A Double-blind, Cross-over, Incomplete Factorial Study to Assess the Local Anesthetic Efficacy and Safety of CTY-5339 Anesthetic Spray (CTY-5339A) When Applied to the Gingival Mucosal Tissue in Normal Volunteers
Phase: PHASE2
Conditions: No Disease State or Condition
Sponsor: Cetylite Industries



Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
 
May 24, 2017 
Page 1 of 49 
Protocol v4.1 
 
 
 
Cetylite Industries, Inc. 
 1. 
STUDY PROTOCOL 
Title: 
A double-blind, cross-over, incomplete factorial study to assess 
the local anesthetic efficacy and safety of CTY-5339 Anesthetic 
Spray (CTY-5339A) when applied to the gingival mucosal tissue 
in normal volunteers 
Test Drugs: 
CTY-5339A (14.0% benzocaine, USP, 2.0% tetracaine HCL, USP)  
CTY-5339CB (14.0% benzocaine, USP) 
CTY-5339P (Vehicle Spray) (only used in Stage 1) 
(1 metered spray will deliver ≈200 µL containing either 
benzocaine 28 mg + tetracaine HCl 4 mg or benzocaine alone 28 
mg or vehicle.) 
Methods: 
Stage1:  Single-center, randomized, single-blind, parallel group. 
Stage 2: Single-center, randomized, double-blind, cross-over, 
incomplete factorial design.   
In both Stages, Pin Prick and QST Heat (QST) will be utilized to 
assess 
efficacy. 
Assessment 
of 
pulse 
oximetry 
and 
methemoglobinemia (blood co-oximetry only in Stage 2) will be 
utilized to assess safety.  In Stages 1 and 2, pulse oximetry will be 
performed at Baseline and every 10 minutes through 1 hour after 
treatment.  In Stage 2, blood sampling will be performed at 
Baseline and after 1 hour of treatment.   
Sponsor Name and 
Address: 
Cetylite Industries, Inc. 
9051 River Road 
Pennsauken, NJ 08110 
Protocol Identification: 
C-003 
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 
 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
 
May 24, 2017 
Page 2 of 49 
Protocol v4.1 
 
 
 
 
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 the International 
Conference on Harmonization and all applicable FDA regulations. 
 
 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
Date 
Version 
Comment(s) 
Author 
April 24, 2017  
1.0 
Draft 
S. Cooper 
May 3, 2017 
1.1 
Draft 
S. Cooper 
 May 11, 2017 
2.0 
Draft 
S. Cooper, G. Doyle 
 May 12, 2017 
3.0 
Draft 
S. Cooper & Team 
 May 15, 2017 
4.0 
Final 
S. Cooper & Team  
May 24, 2017 
4.1 
Deleted stopping rule for QST 
G. Doyle 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 4 of 49 
Protocol v4.1 
 2. 
TABLE OF CONTENTS 
1. STUDY PROTOCOL ................................................................................................. 1 
2. TABLE OF CONTENTS ........................................................................................... 4 
3. CLINICAL PROTOCOL SYNOPSIS ...................................................................... 7 
4. STUDY FLOW CHART .......................................................................................... 15 
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 ....................................................................................................... 24 
8.3 
Outcomes ....................................................................................................... 24 
8.3.1 Primary Outcome Measures ............................................................... 24 
8.3.2 Secondary Outcome Measures ........................................................... 24 
8.4 
Hypothesis for Stage 1 and 2 ......................................................................... 24 
9. SUMMARY OF STUDY DESIGN ......................................................................... 25 
9.1. 
Number of Subjects ........................................................................................ 28 
9.2. 
Inclusion Criteria ............................................................................................ 28 
9.3. 
Exclusion Criteria .......................................................................................... 29 
10. CLINICAL SUPPLIES ............................................................................................ 30 
10.1 
Study Medication and Dosage ....................................................................... 30 
10.2 
Packaging and Labeling ................................................................................. 30 
10.3 
Assignment of Study Medication ................................................................... 31 
10.4 
Administration of Study Medication and Duration of Evaluation ................. 31 
10.5 
Study Medication Accountability .................................................................. 31 
10.5.1 Storage ............................................................................................. 31 
10.5.2 Study Medication Inventory ............................................................. 31 
10.5.3 Return of Study Supplies ................................................................. 32 
11. STUDY PROCEDURES .......................................................................................... 32 
11.1 
Study Conditions ............................................................................................ 32 
11.2 
Schedule of Assessments ............................................................................... 32 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 5 of 49 
Protocol v4.1 
11.2.1 Screening Assessments .................................................................... 32 
11.2.2 Baseline Assessments ...................................................................... 33 
11.2.3 Post-Baseline Assessments .............................................................. 33 
11.3 
Efficacy Assessments ..................................................................................... 34 
11.3.1 Pin Prick Test (PPT) ........................................................................ 34 
11.3.2 Heat Pain Tolerance ......................................................................... 34 
11.4 
Safety Assessments ........................................................................................ 34 
11.5 
Blood Sampling and Pulse Oximetry ............................................................. 35 
11.6 
Concomitant Medication ................................................................................ 35 
11.7 
Study Participant Discontinuation ................................................................. 35 
12. SAFETY .................................................................................................................... 36 
12.1 
Subject Examinations ..................................................................................... 36 
12.2 
Subject Safety Information ............................................................................ 36 
12.3 
Availability of Investigator ............................................................................ 36 
12.4 
Adverse Events .............................................................................................. 36 
12.4.1 Definitions ........................................................................................ 36 
12.4.2 Reporting Adverse Events ............................................................... 38 
12.4.3 Other Reportable Events .................................................................. 39 
12.4.4 Adverse Event Recording and Reporting ......................................... 39 
12.4.5 Breaking the Blind ........................................................................... 39 
12.4.6 Discontinuation of Study due to an SAE ......................................... 40 
13. STATISTICAL METHODS AND DATA HANDLING ...................................... 40 
13.1 
Sample Size Determination ............................................................................ 40 
13.2 
Analysis Populations ...................................................................................... 40 
13.3 
Demographic Data and Baseline Comparability ............................................ 41 
13.4 
Data Adjustments and Derived Endpoints ..................................................... 41 
13.4.1 Time Windows ................................................................................. 41 
13.5 
Statistical Methods for Efficacy Evaluations in Stage 2 ................................ 41 
13.6 
Multiple End Points and Multiple Comparisons ............................................ 42 
13.7 
Safety Analysis .............................................................................................. 42 
14. STUDY ADMINISTRATION ................................................................................. 43 
14.1 
Investigator Study Binder .............................................................................. 43 
14.2 
Subject Identification ..................................................................................... 43 
14.3 
Case Report Forms ......................................................................................... 43 
14.4 
Monitoring of Study ....................................................................................... 44 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 6 of 49 
Protocol v4.1 
14.5 
Protocol Modifications ................................................................................... 44 
14.6 
Discontinuation of Study by Sponsor or PI ................................................... 44 
14.7 
Disclosure of Data/Publications ..................................................................... 44 
14.8 
Informed Consent ........................................................................................... 45 
14.9 
Institutional Review ....................................................................................... 45 
14.10 Retention of Records ...................................................................................... 45 
14.11 Responsibilities of Principal Investigator ...................................................... 47 
14.12 Filing of Protocol with FDA .......................................................................... 47 
15. TEXT REFERENCES ............................................................................................. 48 
 
