ºC/s, while the rate at which it cools 
down is set at 8ºC/s. The maximum thermode temperature is set at 
51ºC. (Note: Hot beverages such as tea and coffee are frequently served 
at temperatures between 500C - 600C.  Burns can occur at 650C.25). 
Heat sensation threshold will be defined as the temperature at which the 
subjects first feel tingling, warmth, heat, or pain.  
At screening, QST-Heat assessments will be performed on each cheek. 
In order to be eligible for the study, for each cheek, subjects must have 
a mean Heat sensation threshold of 48.5oC or less,  based on the last 2 
of the 3 readings.  
During each treatment session, for each assessment, the first stimulus 
will be disregarded and the remaining two stimuli will be averaged for 
data analysis (unless the first two readings are 510C, in which case the 
third assessment will not be done).  At Baseline and at each post 
treatment assessment, the heat sensation threshold will be performed on 
the treated cheek only.  During each treatment session, in order for a 
subject to be eligible to continue in the study, subjects must have a 


Cetylite Industries, Inc.     
CONFIDENTIAL 
Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 10 of 48 
Protocol v10.4 
mean Heat sensation threshold of 48.5oC or less, based on the last 2 of 
the 3 readings.  Post-Baseline, the presence of analgesia/anesthesia will 
be defined when the heat sensation threshold at the treated site is higher 
than the Baseline (“Responder”).  
All tests on the treated cheek will be done near the center of the 
circumscribed area, but in a slightly different place at each consecutive 
evaluation time point.  All tests on the non-treated cheek will be 
performed at approximately the same part of the cheek as those on 
treated cheek.  
Randomization: A randomization code will determine the sequence of 
treatments and to which circumscribed area the treatment is 
administered (left or right cheek).  Sensory testing will be done in the 
following order: pin prick followed, where applicable, immediately by 
heat sensation tolerance.  
Subjects retain the right to withdraw from the study at any time. 
EFFICACY 
MEASUREMENTS 
The primary comparison of interest is one spray of CTY-5339-A 
compared to one spray of CTY-5339-CB. Co-primary efficacy 
variables are duration of effect as determined by PPT and duration of 
effect as measured by QST Heat.  Duration of effect is defined as the 
time (in minutes) from onset to treatment failure (for PPT, treatment 
failure occurs when an assessment of “Same/More” pain, and for QST, 
a treatment failure occurs when the average heat temperature is the 
same or less than the average heat temperature at Baseline up to the 60-
minute time point (at two consecutive time points).   
The secondary efficacy variables include:  
 Duration of anesthesia (PPT and QST Heat) for the two sprays of 
CTY-5339-A compared to one spray of CTY-5339-CB plus CTY-
5339-P 
 Duration of anesthesia (PPT and QST Heat) for the two sprays of 
CTY-5339-A compared to one spray of CTY-5339-A 
 Onset of anesthesia for PPT and QST Heat 
 Percentage of responders for PPT and QST Heat for both onset and 
duration 
 Percentage of responders for PPT and QST Heat at each time point 
OTHER 
MEASUREMENTS 
 
 
 
At Baseline and at the end of the 60-minute test session an ECG, vital 
signs, and a 7 mL blood draw will be taken.  The blood will be 
analyzed for the occurrence of subclinical methemoglobinemia by the 
HUP – Pepper Lab via co-oximetry analysis. At screening and 
throughout each test session, subjects will also be monitored with pulse 
oximetry.  Methemoglobinemia is being defined as >5% of a subject’s 


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
 
 
hemoglobin in the methemoglobin state, or a pulse oximetry reading of 
less than 91%.   
ESTIMATED 
DURATION OF 
SUBJECT 
PARTICIPATION 
IN THE STUDY: 
The subjects will be tested on two separate occasions.  Each session 
will take approximately two hours total time; however, the actual 
efficacy testing will take 60 minutes.  There will be 4-14 days spacing 
between visits.  A phone follow-up will occur 3 days (± 1 day) and 15 
days (± 2 days) after the subject completes Sessions 1 and 2, 
respectively.  If there are any adverse side effects, at the discretion of 
the PI, the subject may be asked to return to the study site for 
evaluation. 
DURATION OF 
STUDY: 
The study will be completed when the last subject completes the last 
follow up phone call.  The expectation is that the study will be 
completed within 4-6 months of the first subject entry. 
NUMBER OF 
SUBJECTS: 
Up to 150 male and female subjects will be screened in order to enroll 
up to 76 ASA Category I or II subjects.  The total number of exposures 
to study medication will be 152 (76 subjects x 2 exposures).  Each of 
the CTY-5339-A treatment regimens will have 38 exposures and the 
CTY-5339-CB will have 76 exposures. 
SAMPLE SIZE 
DETERMINATION: 
The sample size was selected based on evaluating a reasonable number 
of subjects to determine whether CTY-5339-A has a longer duration of 
action than CTY-5339-CB, which contains 14.0% benzocaine only.   
DOSAGE: 
(specific gravity is 
slightly less than 1; 
therefore 200 uL is an 
approximate volume.) 
CTY-5339-A 1-metered spay = 200 mg total (≈200 L) 
Benzocaine 28 mg + Tetracaine HCl 4 mg 
CTY-5339-A 2-metered spays = 400 mg total (≈400 L) 
Benzocaine 56 mg + Tetracaine HCl 8 mg 
CTY-5339-CB = 200 mg (≈200 L) 
Benzocaine 28 mg 
INCLUSION 
CRITERIA: 
a. Male and female subjects between 18-75 years of age with a Body 
Mass Index (BMI) ≤32; 
b. Subjects are ASA Category I or II and are in good physical health 
as judged by physical and laboratory examinations; 
c. Subjects with normal appearance of the oral mucosal tissues; 
d. At screening and at Baseline during Session 1, subjects with PPT 
scores on both cheeks of at least “3” (on a 10 point NRS) on the last 
2 of 3 readings, 1of which must be a score of at least “4”;  
 
e. Subjects with mean QST Heat sensation temperature assessments 


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
on both cheeks of 48.5oC or less based on the average of the last 2 
of the 3 readings at screening or with a mean QST Heat sensation 
temperature assessment of 48.5oC or less based on the average of 
the last 2 of the 3 readings on the treated cheek at Baseline during 
Session 1; 
f. Subjects must agree to refrain from ingesting any systemic or 
topical analgesic medication for 3 days or 5 half-lives of the drug 
prior to and during each study session and alcohol for 1 day prior to 
and during each study session; 
g. Subjects must agree to refrain from using mouth rinses, cough 
drops or throat lozenges on the day of each test session; 
h. Female subjects must be physically incapable of childbearing 
potential (postmenopausal for more than 1 year or surgically sterile) 
or practicing an acceptable method of contraception (hormonal, 
barrier with spermicide, intrauterine device, vasectomized or same 
sex partner, or abstinence).  Subjects using hormonal birth control 
must have been on a stable dose of treatment for at least 30 days 
and received at least 1 cycle of treatment prior to randomization.  
At Screening and at Baseline of both sessions, all females of 
childbearing potential must have a negative urine pregnancy test 
and not be breastfeeding; 
i. Negative urine drug screen for drugs of abuse at Screening and at 
Baseline for each Study Session.  A positive drug screen result may 
be permitted if the subject has been on a stable dose of an allowed 
medication for >30 days;  
j. The subject is capable of reading, comprehending, and signing the 
informed consent form. 
EXCLUSION 
CRITERIA: 
a. Subjects with a history of any significant hepatic, renal, endocrine, 
cardiac, neurological, psychiatric, gastrointestinal, pulmonary, 
hematologic, or metabolic disorders, including glaucoma, diabetes, 
emphysema, and chronic bronchitis; 
b. Subjects with a history of any type of cancer other than skin related 
cancers; 
c. Subjects with conditions that affect the absorption, metabolism, or 
passage of drugs out of the body, (e.g., sprue, celiac disease, 
Crohn’s disease, colitis, or liver, kidney, or thyroid conditions);  
d. Subjects with any history of alcohol or substance abuse (including a 
positive drug screen test); 
e. Subjects that currently have or have a history of uncontrolled  
hypertension; 


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
f. Subjects with a known hypersensitivity to any local anesthetic drug; 
g. Subjects with a hematocrit level significantly below the normal 
range on the screening laboratory examination (as judged by the PI) 
or a pulse oximetry reading of less than 96% at screening or at 
Baseline of either session; 
h. Subjects with any clinically significant abnormal lab result (as 
judged by the PI); 
i. Subjects with any condition or history felt by the Investigator to 
place the subject at increased risk; 
j. Subjects who have smoked or chewed tobacco-containing 
substances within 6 months prior to the start of the study; 
k. Subjects judged by the Investigator to be unable or unwilling to 
comply with the requirements of the protocol; 
l. Subjects who have used an investigational drug within 30 days 
prior to entering the study; 
m. Subjects who have donated blood within 3 months prior to the start 
of the study; 
n. Subjects who have previously participated in the trial; 
o. Subjects who are members of the study site staff directly involved 
with the study or a relative of the Sponsor or other personnel 
involved with the study. 
ECG TIMES: 
ECGs will be taken at screening, and during treatment visits at Baseline 
(Time 0, within 1 hour prior to drug administration) and then 
immediately after the 1 hour test session. 
SAFETY 
EVALUATION: 
 
All potential subjects will receive a blood chemistry test and urine drug 
screen at the screening visit. As a safety precaution, at each study 
session, blood samples will be taken at Baseline and 1 hour after study 
medication to measure methemoglobin levels.   
Pulse oximetry will be performed at screening, and at each session at 
Baseline, and 10, 20, 30, 40, 50 and 60 minutes after drug 
administration. 
All the medications being evaluated in this study are marketed local 
anesthetic products in the United States and are being used within their 
currently indicated dosages and indications. Adverse experiences will 
be recorded as they occur during the treatment phase of the study and if 
voluntarily reported by the subject within 3 days following completion 
of the first study session and within 15 days following the end of the 
subject’s participation in the study.  Treatment-emergent AEs will be 
summarized by incidence. The events will be coded using the Medical 