 
List of Tables  
Table 1- List of formulation components; CTY-5339 and Vehicle Spray………….23 
Table 2- Study Medications………………………………………………….………...30 
 
 
 
 
 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 7 of 49 
Protocol v4.1 
3. 
CLINICAL PROTOCOL SYNOPSIS 
TITLE: 
A double-blind, cross-over, incomplete factorial study to assess the 
local anesthetic efficacy and safety of CTY-5339 Anesthetic Spray 
(CTY-5339A) when applied to the gingival mucosal tissue in normal 
volunteers 
STUDY 
NUMBER: 
C-003 
PRINCIPAL 
INVESTIGATOR: 
Dr. Elliot V. Hersh, Professor of Pharmacology and 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 (14.0% benzocaine, 2.0% 
tetracaine) compared to 14.0% benzocaine alone in normal volunteers 
using experimental sensation including pinprick with a needle (PPT) 
and heat pain threshold (QST).  The objective of this study is to 
demonstrate that the combination of the two constituents in the CTY-
5339 Anesthetic Spray (CTY-5339A) provides longer acting local 
anesthesia than 14.0% benzocaine alone (CTY-5339CB).  The primary 
objective is to demonstrate that the CTY-5339A one-spray dose is 
superior to CTY-5339CB one-spray dose.  The secondary objective is 
to demonstrate that the one spray application of CTY-5339A is a safe 
dosage. 
HYPOTHESIS: 
CTY-5339A when locally applied to gingival 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 the CTY-5339A one-spray dosage is safe.  
(The assumption being made is that benzocaine has a faster onset and 
shorter duration of action than tetracaine.) 
 
 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 8 of 49 
Protocol v4.1 
STUDY 
DESIGN: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will have two stages. 
STAGE 1 
Stage 1 is a randomized, single-blind, single-center, single-dose, 
parallel group study of up to 25 subjects that is designed to assess the 
appropriateness of the methodology.  In a random order, subjects will 
receive one spray of either CTY-5339A, CTY-5339CB or CTY-5339P 
in a 2:2:1 ratio.  These subjects will be evaluated at a single 60-minute 
test session.  A circular area of approximately one half inch in diameter 
will be isolated with cotton rolls on one side of the maxillary gingiva 
adjacent to the incisal frenum (randomly chosen) and marked using an 
indelible oral pencil.  
The Principal Investigator and Sponsor will make the decision on 
whether to proceed to Stage 2 based on the safety of the treatments and 
whether a reasonable efficacy signal was detectable using this 
methodology.  A reasonable efficacy signal is considered a mean time 
for duration of anesthesia for CTY-5339A that is at least 5 minutes 
longer than CTY-5339P and at least 5 minutes longer than CTY-
5339CB. 
STAGE 2 
This is a single-dose, cross-over, randomized, 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. 
This Stage of the study will include 50 subjects who will be evaluated 
for 60 minutes at each test session.  At each session, a circular area of 
approximately one half inch in diameter will be isolated with cotton 
rolls on one side of the maxillary gingiva adjacent to the incisal frenum 
and marked using an indelible oral pencil.  Each session will use a 
different side (right versus left) of the maxillary central incisor area.  
The possible sequences of treatments with the metered spray at the two 
sessions are: 
Session 1 
Session 2 
Formulation 
Sprays 
Formulations 
Sprays 
CTY-5339A 
1 
CTY-5339CB 
1 
CTY-5339CB 
1 
CTY-5339A 
1 
In all other respects, the protocol for Stage 1 and Stage 2 will be 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 9 of 49 
Protocol v4.1 
STUDY 
DESIGN: (cont) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
DESIGN: (cont) 
identical (except for the methemoglobinemia blood draws, which will 
be performed only during Stage 2).    
During both Stage 1 and Stage 2, efficacy evaluations will be done at 1-
5 minute intervals beginning immediately after drug administration and 
will include Pin Prick (PPT) & QST Heat Pain 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 60-minute time point. The right side of the maxilla will be 
defined as the gingival area adjacent to teeth numbers 7 and 8 and the 
left side of the maxilla will be defined as the gingival area adjacent to 
teeth numbers 9 and 10 (maxillary right and left central/lateral 
incisors). 
Pin Prick Test (PPT): The PPT will be assessed, using a 90-mm, 26-
gauge pencil-point spinal needle (Polymedic; Temena S.A., Bondy, 
France or equivalent).  At screening, 2 pin pricks will be performed on 
the gingival tissue.  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, subjects must score at least “3” for the 2 pin pricks and have 
one of those scores be “4” or higher.  The Baseline score will be the 
average of the two scores. 
For each treatment session, at Baseline and at each post-dosing time 
point, 2 pin pricks will be performed at the circumscribed site on the 
gingival mucosa.  At Baseline and at post-Baseline assessments, pin 
pricks will be assessed using the same NRS where 0= no pain and 10= 
severe pain.  The two scores will be averaged for each evaluation time 
point and the post-Baseline scores will be compared to the Baseline 
scores.  For each treatment session, in order for a subject to be eligible 
to continue in the study, both of the Baseline assessment pin pricks 
must have a minimum score of “3”, and one of those scores has to be 
“4” or higher.  Post-Baseline, averaged scores lower than the averaged 
Baseline scores by >1 unit will be recorded as presence of 
analgesia/anesthesia (“Responder”).  
If there is no indication of onset of anesthesia (i.e., the average post-
baseline PPT score is less than 1 unit lower than the average Baseline 
score) by 10 minutes, the subject will be considered a treatment failure 
and the assessment of PPT will be discontinued.  In addition, once 
onset of anesthesia has occurred, if there is no longer any anesthesia (as 
defined above) at two consecutive evaluation time points from 10 
minutes onward, the assessment of PPT will be discontinued.   
Heat Pain Threshold (QST-Heat): The heat stimuli are delivered in 2 
repetitions, with inter-stimulus intervals of 30s. The basal thermode 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 10 of 49 
Protocol v4.1 
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 
50.5ºC.  (Note: Hot beverages such as tea and coffee are frequently 
served at temperatures between 500C - 600C.  Burns can occur at 
650C.25).  Heat Pain threshold will be defined as the temperature at 
which the subjects first feel pain.  
At screening, QST-Heat Pain assessments will be performed on 
gingival mucosal tissue.  In order to be eligible for the study, subjects 
must have a mean Heat Pain threshold of 46.5oC or less, based on the 
average of the 2 readings. 
During each treatment session, the two repetitions will be averaged for 
data analysis.  At Baseline and at each post treatment assessment, the 
Heat Pain threshold will be performed at the site of the treated gingival 
mucosa.  During each treatment session, in order for a subject to remain 
eligible to continue in the study, subjects must have a mean Heat Pain 
threshold at Baseline of 46.5oC or less, based on the average of the 2 
readings at the circumscribed treatment site.  Post-Baseline, the 
presence of analgesia/anesthesia will be defined when the average Heat 
Pain threshold at the treated site is 3oC higher than the average at 
Baseline (“Responder”).  
All tests on the treated gingival tissue will be done near the center of 
the circumscribed area, but in a slightly different place at each 
consecutive evaluation time point.  
Randomization: For Stage 1, a randomization code will determine 
which treatment the subject will receive and to which circumscribed 
area the treatment is administered (left or right side of maxilla).  For 
Stage 2, a randomization code will determine the sequence of 
treatments and to which circumscribed area the treatment is 
administered (left or right side of maxilla).  For both Stages, sensory 
testing will be done in the following order: PPT followed, where 
applicable, immediately by Heat Pain tolerance.  
Subjects retain the right to withdraw from the study at any time. 
 
EFFICACY 
MEASUREMENTS 
 
The primary efficacy variables include:  
The primary comparison of interest is one spray of CTY-5339A 
compared to one spray of CTY-5339CB.  Co-primary efficacy 
variables are duration of effect as determined by PPT and duration of 
effect as measured by QST Heat Pain.  Duration of effect is defined as 
the time (in minutes) from onset to treatment failure (for PPT, 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 11 of 49 
Protocol v4.1 
treatment failure occurs when the average of the two PPTs is similar 
(within 1 unit) or greater than the average of the Baseline PPTs.  For 
QST, a treatment failure occurs when the average heat temperature is 
less than 3 degrees centigrade above the average heat temperature at 
Baseline at two consecutive time points prior to the 60-minute time 
point.  The time used for duration will be the immediate time point 
previous to the offset of analgesia/anesthesia.   
The secondary efficacy variables include:  
• Onset of anesthesia for PPT and QST Heat 
• Percentage of responders for PPT and QST Heat Pain for both onset 
and duration  
• Percentage of responders for PPT and QST Heat Pain at each time 
point 
• Percentage of subjects reaching minimal pain on PPT (≤2 on NRS 
Pain Scale) 
• Duration of minimal pain for PPT (≤2 on NRS Pain Scale) 
• Percentage of subjects reaching maximum heat for QST  
• Duration of maximum heat for QST  
(“Responder” is defined as a lower PPT average pain score (>1 
unit) or higher heat pain threshold average by 3oC compared to 
Baseline.  The final definitions for a Responder will be determined after 
Stage 1.) 
OTHER 
MEASUREMENTS 
 
 
 