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
Dictionary for Regulatory Activities (MedDRA) and summarized by 
system organ class (SOC) and preferred term (PT). 
Irritation and/or infection at the site of application will be assessed.  
The severity, relationship to treatment, action taken, and outcome of the 
events will be documented.  The incidence of all adverse events and 
drug-related adverse events will be evaluated.   In the event of any 
health related emergency, the clinical site will have a trained medical 
staff with a fully equipped emergency crash cart. 
STATISTICAL 
ANALYSIS: 
Primary Efficacy Endpoints: 
 Duration of anesthesia as measured by PPT for one spray CTY-
5339-A compared to the one spray CTY-5339-CB  
 Duration of anesthesia as measured by QST Heat for one spray 
CTY-5339-A compared to the one spray CTY-5339-CB 
Secondary Efficacy Endpoints: 
 Duration of anesthesia as measured by PPT and QST Heat for the 
two spray CTY-5339-A compared to the one spray CTY-5339-CB 
plus one spray CTY-5339-P 
 Duration of anesthesia as measured by PPT and QST Heat for the 
two spray CTY-5339-A compared to the one spray CTY-5339-A  
 Onset of anesthesia for PPT and QST Heat 
 Percentage of responders for PPT and QST Heat for both onset and 
duration 
 Percentage of responders for PPT and QST Heat at each time point 
Safety Data: 
 SBP, DBP, and HR at Baseline and at the end of each 60-minute 
test session, 
 
Pulse oximetry at Baseline and at 10, 20, 30, 40, 50 and 60 minutes 
after drug administration,  
 12 Lead ECG at Baseline and at the end of each 60-minute test 
session, 
 Methemoglobinemia at Baseline and at the end of each 60-minute 
test session, and 
 Analysis of incidence and severity of all adverse events  
For the PPT, a “Responder” is defined based on an assessment of “No 
Pain” or “Less Pain” in response to the pain stimulus at each 
observation time when compared to the non-treated site, (See Appendix 
2).  The % of responders at each time point will be compared between 
treatments. In addition, the % of subjects who have Onset (and 
Duration) will also be compared between treatments. 
  
For the QST, a “Responder” is defined as follows: If the average heat 


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
temperature at each time point is greater than the average heat 
temperature at Baseline, then the subject at that time point will be 
considered a “Responder”.  The % of responders at each time point will 
be compared between treatments. In addition, the % of subjects who 
have Onset (and Duration) will also be compared between treatments. 
Data will be generated as the difference in response between the 
control, non-treated site and the active treatment site within in each 
subject. 
ANOVA and pairwise t-tests will be used to compare CTY-5339-A 
treatment groups to the CTY-5339-CB treatment group. 
 
 


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
4. 
STUDY FLOW CHART 
 
TIME 
Informed 
Consent 
Medical 
 History 
Phys. 
Exam,  
ECG,  
Vital Signs, 
Pulse Ox 
Lab 
Tests, 
Drug 
Screen 
 
Pregnancy 
Test 
Females 
Dosing 
 
Pin Prick= P 
Heat Sensation 
Threshold= H 
(PPT & QST) 
Blood Draw 
AE 
Assessment 
Screening 
 
 
 
 
 
  
 
P (both cheeks),          
H (both cheeks) 
 
 
Test 
Session 1 
  
 
 
* 
 
 
P (both cheeks),          
H (treated cheek)  
 
 
Test 
Session 2 
 
 
 
* 
 
 
P (both cheeks),          
H (treated cheek)   
 
 
-5 min 
 
 
 
 
 
 
 
 
 
0 hr   
 
 
 
 
 
 
  
 
 
1, 2, 3, 4 min 
 
 
 
 
 
 
P (both cheeks) 
 
 
5, 15, 25, 35, 
45, 55 min  
 
 
 
 
 
 
P (both cheeks),          
H (treated cheek) 
 
 
10, 20, 30, 40, 
50 min 
 
 
*** 
 
 
 
P (both cheeks),          
H (treated cheek) 
 
 
60min 
 
 
  
 
 
 
P (both cheeks),          
H (treated cheek) 
 
 
Discharge 
 
 
  
 
 
 
  
 
 
3 or 15-Day 
Call** 
 
 
 
 
 
 
 
 
 
* Urine Drug Screen Only 
**After Session 1, 3-Day Follow-up Call ± 1 day; After Session 2, 15-Day Follow-up Call ± 2 days 
*** Pulse Oximetry Only, if <91%, the subject will be discontinued from the study 
 
P=pinprick evaluation; H=heat tolerance evaluation 
 
 


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
 APPENDIX 1: DESCRIPTION OF TESTING METHODS   
 
Appendix 1A:  Pin Prick Test (PPT) 
Oral Mucosa sensation directly over the circumscribed sites will be assessed with a 90-
mm, 26-gauge pencil-point spinal needle (Polymedic; Temena S.A., Bondy, France or its 
equivalent) at Screening, Baseline and predetermined intervals after application of drug.  
To standardize the methodology, all tests are performed by holding the needle at its hub 
and orienting it perpendicular to the oral mucosa surface.  Pressure is applied until the 
needle shaft bows slightly.  At screening a numerical score on a 0 – 10 pain intensity 
scale (NRS) is recorded for each cheek. After study drug administration, subjects are 
instructed to rate the pinprick sensation perceived over the circumscribed treatment site 
compared to that perceived at the contra-lateral circumscribed, non-treated site and to 
report the sensation as none, less, or similar/more to the non-treated site.  Reports of none 
or less indicate analgesia, while a report of similar/more indicates complete regression of 
analgesia.  At each observation, 3 pin pricks are performed first on the non-treated side, 
and then on the treated side.  For each cheek, the first pin prick will not used for analysis.  
Of the remaining two pin pricks, the one with the most severe pain rating will be used for 
the data analysis. 
 
Appendix 1B: QST Heat Stimulus 
1. 
This procedure uses the QST Heat Stimulator, a commercially available thermo-
sensory analyzer (Medoc, 1 Ha’dekel, St. Ramat Yishai 30095, Israel) that 
delivers heat stimuli to the oral mucosa with a blunt thermode that is 6mm in 
diameter.  A central unit generates and transmits the signal to the thermode.  This 
signal is controlled by proprietary software stored on a laptop connected to the 
central unit.  Also attached to the central unit is a hand-held control (a computer 
mouse) that allows a study subject to stop the heating of the thermode.  As the 
temperature is increased, subjects are asked to report when they first start to feel a 
tingling, warmth, heat, or pain sensation.  The subjects are instructed to turn off 
the heat probe by depressing the mouse when they first start to feel tingling, 
warmth, heat or pain.  The heat is applied in graded increments until the subjects 
depress the mouse or the temperature reaches the maximum of 51oC.  At the 
maximum heat of 510 C, the probe automatically turns off and tissue is not 
damaged.  (Note: Hot beverages such as tea and coffee are frequently served at 
temperatures between 500 C- 600C.25)  
 
2. 
The heat stimuli are delivered, in three repetitions, with inter-stimulus intervals of 
30s. The basal thermode temperature is set at a comfortable 35ºC. The rate at 
which the thermode heats up is set at 0.5ºC/s, while the rate at which it cools 
down is set at 8ºC/s.  The maximum thermode temperature is set at 51ºC.  For 
each assessment, the first stimulus is discarded and the remaining stimuli are 


Cetylite Industries, Inc.     
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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
averaged, unless the first two readings are 51ºC.  In this case, the third assessment 
is not completed.  At Baseline, and at each post-treatment time point, QST will be 
assessed on the treated cheek only.  
APPENDIX 2: CRITERIA FOR A “RESPONDER” 
PPT: 
Based on “No Pain” or “Less Pain” response to the pain stimulus at each 
observation time when compared to the non-treated site, subjects will be 
classified as “Responders” or “Non Responders”.  At each observation, 3 pin 
pricks will be performed at each site (first on the non-treated cheek and then 
on the treated cheek).  The first pin prick will not be used for analysis.  Of the 
remaining two pin pricks, the one with the most severe pain rating will be 
used for the data analysis.  If the most severe pain rating at that time point is 
“No Pain” or “Less Pain”, then the subject at that time point is a “Responder”.  
 
QST:  
The actual temperature data will be recorded at each time point.  
Temperatures will be recorded for "first sensation of tingling, warmth, heat, or 
pain".  Scores will be censored at 51ºC, if no response is obtained. If the 
average heat sensation temperature at each time point is greater than the 
average heat sensation temperature at Baseline, then the subject at that time 
period will be considered a “Responder”. 
 
  
 
 


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CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ANOVA 
Analysis of variance 
CFC 
Chlorofluorocarbons 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
CRF 
Case Report Form 
DESI 
Drug Efficacy Study Implementation 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized as Safe 
HCl 
Hydrochloride 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NF 
National Formulary 
NRS 
Numerical Rating Scale 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PPT 
Pin Prick Test 
PT 
Preferred Term 
QST 
Heat Stimulus Test 
SAE 
Serious Adverse Event 
SOC 
System Organs Class 
TESS 
Treatment Emergent Signs and Symptoms 
USP 
United States Pharmacopeia   


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Amended (#3) Protocol. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
6. 
ETHICS   
6.1 
Independent Ethics Committee or Institutional Review Board 
This protocol, informed consent form, and any amendments, will be submitted to local 
ethics committees or institutional review boards (IRBs) for review and approval.  A copy 
of the written approval or vote must be available and sent to the Sponsor before study 
initiation.  Any amendment made to the approved protocol must be forwarded to and 
approved by the same ethics committees or IRBs before its implementation.  Regulatory 
authority notifications will also be in place and fully documented prior to study start. 
The Investigator and appropriate representatives from the Sponsor will sign the protocol 
to document their willingness to adhere to this protocol and to conduct the study in 
accordance with the FDA guidelines and the International Conference on Harmonization 
(ICH) guidelines for Good Clinical Practice (GCP). 
6.2 
Declaration of Helsinki 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and consistent with good clinical practice (GCP) as 
described by the United States Code of Federal Regulations (21CFR parts 50, 54, 56, and 
312) and by the ICH Guidelines, effective 17 January 1997. 
6.3 
Subject Information and Consent 
Written informed consent, in accordance with local clinical investigation regulations, 
must be obtained from the subject (subjects must be 18 years of age or older) prior to 
participation in the study.  The Investigator must provide a description of the study 
medication (including any potential and possible hazards) and the study procedures to the 
study subjects.  Information must be given both in oral and written form.  The subject 
information provided will be in English, and may not include any language that appears 
to waive any of the subject’s legal rights, or appears to release the Investigator, the 
Sponsor, the Sponsor’s representative, or the institution, from liability or negligence. 
The Investigator will provide the prospective subject sufficient time to consider whether 
or not to participate, minimizing the possibility of coercion or undue influence, and will 
discuss any questions the subjects may have.  The Investigator will explain to the subject 
that withdrawal from the study is possible at any time without detriment to care.  The 
Investigator will then ask the subject to give consent in writing.   
The consent must include acknowledgment that medical records and medical data derived 
from the study may be forwarded to the Sponsor, to the Sponsor’s representative, to the 
FDA or other regulatory authorities.  The informed consent will follow the FDA 
Regulations and ICH Guidelines, effective 17 January 1997. 