 
At screening and throughout each test session, subjects will be 
monitored with vital signs and pulse oximetry.  In Stage 2, at Baseline 
and at the end of the 60-minute test session, a 7mL 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.  Methemoglobinemia is being defined as >5% of a subject’s 
hemoglobin in the methemoglobin state, or a pulse oximetry reading of 
less than 91%.  In the previous C-002 study with up to two sprays of 
CTY-5339A applied to the inner cheek, there was little if any change 
from pre-drug methemoglobin levels.  
ESTIMATED 
DURATION OF 
SUBJECT 
PARTICIPATION 
IN THE STUDY: 
For Stage 1, subjects will be tested once, and the session will take a 
total time of approximately two hours.  Subjects will receive a follow-
up phone call 15 (± 2 day) days after the subject completes the session.  
For Stage 2, the subjects will be tested on two separate occasions.  Each 
session will take approximately two hours time; however, the actual 
efficacy testing will take a maximum of 60 minutes.  There will be 4-14 
days spacing between the two test sessions.  A phone follow-up will 
occur 3 days (± 1 day) after the subject completes Session 1 and 15 
days (± 2 days) after the subject completes Session 2.  If there are any 
adverse side effects, at the discretion of the PI, the subject may be 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
Page 12 of 49 
Protocol v4.1 
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 (for Stage 2).  The expectation is that the study 
will be completed within 4-6 months of the first subject entry. 
NUMBER OF 
SUBJECTS: 
Up to 100 male and female subjects will be screened to enroll up to 25 
and 50 ASA Category I or II subjects in Stage 1 and Stage 2, 
respectively.  During Stage 2 of the study, the total number of 
exposures to study medication will be 100 (50 subjects x 2 exposures).  
Each of the treatment regimens will have 50 exposures. 
SAMPLE SIZE 
DETERMINATION: 
For Stage 2, the sample size was selected based on determining 
whether CTY-5339A has a longer duration of action than CTY-
5339CB, which contains 14.0% benzocaine only.  The sample size is 
based on 80% power and duration for CTY-5339A that is at least 5 
minutes greater than CTY-5339CB with a one-sided .05 alpha for PPT 
and QST as the two primary endpoints. 
DOSAGE: 
(specific gravity is 
slightly less than 1; 
therefore 200 uL is an 
approximate volume.) 
CTY-5339A 1-metered spay = 200 mg total (≈200 µL) 
Benzocaine 28 mg + Tetracaine HCl 4 mg 
CTY-5339CB = 200 mg (≈200 µL) 
Benzocaine 28 mg 
CTY-5339P = 200 mg (≈200 µL) (Vehicle Spray Stage 1 only) 
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 Stage 1 and Sessions 1 and 2, 
of Stage 2 subjects with PPT scores of at least “3” (on a 10 point 
NRS) on the 2 readings, 1 of which must be a score of at least “4”; 
e. Subjects with mean QST Heat Pain sensation temperature 
assessments on the gingival mucosa of 46.5oC or less based on the 
average of the 2 readings at screening and at the Baseline Study 
Sessions for Stages 1 and 2; 
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 a Study Session and alcohol for 1 day prior to 
and during a Study Session; 
g. Subjects must agree to refrain from using mouth rinses, cough 
drops, throat lozenges, or gum on the day of a Test Session; 

Cetylite Industries, Inc.                    
CONFIDENTIAL 
Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
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Protocol v4.1 
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 each Study Session, 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 (Stages 
1 & 2) and at Baseline (Stage 2) 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; 
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 each Study 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; 

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Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
May 24, 2017 
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Protocol v4.1 
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. 
SAFETY 
EVALUATION: 
 
All potential subjects will receive a urine drug screen and blood draw 
for lab tests at the screening visit.  In Stage 2, 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 15 days following 
completion of Stage 1 or within 3 days of the first study session (Stage 
2) and within 15 days following the end of the subject’s participation in 
Stage 2 of the study.  Treatment-emergent AEs will be summarized by 
incidence.  The events will be coded using the Medical 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 recorded.  
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-
5339A compared to the one spray CTY-5339CB  
• Duration of anesthesia as measured by QST Heat Pain for one spray 
CTY-5339A compared to the one spray CTY-5339CB 
Secondary Efficacy Endpoints: 

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• Onset of anesthesia for PPT and QST Heat Pain 
• Percentage of responders for PPT and QST Heat Pain for both onset 
and duration 
• Percentage of responders for PPT and QST Heat Pain at each time 
point 
• Percentage of subjects reaching minimal pain on PPT (≤2 on NRS 
Pain Scale) 
• Duration of minimal pain for PPT (≤2 on NRS Pain Scale) 
• Percentage of subjects reaching maximum heat for QST  
• Duration of maximum heat for QST  
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,  
• Methemoglobin levels at Baseline and at the end of each 60-minute 
test session (Stage 2), and 
• Analysis of incidence and severity of all adverse events  
For the PPT, a “Responder” is defined as a lower PPT average pain 
score (> 1 unit) than the Baseline PPT average score.  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 Stage 1, a QST “Responder” is defined as follows:  If the average 
heat temperature at each time point is 3 degrees 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.  (The final definition of PPT and QST Responders will be 
determined after the Stage 1 data are reviewed.) 
Data will be generated as the difference in response between the 
Baseline scores and the active treatment scores within each subject. 
ANOVA and pairwise t-tests will be used to compare CTY-5339A 
treatment groups to the CTY-5339CB treatment group. 
4. 
STUDY FLOW CHART 
Stage 1 

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Protocol v4.1 
 
TIME 
Informed 
Consent 
Medical 
 History 
Phys. Exam**,  
Vital Signs, 
Pulse Ox 
Lab 
Tests, 
Drug 
Screen 
 
Pregnancy 
Test 
Females 
Dosing 
 
Pin Prick= P 
Heat Sensation 
Threshold= H 
(PPT & QST) 
AE 
Assessment 
Screening 
 
√ 
√ 
√ 
√ 
 √ 
 
P  
H  
√ 
Test 
Session  
  
√ 
√ 
  
√ 
 
P  
H  
√ 
-5 min 
 
 
 
 
 
 
 
√ 
0 hr   
 
 
 
 
 
√ 
  
√ 
1, 2, 3, 4 min 
 
 
 
 
 
 
P 
√ 
5min and then 
q5mins through 
60 minutes 
 
 
 
 
 
 
P  
H 
√ 
10, 20, 30, 40, 
50 and 60 mins 
 
 
√*** 
 
 
 
 
√ 
60 minutes 
 
 
√ 
 
 
 
 
√ 
Discharge 
 
 
  
 
 
 
  
√ 
*Day 15 Phone 
Call 
 
 
 
 
 
 
 
√ 
*15-Day Follow-up Call ± 2 days 
**Physical exam only performed at screening 
*** Pulse Oximetry Only, if <91%, the subject will be discontinued from the study 
P=pinprick evaluation; H=heat pain tolerance evaluation 
 
 

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CTY-5339 Anesthetic Spray (CTY-5339A) 
 
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Protocol v4.1 
Stage 2 
 
TIME 
Informed 
Consent 
Medical 
 History 
Phys. Exam*,  
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  
H  
√ 
√ 
Test 
Session 1 
  
√ 
√ 
√** 
√ 
 
P  
H  
√ 
√ 
Test 
Session 2 
 
√ 
√ 
√** 
√ 
 
P  
H   
√ 
√ 
-5 min 
 
 
 
 
 
 
 
 
√ 
0 hr   
 
 
 
 
 
√ 
  
 
√ 
1, 2, 3, 4 min 
 
 
 
 
 
 
P 
 
√ 
5min and then 
q5mins through 
60 minutes 
 
 
 
 
 
 
P  
H 
 
√ 
10, 20, 30, 40, 
50 and 60 mins 
 
 
√**** 
 
 
 
 
 
√ 
60 minutes 
 
 
√ 
 
 
 
 
√ 
√ 
Discharge 
 
 
  
 
 
 
  
 
√ 
***3 & 15-Day 
Call Session 2 
 
 
 
 
 
 
 
 
√ 
* Physical Exam only performed at Screening 
 **Urine Drug Screen Only 
***After Session 2, 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 pain tolerance evaluation 
 
 

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Protocol C-003  IND # 117147 
CTY-5339 Anesthetic Spray (CTY-5339A) 
 
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Protocol v4.1 
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 gingival 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.  After study drug administration, subjects are instructed to rate 
the pinprick sensation perceived over the circumscribed treatment site on the 11-point 
NRS.  At Baseline of each test session and at each observation, 2 pin pricks are 
performed at the treatment site.  The scores for two pin pricks are then averaged 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 gingival 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 
pain sensation.  The subjects are instructed to turn off the heat probe by 
depressing the mouse when they first start to feel pain.  The heat is applied in 
graded increments until the subjects depress the mouse or the temperature reaches 
the maximum of 50.5oC.  At the maximum heat of 50.50 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 two 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 50.5ºC.  For 
each assessment, both stimuli are averaged, unless the first reading is 50.5ºC.  At 
Baseline, and at each post-treatment time point, QST Heat Pain will be assessed at 
the site of the treated gingival tissue and the two readings averaged for data 
analysis. 

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Protocol v4.1 
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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Protocol v4.1 
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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Protocol v4.1 
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-5339A).  
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 has filed 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-5339A 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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Protocol v4.1 
• 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. 
The experimental Cheek Mucosal study in healthy volunteers (C-002) was initiated in 
November 2016.  In this study, the CTY-5339A or comparator CTY-5339CB 
formulations were sprayed onto a circumscribed approximately one inch diameter area of 
the cheek.  The area was then tested with pin prick (PPT) and heat (QST) to assess onset 
and duration of effect.  The maximal (total) dose of CTY-5339A that a subject received 
during this study was 56 mg benzocaine and 8 mg tetracaine HCl.  The expectation was 
that there would be very low systemic exposure of either benzocaine or tetracaine.  The 
doses used in this study were within the prescribed doses listed on the current Cetacaine® 
Spray label and are known to be safe doses of these local anesthetics.1-24  An interim 
analysis was performed after 38 subjects were entered into the C-002 study and the 
decision was made to redesign the study using a more sensitive oral mucosal tissue.  In 
C-002, it was apparent that the cheek mucosal tissue was not sensitive to the two efficacy 
tests being administered.  There were no safety issues and only one report of an adverse 
event that was related to a blood draw and not related to any drug therapy.    
This redesigned study, C-003, will apply the study medication to the gingival mucosa 
instead of the cheek mucosa.  The expectation is that the gingival mucosa will be more 
sensitive to PPT pain and QST Heat Pain than the cheek mucosa.  The methods being 
employed will be essentially the same as for the C-002 study.  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 

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Protocol v4.1 
4 – 9 fold greater than the maximum tetracaine exposure on the current study.8,10  These 
three studies performed by the PI were approved by the University of Pennsylvania IRB. 
The present study will be conducted in two Stages.  In the first stage, up to 25 subjects 
will receive in random order, a single spray of CTY-5339A, CTY-5339CB, or CTY-
5339P (vehicle) in a 2:2:1 ratio.  This stage will be a single treatment, randomized, 
single-blind, parallel group study.  The results of Stage 1 will determine whether the 
methodology is sensitive enough to continue into Stage 2.  Stage 2 is designed as a 
randomized, double blind, two treatment study comparing as single spray of CTY-5339A 
to a single spray of CTY-5339B.  
Table 1.  Compositions of CTY-5339A, the Benzocaine-Only Comparator (CTY-
5339CB) and the Vehicle Control (CTY-5339P) 
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-5339A: Active formulation containing both 14.0% benzocaine, USP and 2.0% tetracaine 
hydrochloride, USP.  Note: the term CTY-5339A is used to designate the active formulation. 
b CTY-5339CB: comparator formulation containing benzocaine, USP   
cCTY-5339P: Vehicle formulation containing neither active ingredient 
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-5339A is sprayed onto intact gingival mucosal tissue.  If this proof-of-
concept study is successful, then future studies will evaluate CTY-5339A in intubation 
and gingival surgical settings. 

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Protocol v4.1 
8.2 
Objectives 
The objectives of this study are to evaluate the onset and duration of CTY-5339A 
compared to benzocaine only spray (CTY-5339CB) in a human experimental pain model.       
8.3 
Outcomes  
8.3.1 Primary Outcome Measures  
• Duration of anesthesia as measured by PPT  
• Duration of anesthesia as measured by QST Heat Pain    
8.3.2 Secondary Outcome Measures  
• Onset of anesthesia for PPT and QST Heat Pain 
• Percentage of responders for PPT and QST Heat Pain for both 
onset and duration  
• Percentage of responders for PPT and QST Heat Pain at each time 
point 
• Percentage of subjects reaching minimal pain on PPT (≤2 on NRS 
Pain Scale) 
• Duration of minimal pain for PPT (≤2 on NRS Pain Scale) 
• Percentage of subjects reaching maximum heat for QST  
• Duration of maximum heat for QST 
 (“Responder” is defined as a lower average PPT pain score (>1 unit) or higher 
average QST Heat Pain threshold by 3oC than Baseline.  Based on the results of 
Stage 1, these definitions may be modified for Stage 2.) 
8.4 
Hypothesis for Stage 1 and 2 
In Stage 1, the predicted outcome is that CTY-5339A, when locally applied to 
gingival mucosal tissue in the mouth, will have a duration of effect at least 5 minutes 
longer than CTY-5339P and CTY-5339CB.  There will not be any formal statistical 
tests performed on the Stage 1 data. 
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 Pain) for 
CTY-5339A is the same as the corresponding duration for the CTY-5339CB 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: 