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Amended (#3) Protocol C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
7. 
INTRODUCTION 
Cetylite Industries, Inc. (Cetylite) is a small pharmaceutical company based in 
Pennsauken, New Jersey.  The primary product for this company is a local anesthetic 
spray, Cetacaine® Spray, consisting of a combination of the three active ingredients 
benzocaine hydrochloride (HCl), tetracaine HCl, and butamben, USP.  The company also 
makes a liquid (solution) formulation with the same constituents (with the exception of a 
CFC propellant).  The product has been grandfathered by the FDA under the DESI 
review and has been on the market in the US for approximately 60 years.  The current 
indications for Cetacaine® are: 
Cetacaine is a topical anesthetic indicated for the production of anesthesia of all 
accessible mucous membrane except the eyes. Cetacaine® Spray is indicated for use to 
control pain and gagging.  Cetacaine® Spray is indicated to control pain and for use for 
surgical or endoscopic or other procedures in the ear, nose, mouth, pharynx, larynx, 
trachea, bronchi, and esophagus.  
As a result of the Federal mandate to eliminate CFCs and under current Federal 
Regulations and exemptions, Cetylite has to reformulate the spray formulation once its 
supply of CFCs is exhausted (estimated to between 2020 and 2022).  Since Cetacaine® is 
a grandfathered drug that never received an NDA approval; the FDA will now require an 
NDA for the reformulated product.  As part of the recent communication with the FDA, 
Cetylite has agreed to remove butamben from the product and to reformulate a two-drug 
combination consisting of 14.0% benzocaine, USP and 2.0% tetracaine HCl, USP 
delivered without CFCs. The new product is a metered spray designated in this protocol 
as CTY-5339 Anesthetic Spray (CTY-5339-A).  
In Cetylite's most recent correspondence with the FDA in April of 2014, Cetylite outlined 
its proposed program for the conversion of Cetacaine® Spray containing CFC propellant 
to a non-CFC containing spray.  This letter outlined a proposed new alternate 
formulation, a proposed animal toxicology study and a clinical program.  Since then the 
CTY-5339 formulation was developed without propellant as a metered dose pump spray.  
Cetylite has successfully completed a 28-day safety study in rabbits and will file the 
results of this safety study in their IND Application to initiate human clinical trials.  
Summary of Critical Issues and Proposed FDA Questions 
One of the key issues for Cetylite is how the development program translates to the final 
indications for CTY-5339 Anesthetic Spray.  The primary use for CTY-5339-A is for the 
induction of local anesthesia of mucous membranes to suppress the gag reflex during 
intubation procedures.  A secondary, but important, use is for anesthetizing buccal and 
gingival tissues. 
Cetylite's proposed development program to the FDA consisted of the following: 
 A 28-day rabbit study using nasal mucosa (completed in April 2016). 
 A Phase II Cheek Mucosa study in normal volunteers- partial factorial design. 
 A Phase III Nasal Intubation study in normal volunteers- full factorial design. 


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Amended (#3) Protocol C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
 A Phase III Gingival Surgery study in patients requiring gingival surgery- full 
factorial design. 
Based on the successful completion of this program, Cetylite anticipates: 
 Indications for use in the nose, throat and buccal cavity to suppress the gag reflex 
and pain sensation. 
 Indications for use in all oral mucosa tissues for surgical procedures. 
Cetylite's rationale for this development program is: 
 Rabbit nasal mucosa is a highly sensitive and representative tissue type in human 
and provides an acceptable bridge to safety in other mucosal tissues, i.e. throat 
and buccal cavity. 
 The Cheek Mucosa study will serve as the proof of concept study to evaluate the 
superiority of the combination in comparison to benzocaine alone. 
 The Nasal Intubation study will serve as a representative of an airway model: 
 The Gingival Surgery study is designed to demonstrate efficacy in a surgical 
model. 
Table 1.  Compositions of CTY-5339-A, the Benzocaine-Only Comparator (CTY-
5339-CB) and the Vehicle Control (CTY-5339-P) 
Ingredient 
Grade 
CTY-5339- (% w/w)
Aa 
CBb 
Pc
Benzocaine 
USP 
14.0 
14.0 
- 
Tetracaine Hydrochloride 
USP 
2.0 
- 
- 
Dehydrated Alcohol 
USP 
12.0 
12.3 
14.4 
Polyethylene Glycol 300 (PEG 300) 
NF 
29.7 
30.4 
35.5 
Propylene Glycol 
USP 
16.9 
17.3 
20.2 
Purified Water 
USP 
18.0 
18.4 
21.5 
Benzyl Alcohol 
NF 
5.0 
5.1 
6.0 
Benzalkonium Chloride Solution (50%)
NF 
0.5 
0.5 
0.5 
Saccharin Sodium 
USP 
1.4 
1.4 
1.4 
Artificial Banana Flavor 
Food 
0.5 
0.5 
0.5 
a CTY-5339-A: Active formulation containing both 14.0% benzocaine, USP and 2.0% tetracaine 
hydrochloride, USP.  Note: the term CTY-5339-A is used to designate the active formulation. 
b CTY-5339-CB: comparator formulation containing benzocaine, USP   
cCTY-5339-P: Vehicle formulation containing neither active ingredient 
In the proposed human experimental Cheek Mucosal study in healthy volunteers, the 
CTY-5339-A or comparator CTY-5339-CB formulations will be sprayed onto a 


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Amended (#3) Protocol C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
circumscribed approximately one inch diameter area of the cheek.  The area will then be 
tested with pin prick (PPT) and heat (QST) to assess onset and duration of effect.  The 
maximal (total) dose of CTY-5339-A that a subject can receive during this study is 56 mg 
benzocaine and 8 mg tetracaine HCl.  The expectation is that there will be very low 
systemic exposure of either benzocaine or tetracaine.  The doses being used in this study 
are within the prescribed doses listed on the current Cetacaine® Spray label and are 
known to be safe doses of these local anesthetics.1-24 
The dose of benzocaine and tetracaine being employed in this study are indicated doses 
on the Cetacaine® label.  The PI has examined much higher exposures to benzocaine (80 
mg – 200 mg) self-applied by patients to the oral mucous membranes and the offending 
tooth to treat toothache pain with relatively few minor adverse events recorded (no SAEs 
and no clinically discernible methemoglobinemia).13 Likewise in the development of 
another product, the PI and his team have dosed subjects with 18 – 36 mg of tetracaine by 
the intranasal route to obtain maxillary tooth anesthesia with no SAEs reported (again 
this is 2 – 4 fold greater than the maximum tetracaine exposure on the current study.8,10 
These three studies were approved by the University of Pennsylvania IRB. 
8. 
RATIONALE, OBJECTIVES, OUTCOMES, AND HYPOTHESIS 
8.1 
Rationale 
The purpose of this study is to evaluate the onset and duration of analgesia in humans 
when CTY-5339-A is sprayed onto intact cheek mucosal tissue.  If this proof-of-concept 
study is successful, then future studies will evaluate CTY-5339-A in intubation and 
gingival surgical settings. 
8.2 
Objectives 
The objectives of this study are to evaluate the onset and duration of CTY-5339-A 
compared to benzocaine only spray (CTY-5339-CB) in a human experimental pain 
model.       
8.3 
Outcomes 
8.3.1 
Primary Outcome Measures  
 Duration of anesthesia as measured by PPT for the one spray of 
CTY-5339-A compared to the one spray of CTY-5339-CB   
 Duration of anesthesia as measured by QST Heat for the one spray 
of CTY-5339-A compared to the one spray of CTY-5339-CB   
8.3.2 
Secondary Outcome Measures 
 Duration of anesthesia as measured by PPT and QST Heat for the 
two sprays of CTY-5339-A compared to the one spray of CTY-
5339-CB plus one spray of CTY-5339-P   


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 Duration of anesthesia as measured by PPT and QST Heat for the 
two sprays of CTY-5339-A compared to the one spray of CTY-
5339-A 
 Onset of anesthesia for PPT and QST Heat   
 Percentage of responders for PPT and QST Heat for both onset and 
duration 
 Percentage of responders for PPT and QST Heat at each time point 
8.4 
Hypothesis 
The following hypotheses will be tested to analyze the primary outcomes of the study: 
 The null hypothesis that the duration of anesthesia (PPT and QST Heat) for the 
one spray CTY-5339-A group is the same as the corresponding duration for the 
CTY-5339-CB one spray group will be tested against the alternative hypothesis 
that the means are not equal. 
The following hypotheses will be tested to analyze the secondary outcomes of the study: 
 The null hypothesis that the duration of anesthesia (PPT and QST Heat) for the 
two spray CTY-5339-A group is the same as the corresponding duration for the 
CTY-5339-CB one spray plus CTY-5339-P one spray group will be tested against 
the alternative hypothesis that the means are not equal. 
 The null hypothesis that the onset of anesthesia (PPT and QST Heat) for the CTY-
5339-A groups is equal to the corresponding onset for CTY-5339-CB group will 
be tested against the alternative hypothesis that the means are not equal. 
 The null hypothesis that the onset time until the first responder event (PPT and 
QST Heat) for the CTY-5339-A groups is equal to the corresponding onset time 
until a first responder event for CTY-5339-CB group will be tested against the 
alternative hypothesis that the event times are not equal. 
 The null hypothesis that the duration time until the first non-responder event 
(QST and PPT) for the CTY-5339-A groups is equal to the corresponding 
duration time until the first non-responder event for CTY-5339-CB group will be 
tested against the alternative hypothesis that the event times are not equal. 
The predicted outcome is that CTY-5339-A when locally applied to cheek mucosal 
tissue in the mouth will have an onset comparable to the fastest constituent, 
benzocaine, and a prolonged effect comparable to the longest acting constituent, 
tetracaine, of the combination product.  The study also is designed to demonstrate that 
both the CTY-5339-A one and two-spray dosages are safe.  (The assumption is made 
that benzocaine has a faster onset of action than tetracaine HCl.)  