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• The null hypothesis that the onset of anesthesia (PPT and QST Heat Pain) for 
CTY-5339A is equal to the corresponding onset for CTY-5339CB 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 Pain) for CTY-5339A is equal to the corresponding onset time until a 
first responder event for CTY-5339CB 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 CTY-5339A is equal to the corresponding duration time until 
the first non-responder event for CTY-5339CB will be tested against the 
alternative hypothesis that the event times are not equal. 
• The null hypothesis is that the percentage of responders for PPT and QST at each 
time point for CTY-5339A is equal to the corresponding percentage of responders 
for CTY-5339CB will be tested against the alternative hypothesis that the 
percentage of responders are not equal. 
• The null hypothesis is that the duration of minimal pain for PPT or maximum heat 
for QST for CTY-5339A is equal to the corresponding duration of minimal pain 
for PPT or maximum heat for QST for CTY-5339CB will be tested against the 
alternative hypothesis that the duration of minimal pain for PPT or maximum heat 
for QST are not equal.  
• The null hypothesis is that the percentage of responders reaching minimal pain for 
PPT or maximum heat pain for QST for CTY-5339A is equal to the 
corresponding percentage of responders reaching minimal pain for PPT or 
maximum heat pain for QST for CTY-5339CB will be tested against the 
alternative hypothesis that the percentage of responders reaching minimal pain for 
PPT or maximum heat pain for QST are not equal. 
In Stage 2, the predicted outcome is that CTY-5339A, when locally applied to 
gingival 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 the CTY-5339A one-spray dosage is safe.  (The assumption is made 
that benzocaine has a faster onset and shorter duration of action than tetracaine HCl.)  
 
 
9. 
SUMMARY OF STUDY DESIGN 
This study will have two stages. 

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STAGE 1 
Stage 1 is a randomized, single-blind, single-center, single-dose, parallel group study of 
up to 25 subjects that is designed to assess the appropriateness of the methodology.  In a 
random order, subjects will receive one spray of either CTY-5339A, CTY-5339CB or 
CTY-5339P in a 2:2:1 ratio.  These subjects will be evaluated at a single 60-minute test 
session.  A circular area of approximately one half inch in diameter will be isolated with 
cotton rolls on one side of the maxillary gingiva adjacent to the incisal frenum (randomly 
chosen) and marked using an indelible oral pencil.  
The Principal Investigator and Sponsor will make the decision on whether to proceed to 
Stage 2 based on the safety of the treatments and whether a reasonable efficacy signal 
was detectable using this methodology.  A reasonable efficacy signal is considered a 
median time for duration of anesthesia for CTY-5339A that is at least 5 minutes longer 
than CTY-5339P and at least 5 minutes longer than CTY-5339CB. 
STAGE 2 
This is a randomized single-dose, 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. 
This Stage of the study will include 50 subjects who will be evaluated for 60 minutes at 
each test session.  At each test session, a circular area of approximately one half inch in 
diameter will be isolated with cotton rolls on one side of the maxillary gingiva adjacent to 
the incisal frenum and marked using an indelible oral pencil.  Each test session will use a 
different side (right versus left) of the maxillary central incisor area.  The possible 
sequences of treatments with the metered spray at the two sessions are: 
 
Session 1 
Session 2 
Formulation 
Sprays 
Formulations 
Sprays 
CTY-5339A 
1 
CTY-5339CB 
1 
CTY-5339CB 
1 
CTY-5339A 
1 
In all other respects, the protocol for Stage 1 and Stage 2 will be identical identical (with 
the exception of the blood draws for methemoglobinemia, which will be assessed only in 
Stage 2).  During both Stage 1 and Stage 2, efficacy evaluations will be done at 1-5 
minute intervals beginning immediately after drug administration and will include Pin 
Prick (PPT) & QST Heat Pain Tests. 

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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 60-minute time point.    
The right side of the maxilla will be defined as the gingival area adjacent to teeth 
numbers 7 and 8 and the left side of the maxilla will be defined as the gingival area 
adjacent to teeth numbers 9 and 10 (maxillary right and left central/lateral incisors). 
Pin Prick Test (PPT): The PPT will be assessed, using a 90-mm, 26-gauge pencil-point 
spinal needle (Polymedic; Temena S.A., Bondy, France or equivalent).  At screening, 2 
pin pricks will be performed on the gingival tissue.  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, subjects must score at least “3” for the 2 pin pricks and have one of those 
scores be “4” or higher.  The two scores will be averaged. 
For each treatment session, at Baseline and at each post-dosing time point, 2 pin pricks 
will be performed at the circumscribed site on the gingival mucosa.  All pin pricks will be 
assessed using the same NRS where 0= no pain and 10= severe pain.  The two scores will 
be averaged for each evaluation time point and the post-Baseline scores will be compared 
to the Baseline scores.  For each treatment session, in order for a subject to be eligible to 
continue in the study, both of the Baseline assessment pin pricks must have a minimum 
score of “3”, and one of those scores has to be “4” or higher.  Post-Baseline, averaged 
scores lower than the averaged Baseline scores by >1 unit will be recorded as presence of 
analgesia/anesthesia (“Responder”).  If there is no indication of onset of anesthesia (i.e., 
when the average post-baseline PPT score is less than 1 unit lower than the average 
Baseline score) by 10 minutes, the subject will be considered a treatment failure and the 
assessment of PPT 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 (as defined above), the assessment of PPT will be discontinued. 
Heat Pain Threshold (QST-Heat Pain): The heat stimuli are delivered in 2 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 
50.5ºC.  (Note: Hot beverages such as tea and coffee are frequently served at 
temperatures between 500C - 600C.  Burns can occur at 650C.25).  Heat Pain threshold will 
be defined as the temperature at which the subjects first feel pain.  
At screening, QST-Heat Pain assessments will be performed on gingival mucosal tissue.  
In order to be eligible for the study, subjects must have a mean Heat Pain sensation 
threshold of 46.5oC or less, based on the average of the 2 readings.  
During each treatment session, the two repetitions will be averaged for data analysis.  At 
Baseline and at each post treatment assessment, the Heat Pain threshold will be 
performed at the site of the treated gingival mucosa.  During each treatment session, in 
order for a subject to remain eligible to continue in the study, subjects must have a mean 
Heat Pain threshold of 46.5oC or less, based on the average of the 2 readings at the 

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circumscribed treatment site.  Post-Baseline, the presence of analgesia/anesthesia will be 
defined when the Heat Pain threshold at the treated site is 3oC higher than the Baseline 
(“Responder”).  
All tests on the treated gingival tissue will be done near the center of the circumscribed 
area, but in a slightly different place at each consecutive evaluation time point.  
Randomization: For Stage 1, a randomization code will determine which treatment the 
subject will receive and to which circumscribed area the treatment is administered (left or 
right side of maxilla).  For Stage 2, a randomization code will determine the sequence of 
treatments and to which circumscribed area the treatment is administered (left or right 
side of maxilla).  For both Stages, sensory testing will be done in the following order: 
PPT followed, where applicable, immediately by Heat Pain tolerance.  
A safety phone follow-up call will occur 15 days (±2 days) after Stage 1, and in Stage 2, 
3 days (±1 day) after Session 1 and 15 days (±2 days) following Session 2.  Subjects 
retain the right to withdraw from the study at any time.  
9.1. 
Number of Subjects 
Up to 100 male and female subjects will be screened to enroll up to 25 and 50 ASA 
Category I or II subjects in Stage 1 and Stage 2, respectively.  During Stage 2 of the 
study, the total number of exposures to study medication will be 100 (50 subjects x 2 
exposures).  Each of the treatment regimens will have 50 exposures. 
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 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 Stage 1 and Sessions 1 and 2 of Stage 2, subjects 
with PPT scores of at least “3” (on a 10 point NRS) on the two readings, one of which 
must be a score of at least “4”;  
e. Subjects with mean QST Heat Pain sensation temperature assessments on the gingival 
mucosa of 46.5oC or less based on the average of the 2 readings at screening and at 
the Baseline Study Sessions for Stages 1 and 2; 
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 a Study Session 
and alcohol for 1 day prior to and during a Study Session;  
g. Subjects must agree to refrain from using mouth rinses, cough drops, throat lozenges 
or gum on the day of a Test Session; 

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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 
each Study Session, 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 (Stages 1 & 2) and at 
Baseline (Stage 2) 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. 
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);  
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 each Study 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; 

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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-5339A Anesthetic Spray 
1 spray (≈200 µL total) 
14.0% Benzocaine, USP = 28 mg 
2.0% Tetracaine Hydrochloride, USP = 4 mg 
CTY-5339CB 
1 spray (≈200 µL total) 
14.0% Benzocaine, USP = 28 mg 
CTY-5339P 
1 spray (≈200 µL total) 
Vehicle control (no active ingredient) 
(Stage 1 only) 
10.2 
Packaging and Labeling   
In Stage 1, the study medication will be bulk bottles for CTY-5339A, CTY-5339CB and 
CTY-5339P (two bottles of each).  In the single-blind Stage 1, the contents of the bottle 
will be identified on the label, such that the PI or study coordinator who is administering 
the drug will be aware of which treatment is being applied, but the subject will remain 
blinded.  Each bottle will be primed 3 times before each use. 
In Stage 2, study medication for subjects randomized to receive CTY-5339A in one 
treatment session and CTY-5339CB in the other treatment session will be double-blinded 
and packaged individually for each subject. Study medication for each subject will 
consist of one box, which will contain one bottle of CTY-5339A and one bottle of CTY-
5339CB.  Each bottle will be labeled with the appropriate treatment session (A or B) and 
which side of the gingiva the study medication should be applied to (left or right), 
according the randomization schedule.  Each bottle will be primed three times 
immediately prior to use. 
A randomized listing for Stage 2 generated by Statistics Group 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 for Stage 2 will have individually sealed envelopes identifying the drug 
in each bottle for each subject enrolled in the study.  The treatment for an individual 
subject may be unblinded in the event of an emergency and only if medically necessary 

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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. 
For Stage 1, the randomization schedule will randomly assign one of the three treatments 
(CTY-5339A one spray, CTY-5339CB one spray or CTY-5339P one spray) to the 
appropriate area(s) of the gingival mucosa.  For Stage 1, randomization numbers will be 
assigned in a sequential order starting from 001. 
For Stage 2, the randomization schedule will randomly assign one of the two treatments 
(CTY-5339A one spray or CTY-5339CB one spray) to the appropriate area(s) of the 
gingival mucosa.  For Stage 2, randomization numbers will be assigned in a sequential 
order starting from 101. 
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 gingival 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 

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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.   
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-003 
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 during Stage 1 and for up 
to 2 hours at each test session during Stage 2.  The actual test sessions will be 60 
minutes. 
c. 
For Stage 2, subjects will be tested in the same room and by the same coordinator 
team at each evaluation time point during both 60 minute 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. 

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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 Pain assessments of the gingival mucosa 
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 
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 treatment(s) were initiated and completed 
• Any vital signs obtained (require blood pressure)  
11.2.2 
Baseline Assessments 
After confirming continued eligibility, Baseline vital signs, and a blood sample (only for 
Stage 2) will be obtained.  In addition, tissue site evaluations will be performed.  The area 
of the to-be-treated gingiva is isolated with cotton rolls and circumscribed using an oral 
indelible pencil.  Prior to drug administration, the pain score on the NRS after the PPT 
(using a 90-mm, 26-gauge pencil-point spinal needle) will be evaluated.  Heat Pain 
threshold (using QST) also will be assessed in the circumscribed area of the to-be-treated 
side of the gingival mucosa.  These baseline data will be recorded on the CRF.  The drug 
will then be administered onto the assigned circumscribed area of the gingival mucosa.  
In order for a subject to be eligible to continue in the study, the 2 Baseline PPT scores 
must be at least “3” or higher, and 1 must be “4” or higher.  The mean of the 2 Baseline 
QST Heat Pain assessments must be 46.5oC or less. 
11.2.3 
Post-Baseline Assessments 
The time points of the post-baseline efficacy assessments are detailed in section 9 of this 
protocol.   The PPT and the QST will be performed only at the treatment site for the post- 
baseline evaluation time points. 