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Amended (#3) Protocol C-002  IND # 117147
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9. 
SUMMARY OF STUDY DESIGN 
This is a single-dose, double-blind and single-center study with an active control 
treatment.  All subjects will remain at the study center for each of the two 60 minute test 
sessions.  The volunteer subjects will be tested at two different test sessions separated by 
4-14 days and serve as their own control. 
The study will include 76 subjects with 60-minute evaluations at each test session.  
At each session, a circular area of approximately 1 inch in diameter will be isolated on 
one side of the cheek.  Each session will use a different side of the cheek.  The possible 
sequences of treatments at the two sessions are: 
Session 1 
Session 2 
Formulation 
Sprays 
Formulations 
Sprays 
CTY-5339-A  
1 
CTY-5339-CB  
1 
CTY-5339-A  
2 
CTY-5339-CB  
1 
CTY-5339-CB  
1 
CTY-5339-A  
1 
CTY-5339-CB  
1 
CTY-5339-A  
2 
(To maintain double-blind conditions, the CTY-5339-CB subjects in two spray sequences 
will also receive one spray with the vehicle control (CTY-5339-P) just outside the 
circumscribed area.  A third party not involved with evaluating subjects will administer 
the drug.)  
For PPT, evaluations will be done at 1-minute intervals following drug administration for 
the first 5 minutes to capture onset of anesthesia.  Starting at 5 minutes after drug 
administration, both PPT and QST will be done at 5-minute intervals up to the one hour 
time point.  Once onset has occurred, if there is no analgesia at two consecutive 
evaluation time points (from 10 minutes onward), the session will be discontinued.  In 
addition, if onset of analgesia has not occurred by 10 minutes post dose, the subject will 
be considered a treatment failure and no further assessments will be made. 
PPT: The PPT will be assessed, using a 90-mm, 26-gauge pencil-point spinal needle 
(Polymedic or equivalent; Temena S.A., Bondy, France or its equivalent).  At each post 
dosing time point, PPT will be assessed in 3 repetitions on the non-treated site using a 0-
10 Numerical Rating Scale (NRS) with “0” as no pain and “10” as severe pain.  PPT will 
then be assessed in 3 repetitions on the treated site.  These assessments will be compared 
to the contra-lateral, non-treated site as “No pain”, “Less Pain” or “Similar/More Pain”.  
“No Pain” or “Less Pain” at an application site will be recorded as presence of 
analgesia/anesthesia (“Responder”).  


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QST: The heat stimuli are delivered in 3 repetitions, with inter-stimulus intervals of 30s. 
The basal thermode temperature is set at a comfortable 35ºC.  The rate at which the 
thermode heats up is set at 0.5ºC/s, while the rate at which it cools down is set at 8ºC/s. 
The maximum thermode temperature is set at 51ºC.  The first stimulus is disregarded and 
the remaining two stimuli are averaged for data analysis.  In situations where a maximal 
analgesia/anesthesia effect is demonstrated in the initial two repetitions, the QST test will 
not be repeated for the third repetition and the data will be recorded as maximal effect 
(51oC) based on the first two repetitions. 
Heat sensation threshold will be defined as the temperature at which the subjects first 
start to feel tingling, warmth, heat, or pain.  All tests will be done near the center of the 
circumscribed area, but in a different place at each evaluation time point.  For QST, the 
first time point after Baseline will begin at 5 minutes after drug administration.  Subjects 
will have a hand held mouse that turns off the heat probe when they first start to feel 
tingling, warmth, heat, or pain.  At the maximum heat level of 510 C, the heat probe turns 
off automatically.  With a brief exposure at 510 C, there is no damage to the mucosal 
tissue.25  
Randomization: A randomization code will determine in which circumscribed area each 
treatment is administered (left or right cheek).  Immediately prior to beginning each 60 
minute test session, both the contra-lateral cheek and the cheek to be dosed will be 
evaluated with the PPT.  For QST, the screening assessments will be performed on both 
cheeks, while during each treatment Session, at Baseline and all post-dosing time points, 
assessments will be performed on the treated cheek only.  
Subjects retain the right to withdraw from the study at any time. 
The PPT and QST tests will be done near the center of each evaluation area but in a 
different place at each evaluation time point.  For PPT, the non-treated control cheek will 
always be tested before the treated area.  The testing will be done in the following order 
where applicable: PPT and then QST.   
A safety phone follow-up call will occur 3 days (±1 day) after the Session 1 and 15 days 
(±2 days) following Session 2. 
9.1 
Number of Subjects 
The study will include 76 completed subjects. It is anticipated that up to 150 ASA 
Category I and II subjects will be screened to obtain the 76 subjects needed for the study. 
9.2 
Inclusion Criteria 
Individuals may be included in the study provided they meet all of the following 
inclusion criteria:   
a. Male and female subjects between 18-75 years of age with a Body Mass Index (BMI) 
≤32; 
b. Subjects are ASA Category I or II and are in normal physical health as judged by 
physical and laboratory examinations; 


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c. Subjects with normal appearance of the oral mucosal tissues; 
d. At screening and at Baseline during Session 1, subjects with PPT scores on both 
cheeks of at least “3” (on a 10 point NRS) on the last 2 of 3 readings, 1of which must 
be a score of at least “4”;  
e. Subjects with mean QST Heat sensation temperature assessments on both cheeks of 
48.5oC or less based on the average of the last 2 of the 3 readings at screening or with 
a mean QST Heat sensation temperature assessment of 48.5oC or less based on the 
average of the last 2 of the 3 readings on the treated cheek at Baseline during Session 
1; 
f. Subjects must agree to refrain from ingesting any systemic or topical analgesic 
medication for 3 days or 5 half-lives of the drug prior to and during each study 
session and alcohol for 1 day prior to and during each study session; 
g. Subjects must agree to refrain from using mouth rinses, cough drops or throat 
lozenges on the day of each test session; 
h. Female subjects must be physically incapable of childbearing potential 
(postmenopausal for more than 1 year or surgically sterile) or practicing an acceptable 
method of contraception (hormonal, barrier with spermicide, intrauterine device, 
vasectomized or same sex partner, or abstinence).  Subjects using hormonal birth 
control must have been on a stable dose of treatment for at least 30 days and received 
at least 1 cycle of treatment prior to randomization.  At Screening and at Baseline of 
both sessions, all females of childbearing potential must have a negative urine 
pregnancy test and not be breastfeeding; 
i.  Negative urine drug screen for drugs of abuse at Screening and at Baseline for each 
treatment session.  A positive drug screen result may be permitted if the subject has 
been on a stable dose of an allowed medication for >30 days;  
j. The subject is capable reading, comprehending, and signing the informed consent 
form. 
9.3 
Exclusion Criteria 
Individuals are not eligible for participation in the study if any of the following are noted:  
a. Subjects with a history of any significant hepatic, renal, endocrine, cardiac, 
neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic 
disorders, including glaucoma, diabetes, emphysema, and chronic bronchitis; 
b. Subjects with a history of any type of cancer other than skin related cancers; 
 
c. Subjects with conditions that affect the absorption, metabolism, or passage of drugs 
out of the body, (e.g., sprue, celiac disease, Crohn’s disease, colitis, or liver, kidney, 
or thyroid conditions);  


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d. Subjects with any history of alcohol or substance abuse (including a positive drug 
screen test); 
e. Subjects that currently have or have a history of uncontrolled hypertension; 
f. Subjects with a known hypersensitivity to any local anesthetic drug; 
g. Subjects with a hematocrit level significantly below the normal range on the 
screening laboratory examination (as judged by the PI) or a pulse oximetry reading of 
less than 96% at screening or at Baseline of either session; 
h. Subjects with any clinically significant abnormal lab result (as judged by the PI); 
i. Subjects with any condition or history felt by the Investigator to place the subject at 
increased risk; 
j. Subjects who have smoked or chewed tobacco-containing substances within 6 months 
prior to the start of the study; 
k. Subjects judged by the Investigator to be unable or unwilling to comply with the 
requirements of the protocol; 
l. Subjects who have used an investigational drug within 30 days prior to entering the 
study; 
m. Subjects who have donated blood within 3 months prior to the start of the study; 
n. Subjects who have previously participated in the trial; 
o. Subjects who are members of the study site staff directly involved with the study or a 
relative of the Sponsor or other personnel involved with the study. 
10. 
CLINICAL SUPPLIES  
10.1 
Study Medication and Dosage 
The Sponsor will supply the following study medication for administration: 
Table 2.  Study Medication 
Treatment Group 
Contents of Metered Spray Bottle 
CTY-5339 Anesthetic Spray 
1 spray (≈200 L total) 
14.0% Benzocaine, USP = 28 mg 
2.0% Tetracaine Hydrochloride, USP = 4 mg 
CTY-5339 Anesthetic Spray 
2 spray (≈400 L total) 
14.0% Benzocaine, USP = 56 mg 
2.0% Tetracaine Hydrochloride, USP = 8 mg 
CTY-5339-CB 
1 spray (≈200 L total) 
14.0% Benzocaine, USP = 28 mg 
CTY-5339-P 
1 spray (≈200 L total) 
Vehicle control (no active ingredient) 


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Amended (#3) Protocol C-002  IND # 117147
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Protocol v10.4 
10.2 
Packaging and Labeling 
All study medication bottles will be labeled according to the FDA guidelines. In order to 
maintain the double-blind conditions for all treatment groups, the person(s) preparing and 
administering the test treatments will be different from the person(s) doing the clinical 
efficacy evaluations.  A randomization list generated by the Statistics Group will list the 
investigational product(s) to be assigned to each subject during each treatment session, 
and which cheek (left or right) the study medication should be applied to.  Subjects will 
be numbered starting from 101. 
 Study medication for subjects randomized to receive CTY-5339-A one spray in one 
treatment session and CTY-5339-CB one spray in the other treatment session will be 
double-blinded and packaged individually.  Study medication for each subject will 
consist of 2 bottles, one bottle containing CTY-5339-A, and one bottle containing CTY-
5339-CB. Each bottle will be labeled with the appropriate treatment session (A or B) and 
which cheek the study medication should be applied to (left or right), according the 
randomization schedule. The two bottles will be packaged in a box.  Each bottle will be 
primed three times immediately prior to use. 
Study medication for subjects randomized to receive CTY-5339-A two sprays in one 
treatment session and CTY-5339-CB one spray and CTY-5339-P one spray in the other 
treatment session will be packaged in bulk.  The label for each bottle will contain the 
identity of its contents (CTY-5339-A, CTY-5339-CB, or CTY-5339-P). The person 
preparing and administering the test treatments will use the randomization list generated 
by the Statistics Group to apply the appropriate product to the appropriate cheek, and the 
appropriate area(s) of the cheek. The bottle will be primed three times prior to each use. 
Another randomized listing generated by Statistics Group that has the same treatment 
assignments will be sent to the appropriate party responsible for packaging and labeling 
the study medications.   
In addition, a master code will be kept by the Sponsor and at the study site.  The study 
site master code will have individually sealed envelopes identifying the drug in each 
bottle for each patient enrolled in the study.  The treatment for an individual subject may 
be unblinded in the event of an emergency and only if medically necessary without 
breaking the code for any other subject.  Procedures to be followed for unblinding, 
notification responsibilities, and regulatory requirements are detailed in Section 12.4.5.   
10.3 
Assignment of Study Medication  
Treatment assignments will be determined by a computer-generated randomization 
schedule maintained by the Statistics Group. 
The randomization schedule will randomly assign one of the four treatments (CTY-5339-
A one spray, CTY-5339-A two sprays, CTY-5339-CB one spray, or CTY-5339-CB one 
spray plus CTY-5339-P one spray) to the appropriate area(s) of the cheek mucosa.  For 
PPT assessments, the untreated, control area on the contra-lateral side will always receive 
the stimulus assessment first.   


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Amended (#3) Protocol C-002  IND # 117147
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Protocol v10.4 
Randomization numbers will be assigned in a sequential order starting from 101.  A drug 
delivery team (different for the evaluators or other study personnel) will administer the 
treatments to the cheek mucosal area. 
The randomization number assigned to the subject will be recorded in the CRF.  
10.4 
Administration of Study Medication and Duration of Evaluation 
Each subject entered into the study will be given the randomly assigned study 
medications in the assigned circumscribed areas of the cheek mucosa at Baseline (Time = 
0 hour).  The duration of in-house treatment evaluations will last up to 60 minutes.  The 
same team of coordinators and/or investigators will do all the evaluations.      
10.5 
Study Medication Accountability 
10.5.1 
Storage 
All materials for this study must be stored in an area free from environmental extremes in 
a locked closet and with restricted access.  A Cetylite representative will inspect the study 
medication storage area and discuss the study medication accountability system with the 
PI and site coordinators prior to shipment of the study medication to the site.  
10.5.2 
Study Medication Inventory 
Upon receipt at the study site, the carton containing the study medication supplies will be 
stored unopened in the study medication storage room.  At the study initiation, the PI or 
an appropriate designee, and a representative of Cetylite will conduct an inventory and 
complete the study medication inventory record.  The original will be sent to Cetylite, 
and the PI will retain a copy.  Any interim shipments will be inventoried by the PI or 
his/her designee.  For all interim shipments, a study medication inventory record will be 
completed.  The original will be returned to Cetylite, and the PI will retain a copy. 
The PI or an appropriate designee, upon dispensing the study medication, must record the 
information on a study medication dispensing/return log.  For accounting purposes and 
assessing subject compliance, a representative of Cetylite will review the study 
medication dispensing/return log, inventory the study medication, and inspect the storage 
facility at appropriate time intervals throughout the clinical investigation, depending on 
the length of the study.  The PI must account for any discrepancy and/or deficiency. 
10.5.3 
Return of Study Supplies 
All unused study medication shipped for this clinical trial will be returned to the Sponsor 
at the termination of the study.  At the conclusion of the study, the PI or an appropriate 
designee, and a representative of Cetylite will inventory all used and unused study 
medication.  The study medication inventory record for returned study medication will 
then be completed.  Cetylite will retain the original, and the Investigator will retain a 
copy for his files.   
 


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Amended (#3) Protocol C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
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Protocol v10.4 
All unused study medication will then be returned to: 
Cetylite Industries, Inc.  
9051 River Road 
Pennsauken, NJ 08110 
Attention:  Returned Study Supplies 
Protocol No. C-002 
 
Upon receipt at Cetylite, a letter acknowledging the receipt of returned materials and a 
copy of the Study Medication Inventory Record will be sent to the Cetylite Medical 
Monitor. 
11. 
STUDY PROCEDURES 
11.1 
Study Conditions 
a. 
Only subjects who satisfy all inclusion and exclusion criteria and provide written 
informed consent may participate in the trial; 
b. 
Subjects will remain at the study site for up to 2 hours at each of two test sessions.   
c. 
Subjects will be tested in the same room and by the same coordinator team at each 
evaluation time point during both 1hour test sessions.  
11.2 
Schedule of Assessments  
  
11.2.1 
Screening Assessments 
During the screening period, the PI or his designee will examine each subject and 
complete a checklist of the inclusion and exclusion criteria (see Sections 9.2 and 9.3, 
respectively) in order to determine the subject’s eligibility.  The Investigator or study 
coordinator will enter the pertinent historical information (including any medication 
taken recently) and clinical findings (including blood pressure) in the appropriate 
section(s) of the source documents. 
A Subject Screening Log (provided by Cetylite) will be maintained in the site central file 
to document all subjects screened for entry into the study.  Subjects will be screened only 
once.  All subjects who meet the entrance criteria will provide written informed consent 
before participating in the study.  Subjects are required to read, comprehend, and sign the 
informed consent.  The screening procedure will also include evaluation of: 
a. PPT and QST heat sensation assessments of each cheek 
b. Vital signs (pulse rate and blood pressure in supine or reclining position, body 
temperature) and pulse oximetry (must be ≥ 96%) 
c. Safety bloods including section Clinical chemistry (Sodium, Potassium, Creatinine, 
AST, ALT, Alkaline Phosphatase, LDH and Bilirubin), Hematology (Hemoglobin, 
Hematocrit, Thrombocytes, Erythrocytes and Full blood differential) 
d. Urine drug screen and pregnancy test 


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e. 12 lead ECG (PR, QRS, QT interval, heart rate and rhythm) 
Appropriate screening information for eligible subjects who are assigned a subject 
number and receive study medication will be transcribed onto the corresponding sections 
of the CRF.  The experiment must occur within 30 days of the screening visit.  
The following will be noted and recorded on the CRF: 
 Date and time the drugs treatments were initiated and completed 
 Any vital signs obtained (require blood pressure)  
11.2.2 
Baseline Assessments 
After confirming continued eligibility, Baseline ECG, vital signs, and blood sample will 
be obtained.  In addition, tissue site evaluations will be performed.  The area of the 
treated cheek is circumscribed using an oral indelible pencil. Prior to drug administration, 
the presence or absence of pain after the PPT (using a 90-mm, 26-gauge pencil-point 
spinal needle), will be evaluated on both cheeks  Heat sensation threshold (using QST) 
will be assessed in the circumcised area of the to-be-treated side of the cheek.  These 
baseline data will be recorded on the CRF.  The drug will then be administered onto the 
assigned circumscribed area.  In order for a subject to be eligible to continue in the study, 
the last 2 of the 3 baseline PPT scores must be at least “3” or higher, and 1 must be “4” or 
higher.  The mean of the last 2 of the 3 baseline temperature assessments must be 48.5oC 
or less. 
11.2.3 
Post-Baseline Assessments 
The time points of the post-baseline efficacy assessment are detailed in section 9 of this 
protocol.   The PPT will be performed on both the control and treatment sites at each 
evaluation time point.  The QST will be performed only at the treatment site for the post 
baseline evaluation time points. 
11.3 
Efficacy Assessments 
11.3.1 
Pin Prick Test (PPT) 
Oral mucosal sensation directly over control and drug sites will be assessed with a 90-
mm, 26-gauge pencil-point spinal needle (Polymedic; Temena S.A., Bondy, France or its 
equivalent) at Baseline and predetermined intervals after application of drug.  To 
standardize the methodology, all tests are performed by holding the needle at its hub and 
orienting it perpendicular to the oral mucosa surface.  Pressure is applied until the needle 
shaft bows slightly.  For each test, the subject is instructed to rate the pinprick sensation 
perceived over the treatment sites compared to that perceived at the contra-lateral non-
drug site, and to report the sensation as none, less, or similar/more to the treated site.  
Subjects will rate pain at the control site on a 0-10 Numerical Rating Scale with “0” as no 
pain and “10” as severe pain.  Reports of none or less at the treatment site indicate 
analgesia, while a report of similar/more indicates complete regression or absence of 
analgesia. 