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11.3 
Efficacy Assessments 
  11.3.1 
Pin Prick Test (PPT) 
Gingival mucosal sensation directly over the drug site 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 gingival 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 site as 0-10 on the Numerical Rating Scale with 
“0” as no pain and “10” as severe pain.  At each observation, 2 pin pricks are performed 
at the treatment site and the average pain rating is used for the data analysis.  Reports of 
less pain by >1 unit than Baseline at the treatment site indicate analgesia; while a report 
of similar (within 1 unit) or more pain than Baseline indicates complete regression or 
absence of analgesia. 
11.3.2 Heat Pain Tolerance 
This procedure uses the QST Heat Stimulator, a commercially available thermo-sensory 
analyzer that delivers heat stimuli to the gingival 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 pain or the temperature reaches the maximum of 50.5ºC (Note: Hot 
beverages such as tea and coffee are frequently served at temperatures between 500C - 
600C.25)  
The heat stimuli are delivered, in 2 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 50.5ºC.  The 2 stimuli are then averaged.  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. 

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11.5 
Blood Sampling and Pulse Oximetry 
A blood sample (7 mL) will be taken at screening for purposes of assessing normal 
values for the subjects.  In Stage 2, 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.  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, 
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, gum 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 2 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 46.5oC based on the average of the 2 assessments at 
Baseline prior to the start of a test session. 
f. 
Any subject who has a methemoglobinemia (5%) or a pulse oximetry reading 
below 91% during any test session. 
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. 

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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. 
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: 

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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. 
 
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; 

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§ 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: 
• 
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 

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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: 
• 
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 
For Stage 2, 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.  

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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. 
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 
For Stage 2, 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-5339A one has a relevant 
efficacy advantage over CTY-5339CB.  The Stage 1 results will determine if the study 
progresses to Stage 2.  The Principal Investigator and Sponsor will make the decision on 
whether to proceed to Stage 2 based on the safety of the treatments and whether a 
reasonable efficacy signal was detectable using this methodology.  A reasonable efficacy 
signal is considered a mean time for duration of anesthesia for CTY-5339A that is at least 
5 minutes longer than CTY-5339P and at least 5 minutes longer than CTY-5339CB. 
Although a statistically significant difference is desirable in Stage 2, a clear-cut trend for 
increased duration of analgesia would be acceptable.  A sample of 50 subjects in the 
double-blinded efficacy evaluation part was calculated to provide greater than 80% 
power assuming a 5 minute duration advantage exists for CTY-5339A over CTY-
5339CB. 
13.2 
Analysis Populations 
For Stage 2, there will be three analysis populations: 
Safety population: will include all randomized subjects in Stage 2 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 in Stage 2 and provided a Baseline assessment.  All secondary efficacy 
analyses and summaries will be performed using this population.     

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Modified Intent-to-Treat (mITT) population: will include all randomized subjects in 
Stage 2 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 
between the treatment groups will be performed.  Demographic data summary for Stages 
1 and 2 will include age, gender and race.  For Stage 2, 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 in Stage 2 
The primary efficacy analyses will be based on Modified Intent-to-Treat Population.  The 
key comparison will be: 
CTY-5339A, one spray versus CTY-5339CB, one spray 
The co-primary efficacy variables are duration of effect as measured by PPT and QST 
Heat Pain.  Duration of effect is defined as the time (in minutes) from onset to treatment 

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failure (i.e., for PPT, two consecutive assessments of “Similar/More” pain than Baseline, 
and for QST Heat Pain, the average heat temperature is greater than the average heat 
temperature by 3ºC at Baseline at two consecutive assessments, up to the 60-minute time 
point.  (For PPT and QST Heat Pain, these definitions may be revised, based on the 
outcome of Stage 1.)  For those subjects 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:  
• 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 Pain at each time point 
• Percentage of subjects reaching minimal pain on PPT (≤2 on NRS Pain Scale) 
• Duration of minimal pain for PPT (≤2 on NRS Pain Scale) 
• Percentage of subjects reaching maximum heat for QST  
• Duration of maximum heat for QST  
(“Responder” is defined as a lower PPT pain score by >1 unit or higher heat pain 
threshold than Baseline by 3oC.  For PPT and QST Heat Pain, the “Responder” 
definitions may be revised based on the outcome of Stage 1.) 
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 Pain 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 in 
Stages 1 and 2. 
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 

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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.  
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. 
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 
Source Documents provided by Cetylite will be used to document all subject data and will 
be typed or printed legibly in black or blue ink.  Data will e collected from the study site as 
eCRFs.  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. 

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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 
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. 

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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 
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 

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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”. 
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 

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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 
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. 

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15. 
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13. Hersh EV, Ciancio SG, Kuperstein AS, Stoopler ET, Moore PA, Boynes SG, Levine SC, 
Casamassimo P, Leyva R, Mathew T, Shibly O, Creighton P, Jeffers GE, Corby PM, 
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17. Noorily, AD, Noorily, SH, Otto, RA. Cocaine, lidocaine, tetracaine: which is best for 
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18. Noorily, AD, Otto, RA, Noorily, SH. Intranasal anesthetic effects of lidocaine and 
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19. Rømsing, J, Henneberg, SW, Walther-Larsen, S, Kjeldsen, C. Tetracaine gel vs EMLA 
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21. Rosivack, RG, Koenigsberg, SR, Maxwell, KC. An analysis of the effectiveness of two 
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