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At each observation, 3 pin pricks are performed at each site, first at the non-treated cheek 
and then at the treated cheek.  The first pin prick is not used for analysis.  Of the 
remaining 2 pin pricks, the one with the most severe pain rating is used for the data 
analysis.   
11.3.2 
Heat Sensation Tolerance 
This procedure uses the QST Heat Stimulator, a commercially available thermo-sensory 
analyzer that delivers heat stimuli to the oral mucosa with a blunt thermode that is 6mm 
in diameter.  A central unit generates and transmits the signal to the thermode.  This 
signal is controlled by proprietary software stored on a laptop connected to the central 
unit.  Also attached to the central unit is a hand-held control that allows a study subject to 
stop the heating of the thermode.  The heat is applied in graded increments until the 
subject first reports either tingling, warmth, heat, or pain or the temperature reaches the 
maximum of 51ºC (Note: Hot beverages such as tea and coffee are frequently served at 
temperatures between 500C - 600C.25)  
The heat stimuli are delivered, in 3 repetitions, with inter-stimulus intervals of 30s. The 
basal thermode temperature is set at a comfortable 35ºC.  The rate at which the thermode 
heats up is set at 0.5ºC/s, while the rate at which it cools down is set at 8ºC/s. The 
maximum thermode temperature is set at 51ºC.  The first stimulus is discarded and the 
remaining 2 stimuli are then averaged (unless the first two stimuli reach the maximum of 
51ºC).  All tests will be done near the center of each circumscribed area, but in a different 
place at each evaluation time point.   
11.4 
Safety Assessments  
Adverse events will be recorded when they are reported or observed.  The AE collection 
period will begin at the time the subject is initially screened and continue for 15 days 
after the subject’s last administration of study medication.  Only the PI will determine the 
relationship to study medication for each AE prior to breaking the blind.  The information 
will be recorded on the appropriate study center CRF and outpatient diary.   In addition, 
vital signs (DBP, SBP, HR) will be assessed at the beginning and end of each 60 minute 
test session. 
11.5 
Blood Sampling, ECG and Pulse Oximetry 
A blood sample (7 mL) will be taken at screening for purposes of assessing normal 
values for the subjects.  Additional blood samples (7 mL each) will be taken at the 
beginning and end of each 60 minute test session to assess for the possible occurrence of 
subclinical methemoglobinemia.  An ECG also will be performed both at Baseline and 
after the 60 minute sessions.  All blood test analyses will be performed by the laboratory 
at Hospital of University of Pennsylvania-Pepper Lab.  During each test session, subjects 
will also be monitored using pulse oximetry at Baseline and at 10, 20, 30, 40, 50 and 60 
minutes. 
Methemoglobinemia 
is 
being 
defined 
as 
>5% 
of 
a 
subject’s 
hemoglobin is in the methemoglobin state or a pulse oximetry reading is below 91%.  
The 5% level is still below the threshold where any clinically observable signs (blue lips, 


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chocolate-brown blood color or shortness of breath) would be seen.  The study will be 
discontinued if a pulse oximetry reading falls below 91% or if the level of 
methemoglobinemia reaches > 5% in any subject. 
11.6 
Concomitant Medication 
No other medications expected to confound the evaluation of the study medication will 
be allowed prior to or during the test sessions.  This includes, but is not limited to, the use 
of any analgesics, oral rinses and mouth lozenges.  All concomitant medications used 
during the study will be recorded in the CRF. 
11.7 
Study Participant Discontinuation 
A subject will be considered discontinued from the study at any time under the following 
circumstances and will be replaced: 
a. 
Any subject who violates any condition of the entrance criteria after having been 
entered into the study; 
b. 
Any subject who develops a confounding concomitant illness (as determined by 
the subject, research coordinator or Investigator), serious adverse event, or a 
hypersensitivity to the study medication; 
c. 
Any subject who becomes uncooperative, does not adhere to the requirements of 
the study protocol, or refuses to complete the study; 
d. 
Any subject who requires any concomitant medication during the course of the 
study that could confound the study results; 
e. 
Any subject who for the last 2 of the 3 assessments has PPT scores of less than 
“3” and does not have at least 1 assessment of “4” or greater, or has a QST mean 
heat sensation assessment higher than 48.5oC based on the last 2 of the 3 
assessments at Baseline prior to the start of each Session. 
f. 
Any subject who has a methemoglobinemia (>5%) or a pulse oximetry reading 
below 91% during Session 1 or Session 2. 
If necessary, additional coded study medication will be provided to the study site for 
replacement subjects.  A representative of Cetylite will provide the replacement number 
to the study site. 
Subjects who discontinue due to an adverse event will not be replaced.  All discontinued 
subjects will record no further assessments after their time of discontinuation, and any 
recorded efficacy data will be included in the intent-to-treat (ITT) efficacy analysis but 
not in the evaluable subject analysis.  All subjects taking study medication with follow-up 
safety data will be included in the safety analysis.  Details of the reason(s) why a subject 
has been discontinued from the study should be recorded in the appropriate section of the 
CRF. 


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12. 
SAFETY  
 
12.1 
Subject Examinations 
To ensure the safety and well-being of each subject entered into the study, the subject 
must first be examined by the PI or Sub-Investigator and medically cleared to participate 
as required by the protocol.  Each subject will be observed for adverse events (AEs) and 
will be required to report any adverse events that develop during the course of the study 
and for 15 days post-drug treatment.  If at any time during the study, the subject has a 
serious adverse event (SAE) or abnormality, the subject must be withdrawn from the 
study and appropriate care should be initiated. 
12.2 
Subject Safety Information 
In accordance with the regulatory requirements regarding informed consent (21 CFR Part 
50 Protection of Human Subjects), the subject will receive a copy of the informed 
consent form when discharged from the clinic.  The informed consent form will include 
the information needed to contact the PI, along with a description of the study medication 
the subject may have received. 
12.3 
Availability of Investigator 
Either the PI or an appropriate designee will be available to the subject at all times during 
the study and names and phone numbers of the PI and/or appropriate designee will be 
listed on the informed consent form. 
12.4 
Adverse Events 
12.4.1 
Definitions 
Adverse Event 
An adverse event (AE) will be defined as any untoward medical occurrence in a subject 
administered study medication.  The adverse event does not necessarily have to have 
causal relationship with the study medication.  An AE can therefore be an unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease, 
which is a change from baseline and is temporally associated with the use of the study 
medication, whether or not it is considered related to the study medication. 
 
Severity 
The following definitions will be used for grading severity of adverse events: 
Mild - Either asymptomatic or subject is aware of the sign, symptom or event, but 
it is easily tolerated. 
Moderate - Discomfort enough to cause interference with usual activity and may 
warrant intervention. 
Severe - Incapacitating with inability to do usual activities. 
 


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Causal Assessment 
The causal relationship between an AE and the study medication will be determined by 
the PI on the basis of his clinical judgment and the following definitions: 
 
Associated:  There is a reasonable possibility that the AE may have been caused by 
the study medication.  This definition applies to those AEs that are considered 
definitely, probably, and possibly related to the use of the study medication. 
a. Definitely Related:  An AE that: follows a reasonable temporal sequence from 
administration of the study medication; follows a known response pattern to the 
study medication; and, when appropriate to the protocol, is confirmed by 
improvement after stopping the study medication (positive de-challenge) and by 
reappearance of the reaction after repeat exposure (positive re-challenge); and 
cannot be reasonably explained by known characteristics of the subject’s 
clinical state or by other therapies. 
b. Probably Related:  An AE that: follows a reasonable temporal sequence from 
administration of the study medication; follows a known response pattern to the 
study medication; and, when appropriate to the protocol, is confirmed by 
improvement after de-challenge; and cannot be reasonably explained by the 
known characteristics of the subject’s clinical state or by other therapies. 
c. Possibly Related:  An AE that: follows a reasonable temporal sequence from 
administration of the study medication and follows a known response pattern to 
the study medication but could have been produced by the subject’s clinical 
state or by other therapies. 
 
Not Associated:   
a. Unlikely: An AE that does not follow a reasonable temporal relationship after 
administration of the study medication or could have been produced by the 
subject’s clinical state or other therapies.  
b. Not related: An AE for which sufficient information exists to indicate that the 
etiology is unrelated to the study medication.  Two or more of the following 
variables apply: 
 The AE does not follow a reasonable temporal sequence after administration 
of the study medication; 
 The AE is readily explained by the subject’s clinical state or other therapies; 
 Negative de-challenge—the AE does not abate upon dose reduction or 
cessation of therapy (assuming that it is reasonable to expect abatement of 
the AE within the observed interval). 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that occurs at any 
dose and: 


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 
Results in death; 
 
Is life threatening; 
 
Requires inpatient hospitalization or prolongation of an existing hospitalization;  
 
Results in persistent or significant disability/incapacity;  
 
Is a congenital anomaly/birth defect. 
 
Is a medically important condition: Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered a SAE 
when, based upon appropriate medical judgment, the event(s) may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.   
12.4.2 
Reporting Adverse Events 
Any SAE, regardless of causal relationship, must be reported immediately to the Medical 
Monitor at Cetylite no later than 24-hours after awareness of the SAE.  Initial SAE 
reports may be made by telephone, and then followed by faxing a completed “Serious 
Adverse Event Form” and confirming by telephone that the fax was received.  
Compliance with this time requirement is essential so that Cetylite may comply with its 
regulatory obligations.   
 
Contact: 
Medical Monitor: 
Name: 
Stephen A. Cooper, D.M.D., Ph.D. 
Address: 
117 Dalena Way 
Palm Beach Gardens, FL  33410  
Telephone: 
973-710-6677 
Fax: 
Same 
 
Follow up information relating to a serious adverse event must be reported to the Medical 
Monitor and to Cetylite within 24 hours of receipt by the PI by faxing a completed 
“Serious Adverse Event Form” to Cetylite and confirming by telephone that the fax was 
received.  The subject will be observed and monitored carefully until the condition 
resolves or stabilizes and its cause is identified.  The PI also will promptly notify the 
appropriate Institutional Review Board about the serious adverse event.  
12.4.3 
Other Reportable Events 
The following events will be recorded and reported in the same time frame and following 
the same process as for serious adverse events: 


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 
Overdose or abuse of the study medication with or without adverse events (for 
this protocol, a total daily dose of benzocaine exceeding 56 mg/day) or tetracaine 
exceeding 8 mg/day; 
 
Inadvertent or accidental exposure to the study medication with or without an 
adverse event. 
12.4.4 
Adverse Event Recording and Reporting 
All AEs, whether serious or not, will be recorded on source documents and CRFs.  The 
recording period for AEs and SAEs starts at the time the subject is screened.  The 
recording period for both AEs and SAEs lasts through 15 days after the subject’s last 
administration of study medication, regardless of the relationship to the study medication. 
The PI must follow up as medically necessary on all AEs, SAEs, and other reportable 
events until the event has subsided or values have returned to baseline, or in the case of 
permanent impairment, until the condition stabilizes. 
For SAEs, the PI will provide all documentation pertaining to the event (e.g. additional 
laboratory tests, consultation reports, discharge summaries, postmortem reports, etc.) to 
the Cetylite Medical Monitor in a timely manner.  Reports relative to the subject’s course 
must be submitted to Cetylite until the event has subsided or, in the case or permanent 
impairment, until the condition stabilizes. 
Information about all adverse events, serious and non-serious, including the event’s 
severity, start and stop times/dates, chronicity, relatedness to study medication, and any 
actions taken, must be recorded on the appropriate CRFs.  The information recorded will 
be based on the signs and symptoms detected during the physical examination and 
clinical evaluation of the subject as well as information recorded in the subject’s diary, 
when applicable. 
12.4.5 
Breaking the Blind 
A set of tamper-proof sealed individual envelopes containing the bottle numbers on the 
outside of the envelope and the treatment code inside the envelope, will be sent to the 
investigative site.  In the event of a medical emergency that necessitates breaking the 
code, the sealed envelope containing the treatment code may be opened.  The seal will 
only be broken by the Investigator in the event of an emergency for which knowledge of 
the subject’s double-blind investigational product will have a direct impact on treatment 
decisions.  Every effort will be made to discuss the decision to break the blind with the 
Cetylite Medical Monitor in advance.  
When the blind is broken, the Investigator will notify the Sponsor’s Medical Monitor 
immediately in order to document the reason and date of the unblinding.  The event will 
also be recorded on the CRF and in the source document.  The Investigator will submit a 
written explanation to the Sponsor describing the event within 5 business days. 


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12.4.6 
Discontinuation of Study due to an SAE 
The study will be discontinued for safety reasons if a serious adverse event occurs in one 
subject unless it is demonstrated that the serious adverse event is not related (as defined 
in section 12.4.1 of this protocol) to study drug, in which case the study will not be 
required to stop. 
The IRB will be notified within 24 hours of any event that results in discontinuation 
of the study. 
 
13. 
STATISTICAL METHODS AND DATA HANDLING 
The Statistics Group will perform statistical analyses of efficacy data.  All computations 
will be performed using SAS® version 9.1 or higher (SAS Institute, Cary, NC).  
Statistical significance will be declared if the p-value is 0.05.   
Descriptive statistics for numerical variables will include n (number of subjects 
involved), mean, standard deviation, median, minimum, and maximum values.  
Categorical variables will be described by number and percent.   
13.1 
Sample Size Determination 
This study is a proof-of-concept study to determine if CTY-5339-A one or two sprays 
have a relevant efficacy advantage over CTY-5339-CB.  Although a statistically 
significant difference is desirable, a clear-cut trend for increased duration of analgesia 
would be acceptable.  A sample of 76 subjects in the efficacy evaluation part was felt to 
be adequate for the purposes of this proof-of-concept study.   
13.2 
Analysis Populations 
There will be three analysis populations: 
Safety population: will include all randomized subjects who received the study 
medication.  This population will be used for all safety summaries. 
Intent-to-Treat (ITT) population: will include all randomized subjects who dosed with 
study medication and provided a Baseline assessment.  All secondary efficacy analyses 
and summaries will be performed using this population.     
Modified Intent-to-Treat (mITT) population: will include all randomized subjects who, as 
documented prior to the breaking of the study blind: (1) met all the inclusion and 
exclusion criteria and; (2) either completed the two 60 minute test sessions or returned to 
baseline values in all the evaluation tests.  The primary efficacy analyses will be 
performed using this population. 
13.3 
Demographic Data and Baseline Comparability 
Quantitative demographic data will be described by summary statistics (number of 
subjects, mean, standard deviation, median and range).  The number and percentage of 
subjects will be presented for categorical variables.  No formal statistical comparison 


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between the treatment groups will be performed.  Demographic data summary will 
include age, gender and race.  These data will be presented for the overall safety 
population only, unless the sample sizes for ITT and mITT subject populations are very 
different from that of safety population (differ by more than 3 subjects).  In this case, 
demographic data will be presented for that population.  Baseline efficacy assessments 
will also be presented by treatment group. 
13.4 
Data Adjustments and Derived Endpoints  
13.4.1 
Time Windows  
Because some subjects may complete their assessments at times differing from the 
scheduled times, each such score will be adjusted so as to reflect more accurately the 
score that would have been observed had it been recorded at the scheduled time.  With 
the exception of the 1-5 minute PPT evaluations, time windows will be created for each 
of the 5-minute scheduled PPT time points, the widths being 3 minutes.  The time 
window for the 1-5 minute PPT evaluations will be 30 seconds. 
 If an assessment is performed within a time point window, the corresponding 
value will be assigned to that time point (e.g., an assessment performed anywhere 
between 3 and 7 minutes from the previous evaluation, regardless of when it was 
scheduled, will be assigned to the scheduled 5 minute time point).   
If a particular time point has no value within its window, then the PPT or QST Heat value 
with be assigned using either Last Observation Carried Forward (LOCF) or Next 
Observation Carried Backward (NOCB). In particular, LOCF will be used for missing 
data prior to onset, and NOCB will be used for missing data after onset to conservatively 
estimate both onset and duration. 
13.5 
Statistical Methods for Efficacy Evaluations 
The primary efficacy analyses will be based on Modified Intent-to-Treat Population.  The 
key comparisons will include: 
1. CTY-5339-A, one spray versus CTY-5339-CB, one spray 
The co-primary efficacy variables are duration of effect as measured by PPT and QST 
Heat.  Duration of effect is defined as the time (in minutes) from onset to treatment 
failure (i.e., for PPT, an assessment of “Same/More” pain, and for QST, the average heat 
temperature is greater than the average heat temperature at Baseline (non-treated cheek), 
up to the 60-minute time point (at two consecutive time points). For those discontinuing 
from the study for any other reason, the time to treatment failure will be censored at the 
last assessment time.   
The secondary efficacy variables include:  
 Duration of effect (PPT and QST) for CTY-5339A two sprays versus CTY-5339-
CB, one spray plus CTY-5339-P one spray 


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Amended (#3) Protocol C-002  IND # 117147
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 Duration of effect (PPT and QST) for CTY-5339A two sprays versus CTY-5339-
A one spray 
 Onset of anesthesia in minutes for PPT and QST Heat 
 Percentage of responders at each time point for PPT and QST Heat for both onset 
and duration 
Continuous variables will be analyzed via an ANOVA model with treatment effects at 
each of assessed time points.  Pairwise comparisons for variables related to percentages 
will be analyzed via chi square tests.  The 95% confidence intervals of the treatment 
differences will be presented using normal approximation with continuity correction, if 
appropriate.  Pairwise comparisons for time-to-event related variables will be analyzed 
via a log rank model with treatment effects.  Median time to event will be estimated and 
the 95% confidence intervals for the median will be presented, if appropriate. 
13.6 
Multiple End Points and Multiple Comparisons  
Duration of Effect, as assessed by PPT and QST Heat are co-primary efficacy 
parameters.  In order to control the overall significance level for the two primary 
endpoints, the total alpha level of 0.1 is Bonferroni adjusted to 0.10/2 = 0.05 (since this is 
a proof of concept study, the total alpha level of 0.1 instead of 0.05 has been selected).  
The study will be considered successful if either of the two primary endpoints is 
statistically significant.  
13.7 
Safety Analysis 
The safety population will consist of all subjects who received the study medication and had 
follow up data. 
Adverse event (AE) analyses will include all AEs which initially occurred, or worsened 
following treatment (i.e., treatment emergent signs and symptoms, TESS).  AEs will be 
summarized by the MedDRA preferred term and by system organ class and classified 
according to their severity (mild, moderate, or severe) and relationship (“Suspect” or “Not 
Suspect”) to study medication.  For the summary by severity, subjects who have multiple 
occurrences of the same AE will be classified according to the worst reported severity of the 
AE.  Similarly, for the summary by relationship to the study medication, the AE will be 
classified according to the worst relationship.  
ECG data will be summarized and presented based on assessment category (“Normal”, 
“Abnormal, but not clinically significant” or “Abnormal, clinically significant”) by 
treatment group.  Changes in SBP, DBP, and methemoglobinemia rate from Baseline to 
60 minutes will be summarized by treatment group.  Pulse oximetry will be summarized 
at each time point by treatment group. 


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14. 
STUDY ADMINISTRATION 
14.1 
Investigator Study Binder 
The Sponsor will supply to the PI an Investigator Study Binder that must be maintained at 
the study site, unless an alternative filing system is deemed appropriate by the Cetylite 
representative.   
Included in this binder will be tabbed sections for maintaining the following:  study 
identification and study site staff signature list, monitoring visit record, protocol and 
amendments/administrative changes, curricula vitae, Institutional Review Board 
documentation, informed consent form, product receipt and accountability forms, 
correspondence, subject screening record, and master subject log.  This binder must be kept 
current and be available for review by representatives of the Sponsor and any official 
regulatory body. 
14.2 
Subject Identification 
For purposes of confidentiality and to maintain anonymity, subjects will be assigned 
identification numbers.  Subjects will be numbered sequentially as they enter the study.  
Once subjects meet the entry criteria, they will be assigned a randomization number 
corresponding to study medication.  Subjects should be identified to the Sponsor only by 
their assigned number, initials and date of birth.  The PI or his designee will maintain a 
complete list of all subjects enrolled in the study with their current mailing address on the 
master subject log.  This list is necessary should contact of subjects be required in the future. 
14.3 
Case Report Forms 
Case report forms (CRFs) provided by Cetylite will be used to document all subject data and 
will be typed or printed legibly in black or blue ink.  Prior to submission to Cetylite the PI 
will review all CRFs and sign where necessary.  It is important that the CRFs be completed 
in a timely manner for each subject evaluation in order that the progress and results of the 
study may be closely followed by the Sponsor.  Corrections to CRFs must not obscure the 
original entry; a single line through the original entry is sufficient.  All corrections must be 
initialed and dated by the responsible individual. 
CRFs are to be completed and held for retrieval by a representative of Cetylite, unless 
otherwise directed.  All study records must be retained in accordance with Section 14.10.  A 
study site may use forms of their own design, following approval of the form by Cetylite, as 
source documents only. 
14.4 
Monitoring of Study 
The study will be monitored by representatives of Cetylite.   On-site visits will be made 
before the study begins, at regular intervals during the conduct of the study, and at the 
completion of the study.  Communication by telephone, mail, and facsimile may also be 
used to supplement on-site visits. 
The representative of Cetylite will inspect all CRFs and corresponding portions of the 
subject's original office and/or hospital records.  These inspections are for the purpose of 


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verifying adherence to the protocol and determining the completeness and exactness of the 
data entered on the CRF and study medication log. 
As a part of monitoring and inspection of this study, the PI agrees that Cetylite, its 
employees or representatives, Institutional Review Board or Independent Ethics Committee, 
as well as representatives of the FDA will have the right to inspect and review pertinent 
medical records relating to this trial.  In addition, informed consent documents signed by 
study participants will indicate approval to release their medical records for review while 
maintaining their confidentiality.  
14.5 
Protocol Modifications 
As the study progresses, any necessary additions or changes to the protocol will be decided 
by mutual agreement of the PI and the Clinical/Medical Monitor.  An amendment to this 
effect will be submitted first to Cetylite for review and approval and then to the Institutional 
Review Board for review and approval prior to implementation.  If the protocol change 
impacts the conduct of the study, the informed consent form will be amended, as 
appropriate.  A protocol change to eliminate an apparent immediate hazard to subjects may 
be implemented immediately, provided the reviewing Institutional Review Board is notified 
in accordance with 21 CFR 56.104(c).  Otherwise, no deviations will be permitted.  
Approved amendments will become part of the protocol and will be reported to the 
appropriate regulatory authority prior to implementation.  
14.6 
Discontinuation of Study by Sponsor or PI 
Cetylite reserves the right to discontinue the study for administrative reasons at any time.  
All study medication and CRFs will then be returned to the Sponsor.  
If the PI discontinues the study prematurely, the PI will return all study medication and 
CRFs to the Sponsor and provide a written explanation as to why the study was ended. 
14.7 
Disclosure of Data/Publications 
All information obtained during the conduct of the study will be regarded as confidential.  
Agreement from Cetylite must be obtained prior to disclosing any information relative to the 
study. 
Upon completion of the study, Cetylite may decide to publish the results with the PI in a 
recognized scientific journal and/or present the results (as a poster or oral presentation) at a 
meeting of a recognized scientific association.  In order to safeguard against disclosure of 
confidential information, however, Cetylite requires that it has the right to review any 
manuscript and/or abstract prior to submission.  A draft manuscript must be reviewed by 
Cetylite 60 days prior to submission of the final version to the journal.  Abstracts of 
presentations must be reviewed by Cetylite 15 days prior to submission.  Cetylite assures the 
PI that all manuscripts and abstracts will be reviewed promptly.   
14.8 
Informed Consent 
Regulations require that written informed consent must be obtained for each subject prior 
to entry into the study.  Informed consent means the knowing consent of an individual, so 


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situated so as to exercise free power of choice without undue inducement or constraint or 
coercion.  The informed consent form will include all elements required by the FDA.  A 
copy of the consent form will be provided to the subject. 
The Investigator will provide Cetylite with a copy of the consent form as approved by the 
Institutional Review Board at University of Pennsylvania. 
The PI will ensure that this study is in full conformance with the principles of the 
Declaration of Helsinki (as amended in Tokyo, Venice, Hong Kong South Africa and 
Scotland) as well as GCP and ICH guidelines.  
14.9 
Institutional Review 
Prior to initiating the study, the protocol and amendments, informed consent form, any 
advertisement, PI’s and sub-investigators’ curriculum vitae, and investigational product 
brochure must be reviewed and approved by a properly constituted Institutional Review 
Board as required by the FDA and the International Conference on Harmonization 
Guidelines.   
The PI must certify to Cetylite that the Institutional Review Board meets all the legal 
requirements as specified by the FDA.  The Institutional Review Board must provide a 
signed and dated statement that the protocol, informed consent form, and other pertinent 
documents, such as recruitment advertisements (in any medium) have been approved by the 
Committee.  If the study continues longer than one year, re-approval must be obtained from 
the Institutional Review Board on an annual basis.  The Institutional Review Board must be 
informed of any changes in research activity including amendments to the protocol and/or 
informed consent form, advertisements, and serious adverse events. 
At the conclusion of the study, the PI must submit a summary of the study to the 
Institutional Review Board with a copy forwarded to Cetylite no later than 60 days after the 
study closeout visit. 
14.10 
Retention of Records 
International Conference on Harmonization (ICH) and FDA regulations require that all 
study records be kept in the files of the PI for two years following the date a marketing 
application is approved for the indication which was investigated, or if no application is 
filed or if the application is withdrawn, two years after the investigation is discontinued 
and the regulatory authority is notified.  Additionally, the master subject log must be 
maintained for a minimum period of 10 years from the dates defined above.  Cetylite will 
notify the PI of the above date.  No study documents may be destroyed or moved to a 
new location without prior written approval from Cetylite.  
If at any time the PI is no longer able to maintain the required study records, or if the PI 
relocates or delegates custody of the records to another, Cetylite must be notified in 
writing as soon as possible.  In any case, Cetylite retains the right to reclaim all study 
records.  If Cetylite reclaims the study records, the master subject log, which contains 
confidential information identifying and how to contact the study subjects, will be 
provided to Cetylite in a sealed envelope labeled “confidential”. 


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The PI assumes the responsibility of retaining the following records: 
a. Signed and dated protocol and amendments, written authorization to allow enrollment 
of potentially ineligible subjects or otherwise amend the protocol; 
b. Curriculum vitae of the Principal Investigator and sub-investigators; 
c. Investigational Product Brochure or full prescribing information, instructions to 
Principal Investigator, or other information provided by Cetylite for conducting the 
clinical study; 
d. Records of receipt and disposition of all product supplies, including: 
 Dates and amounts of product received from Cetylite 
 Lot numbers or other identification 
 Dates and quantity dispensed and returned for each subject 
 Dates and amounts of product returned to Cetylite 
e. Institutional Review Board approval, correspondence, interim reports, and final study 
summary; 
f. Documented informed consent for each subject 
g. Completed CRFs and diaries (if applicable) for each subject including all source 
documents from which the CRFs were prepared 
h. Subject screening record indicating disposition of each subject and reason for 
exclusion when appropriate 
i. Master subject log indicating all subjects enrolled in the study with their current 
mailing address 
j. Detailed medical histories for each subject containing medical history prior to 
enrollment with basic identifying information linking records to CRFs, results of all 
diagnoses made, therapy provided, any other data on subject's physical state 
k. Medical history during the study including documentation of enrollment, concomitant 
or concurrently administered therapy, observations on subject's condition during the 
study, any factors that might alter the effects of the test product, adverse event or 
laboratory abnormality reports and follow-up where appropriate 
l. Copies of tests and/or examinations results required by the protocol, including 
laboratory normal values and accreditation, if applicable 
m. Copies of interim and final reports issued to the Institutional Review Board or 
Cetylite 
n. Documentation of contacts between Cetylite and the PI and/or other study site 
personnel, including all correspondence 
o. Copies of any reports on serious adverse events, death, or life-threatening symptoms 


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p. Roster of all study personnel with their signatures and signed initials 
q. Monitoring visit record 
14.11 
Responsibilities of Principal Investigator 
In agreeing to conduct this study, the PI assumes certain responsibilities mandated by 
FDA regulations: an Investigator is responsible for ensuring that an investigation is 
conducted according to the signed investigator statement, the investigational plan as 
defined by the protocol, and applicable regulations; for protecting the rights, safety, and 
welfare of subjects under the Investigator's care; and for the control of the products under 
investigation.  An Investigator will, in accordance with the appropriate regulations, obtain 
the informed consent of each human subject to whom the product is administered.  The 
Investigator will retain all study documents as stipulated in Section 14.10.  The 
Investigator certifies that he/she has not been disbarred by any regulatory agency from 
conducting clinical trials. The Investigator will comply with the requirements outlined in 
the CFR final ruling, Financial Disclosure by Clinical Investigators, effective February 2, 
1999. 
14.12 
Filing of Protocol with FDA 
This protocol and data from this study may be subsequently filed with the U.S. FDA. 


Cetylite Industries, Inc.                  
CONFIDENTIAL 
Amended Protocol No. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 47 of 48 
Protocol v10.4 
15. 
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Cetylite Industries, Inc.                  
CONFIDENTIAL 
Amended Protocol No. C-002  IND # 117147
CTY-5339 Anesthetic Spray (CTY-5339-A)
 
November 10, 2016 
Page 48 of 48 
Protocol v10.4 
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